netherlands journal of critical care

Copyright ©2008, Nederlandse Vereniging voor Intensive Care. All Rights Reserved. Received October 2007; accepted April 2008

r e v i e w

Metabolic alkalosis in the Intensive Care Unit

N Shah1, C Shaw1, LG Forni2

1 Department of Renal Medicine, Worthing Hospital, Worthing, West Sussex, United Kingdom 2 Department of Critical Care, Worthing Hospital and Brighton & Sussex Medical School, University of Sussex, Brighton, United Kingdom

Abstract. Metabolic alkalosis is a relatively common finding in the critically ill and has a varied aetiology. We outline the funda- mental principles that govern both the generation and maintenance of a metabolic alkalosis. Causes are discussed with particular attention to those which predominate in the critically ill. Signs and symptoms of metabolic alkalosis are described together with both general and specific treatments for this relatively common disturbance in acid-base homeostasis.

Introduction #L (#/ 4UBULAR,UMEN As an acid-base disturbance, metabolic alkalosis fails to attract the  attention that its acidotic counterpart receives but, despite this, it is still a relatively common metabolic derangement encountered in the

critically ill [1,2]. Manifest as an alkalaemia with a pH>7.45 it can #L (#/ be defined simply as an acid-base disturbance initiated by a primary - #! #/ increase in plasma bicarbonate concentration ([HCO3 ]) either as  #OLLECTING4UBULE a consequence of H+ losses or through an increase or retention in

- ( / /( ( HCO3 [3,4]. Clinically, metabolic alkalosis is often induced through  the loss of gastric secretions or secondary to diuretic therapy. In

the intensive care unit the consequences of a metabolic alkalosis ( may be evident through a decrease in cardiac output, depression of central ventilation and its effects on the oxyhaemoglobin saturation 0ERITUBULAR#APILLARY curve. From a practical point of view, the presence of a metabolic alkalosis may cause disturbances in the balance of other important Figure 1. Tubular secretion of bicarbonate Schematic representation of the mechanisms involved in secretion of protons and ions including worsening of hypokalaemia and hypophosphataemia bicarbonate/K+ reabsorption by the cortical collecting tubule. Dissociation of water and may also affect the ability to wean patients from mechanical generates OH- which generates bicarbonate via the enzyme carbonic anhydrase ventilation [5-7]. Furthermore, the mortality associated with severe (CA) catalysed reaction with CO2. The bicarbonate anion is then resorbed into the systemic circulation through Cl-HCO3 exchangers into the tubular lumen the energy metabolic alkalosis is considerable with mortality rates of 45% being for which is again generated through the favourable concentration gradient for Cl-. observed in patients with an arterial blood pH of 7.55 and rising to The H+ formed from dissociation are actively secreted by sodium ATPases in the 80% when the pH was greater than 7.65 [8,9]. luminal membrane principally combining with ammonia to form the ammonium ion.

Pathophysiology that, all additional water is lost. This is sometimes referred to as the Metabolic alkalosis occurs through the development of an alkaemia ‘waterfall effect’. Renal secretion of bicarbonate by the kidney is through an increase in the concentration of plasma bicarbonate schematically outlined in Figure 1. together with a decrease in the overall bicarbonate excretion in order Development of a metabolic alkalosis in a non-ventilated individual to sustain this metabolic abnormality. In order to understand both the results in a compensatory alveolar hypoventilation leading to a rise genesis and maintenance of a metabolic alkalosis the fundamental in the arterial carbon dioxide tension (PaCO2) which attenuates any principles involved are outlined in brief below. rise in pH. This compensatory response is rapid and arterial PaCO2 increases by 0.5 to 0.7 mm Hg for every 1 mmol/l increase in plasma i) The normal response bicarbonate concentration. The expected PaCO2 due to appropriate The normal renal response to a plasma bicarbonate over 24mmols/l hypoventilation in a simple metabolic alkalosis can be estimated is prompt and effective bicarbonate excretion in the urine. This ability from the following formula: of the kidney to rapidly excrete supranormal levels of bicarbonate - contrasts to the response to a low plasma bicarbonate where almost Expected PaCO2 = 0.7 [HCO3 ] + 20 mm Hg +/- 5 (i) all the filtered load is reabsorbed. A useful analogy is that of filling a bucket with water. No water is lost until the bucket is full, but after This response is somewhat variable in the clinical setting due to factors affecting minute ventilation such as pain, pulmonary

Correspondence congestion, hypoxaemia and in the intensive care unit, mechanical ventilation. LG Forni E-mail: [email protected]

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Gastrointestinal Lumen

- + - + ( (+ 4UBULAR,UMEN Cl H HCO3 Na

- + - - + + ( (+ Cl H + HCO 3 HCO3 + H Na Pancreatic Gastric ( / Parietal Cell  #OLLECTING4UBULE Cell H O H O 2 2 #! + + /( #/ (#/ #L CO   2 CO2

(#/ #L - - + + Cl HCO H Na 0ERITUBULAR#APILLARY 3 Systemic Circulation Figure 3. Tubular secretion of hydrogen ion. Figure 2. Acid-base homeostasis in the gastrointestinal tract . Schematic representation of the mechanisms involved in secretion of protons and bicar- Schematic representation of the mechanisms involved in formation of gastric bonate/K+ reabsorption by the cortical collecting tubule. Dissociation of water generates OH- which generates bicarbonate via the enzyme carbonic anhydrase (CA) catalysed reaction acid from water and CO2 by the gastric parietal cell. The formed bicarbonate ion - with CO2. The bicarbonate anion is then resorbed into the systemic circulation through Cl- is then secreted into the systemic circulation through Cl-HCO3 exchangers the Cl then binding with H+. Passage of acidic gastric fluid enters the small intestine HCO3 exchangers into the tubular lumen the energy for which is again generated through - + the favourable concentration gradient for Cl-. The H+ formed from dissociation are actively stimulating pancreatic secretion of HCO3 into the gut and H into the systemic circulation. Reduced acid load into the gut thereby reduces pancreatic secretion of secreted by sodium ATPases in the luminal membrane principally combining with ammonia + - to form the ammonium ion. H into the circulation which results in no buffering of the HCO3 formed from HCl formation and hence leading to metabolic alkalosis. iii) Hydrogen ion shift into cells ii) Development of alkalosis In the presence of hypokalaemia, potassium ions move from the The pathogenesis of metabolic alkalosis depends on the source of the intracellular to the extracellular space. To maintain neutrality, excess alkali, which is the primary event responsible for generation of H+ shift from the extracellular to intracellular space, leading to a the hyperbicarbonataemia. This may result through several potential decrease in plasma H+ concentration and hence alkaemia. mechanisms including hydrogen ion losses, shift of hydrogen ions or volume depletion: iv) Bicarbonate/alkali administration Administration of alkali over and above that of the kidneys’ ability to i) Gastrointestinal hydrogen ion loss excrete this excess alkali load may result in a metabolic alkalosis. The Excessive loss of gastric contents leads to a loss of hydrogen ions renal capacity for excretion of bicarbonate is reduced in renal failure (H+) as well as potassium and chloride ions. This, together with or when enhanced tubular absorption occurs, such as in volume volume losses, leads to the development of a hypochloraemic hyper­ depleted states. bicarbonataemia metabolic alkalosis. The formation of gastric acid together with its effective ‘neutralization’ are shown in Figure 2 where v) Volume depletion where the extracellular bicarbonate concentration is it is seen that bicarbonate generated during the production of gastric constant (so-called ‘contraction alkalosis’). acid returns to the circulation. Under normal conditions the excretion This phenomenon is observed when there is loss of relatively large of acidic gastric contents into the duodenum stimulates pancreatic volumes of chloride-rich and bicarbonate-poor extracellular fluid secretion of both bicarbonate ions into the gut (to neutralise the HCl) such as with diuretic therapy or profuse gastro-intestinal losses. and hydrogen ions (to buffer the generated bicarbonate ion) into the Under such conditions there is ‘contraction’ of the extracellular circulation. It follows that excessive vomiting or gastrointestinal volume but the total extracellular bicarbonate is relatively unchanged losses by other routes such as large nasogastric aspirates, reduces and thus the observed plasma bicarbonate concentration rises. the acid load entering the gut. This, in turn, results in systemic However, this observed increase rarely exceeds 2-4 mmol/l as it is accumulation of bicarbonate ion and hence a metabolic alkalosis. minimized by intracellular buffering [10,11].

ii) Renal hydrogen ion loss iii) Maintenance of alkalosis Ionic equilibrium is maintained by the kidney through balance of the As outlined, renal excretion of bicarbonate is an efficient process negatively charged bicarbonate and chloride ions with the positively therefore, for metabolic alkalosis to ensue there must be either: charged sodium and potassium ions. Na+ reabsorption by the renal • a concomitant decrease in renal bicarbonate excretion tubule is linked to Cl- reabsorption, H+ secretion and K+ exchange • enhanced renal reabsorption of bicarbonate (Figures 1 and 3). Furthermore, renal loss of H+ occurs in the distal • or a combination of both processes. tubule when distal delivery of sodium increases in the presence of In the intensive care unit this often reflects renal injury, however, in excess aldosterone which in turn stimulates reabsorption of sodium the patient with normal renal function the hyperbicarbonataemia ions. This results in enhanced excretion of H+ and K+. A fall in the is sustained by one, or more often, several other factors. The filtered chloride load leads to reduced sodium resorption which, predominant factors responsible for this include: in turn, is accompanied by H+ or K+ secretion and generation of a • hypokalaemia, metabolic alkalosis. • chloride depletion • effective circulating volume depletion.

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Table 1. Main causes of metabolic alkalosis Causes of metabolic alkalosis H+ loss through GI Tract Vomiting i) General causes: NG suction As pointed out metabolic alkalosis is a relatively common clinical High output fistula problem with the commonest causes being diuretic treatment or the Renal H+ loss Mineralocorticoid loss (Primary) loss of gastric secretions. Table 1 shows the commonly encountered Diuretic usage (Thiazide or Loop) Post hypercapnic alkalosis causes of metabolic alkalosis. Also listed are the rarer, principally Hypercalcaemia inherited conditions which will not be explored further here and are Milk-Alkali Syndrome discussed in detail elsewhere[16]. Apparent H+ loss through intracel- Hypokalaemia With regard to ICU practice, perhaps the most common causes lular shift are the loss of gastric secretions coupled with hypokalaemia. These Alkali administration Citrate factors are intimately linked because the major causes of metabolic Cocaine abuse alkalosis (vomiting, diuretics, mineralocorticoid excess), directly ‘Contraction’ alkalosis Over-diuresis Villous adenoma cause both potassium ion and hydrogen ion loss. Although renal Factitious diarrhoea acid loss is a well recognized cause of metabolic alkalosis, in the Rare genetic causes Bartter’s Syndrome intensive care unit it is uncommon apart from that following chronic Gitelman’s Syndrome respiratory acidosis. Other Substance abuse Any condition that leads to primary mineralocorticoid hyper­ Antibiotics secretion can lead to a metabolic alkalosis although this is often in the presence of hypertension. In contrast, untreated secondary hyperaldosteronism such as that found with congestive heart failure i) Hypokalaemia or cirrhosis do not present with metabolic alkalosis or hypokalaemia. Hypokalaemia directly increases bicarbonate reabsorption. A fall in Under these conditions the decreased distal renal tubular sodium the plasma [K+] results in a shift of K+ out of the cells to partially delivery negates the stimulatory effect of aldosterone. In thiazide or replenish the extracellular stores with electroneutrality being loop diuretic therapy adequate distal renal tubular sodium delivery maintained by the entry of extracellular hydrogen ions into the persists together with an increased of aldosterone secretion. This cells. The resulting intracellular acidosis stimulates bicarbonate leads to an increase in urinary hydrogen secretion coupled with reabsorption [12]. Furthermore, hypokalaemia also directly decreases further volume contraction thereby leading to a metabolic alkalosis glomerular filtration rate, which in turn decreases the filtered load of [17]. bicarbonate and in the presence of volume depletion, this impairs Generation of a metabolic alkalosis through alkali ingestion in renal excretion of the excess bicarbonate further. the presence of normal renal function is rare due to the efficiency with which bicarbonate is excreted. However, acute administration ii) Chloride depletion in large quantities to correct a metabolic acidosis such as lactic Hypochloraemia can contribute to the overall reduction in bicarbonate acidosis or diabetic ketoacidosis may lead to a metabolic alkalosis. excretion by increasing both distal tubular reabsorption of bicarbonate Under such conditions correction of the underlying condition as well as reducing distal tubular secretion of bicarbonate. Bicarbonate driving the acidosis will result in eventual metabolism of the organic is directly secreted through H-ATPase pumps in the collecting acids to bicarbonate. Therefore the administered alkali is effectively tubule. Dissociation of water within the cell leads to H+ resorption ‘excess’ and an alkalosis may ensue. However, the beneficial effects into the peritubular capillary with the concomitantly generated OH- of correction of an underlying metabolic acidosis should not be combining with CO2 via carbonic anhydrase to form bicarbonate underestimated [18]. Other rarer causes include drug abuse and which is then secreted into the tubular lumen through the action of metabolic alkalosis with hypomagnesaemia has also been reported - - Cl -HCO3 exchangers. This process is driven by the energetically with aminoglycoside therapy [19]. favourable [Cl-] gradient. Under conditions of alkalosis this process - is increased in an attempt to excrete the HCO3 , however, where low ii) Causes of metabolic alkalosis found in the ICU population tubular chloride concentrations exist the favourable conditions for There are several causes of metabolic alkalosis that are almost entirely - HCO3 secretion is diminished and the observed alkalosis persists. encountered in the intensive care setting. These include respiratory Similarly, resorption of bicarbonate relies on passive co-secretion of acidosis, complications of renal replacement therapy and therapeutic chloride ions to maintain electroneutrality. However, a fall in tubular plasma exchange as well as that associated with hypoalbuminaemia. chloride concentration promotes chloride secretion which in turn will result in enhanced bicarbonate resorption again maintaining a) Chronic respiratory acidosis electroneutrality [13]. Chronic respiratory acidosis may be seen in the intensive care setting either as an acute exacerbation of an underlying respiratory condition iii) Volume depletion or following a prolonged period of hypercapnic ventilation. Under Volume depletion leads to a reduction in renal sodium bicarbonate conditions of chronic respiratory acidosis there is a loss of protons excretion through a fall in glomerular filtration rate as well as sodium from the kidney and this excretion of hydrogen ion is an entirely retention [14]. This process occurs predominantly in the collecting appropriate physiological response. This will lead to, as highlighted tubules driven, in part, by secondary hyperaldosteronism [15]. above, a rise in the plasma bicarbonate concentration and hence restoration of the normal pH. Consequently any rapid correction of a chronically elevated PaCO2 through over- zealous mechanical ventilation will lead to a metabolic alkalosis due to the subsequent

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increase in plasma bicarbonate concentration. However, such an seen in the intensive care population [30]. The exact mechanism approach is not to be recommended as a dramatic fall in PaCO2 also of this observed alkalosis is still far from clear although it appears carries a significant risk of neurological abnormalities and death. to be a temporary acid-base disturbance principally involving the Moreover, the observed hyperbicarbonateaemia is often associated early recovery period [31]. Various causes have been considered with a degree of hypochloridaemia and hence the metabolic including gain of base from blood products, improvement in renal alkalosis may persist until this is addressed, usually through saline function and hence increased removal of filtered acids, and excessive administration. Consequently, posthypercapnic alkalosis may persist gastrointestinal losses but it is likely a multifactorial process [32]. until sodium chloride is given to correct the chloride deficit and allow the excess bicarbonate to be excreted [20,21]. d) Hypoalbuminaemia Hypoalbuminaemia is almost a ubiquitous finding in the critically b) Complications of renal replacement therapy ill. Unlike other serum globulins which do not carry a significant Renal replacement therapy for the patient with multi-organ failure net electric charge at pH values prevailing in plasma, albumin has a has various guises but the commonest remains continuous veno- variable net negative charge at physiological pH. As a consequence venous haemofiltration techniques [22,23]. As this utilizes an much work has focused on its role in acid-base balance particularly extracorporeal circuit then anticoagulation is often, but not always, in the critically ill [33]. Hypoproteinaemia itself is a well recognized required. Heparin and its derivatives, remains the most frequently cause of metabolic alkalosis. This is principally due to loss of the used anticoagulant but is associated with several disadvantages, not normal buffering plasma proteins which can act as weak acids under least those associated with bleeding [24]. An alternative approach is physiological conditions. It follows that any loss of such non-volatile the use of regional anticoagulation with trisodium citrate particularly weak acids will result in alkaemia. This has been demonstrated in- in individuals at increased risk of bleeding or those with suspected vitro where the acid-base effects of altering the concentration of heparin-induced thrombocytopenia [25]. This technique has recently plasma proteins have been quantified under controlled conditions gained much popularity despite the fact that it was first described in [34]. haemodialysis over 20 years ago and was being used in continuous techniques over 15 years ago [26]. The anticoagulant effect of citrate The anion gap is mediated through chelation of ionized calcium which is directly This phenomenon has particular relevance to calculations of the involved in platelet activation and interaction of platelets with clotting anion gap, one of the earliest tools for addressing the potential factors and other calcium-dependant enzyme systems. Regional aetiology of metabolic acidosis, which even in its simplest form anticoagulation also has the theoretical benefit of exclusively helps to characterize many cases of metabolic acidosis. The normal anticoagulating the extracorporeal circuit thereby avoiding systemic value is approximately 15 mmol/l calculated from: complications [27]. However the use of citrate is not without + + - - adverse effects principally those of hypernatraemia, hypocalcaemia ([Na ] + [K ]) - ([C1 ] + [HCO3 ]) = AG (2) and metabolic alkalosis. The generation of the observed metabolic alkalosis is through the metabolism of citrate itself. This occurs When some additional “unidentified anions” are present (in principally in the mitochondria via the tricarboxylic acid pathway addition to the normal unidentified anions that correspond to the to generate bicarbonate and eventually CO2. Stochiometrically this net negative charges on the proteins), the gap is increased [35]. leads to three bicarbonate molecules generated for each one of citrate Therefore the value of the ‘normal’ anion gap should depend on compounding the effect on acid-base balance. Indeed, a recent the concentration of plasma proteins and indeed, low values of study on citrate anticoagulation reported an incidence of metabolic the anion gap with hypoproteinaemia and high values attributable alkalosis, defined as a pH > 7.45 of 15% with the increase in arterial to hyperproteinaemia have been observed in patients. This effect pH being associated with an increase in the base excess of >3 is significant given that for every 10 g/l fall in the plasma albumin mmol/l. In this study an increase in the dialysate flow was required concentration, the reference range for the anion gap falls by 2.5 within the following 24 h through incremental increases of 500 mmol/l. It follows that if hypoproteinaemia is present and the usual ml/h. This increased the net removal of buffer base with acid-base normal numerical value of the anion gap is found, one has to suspect values returning to normal in most cases within 24 hours [28]. The that some unidentified anions (lactate, ketoacids) are present, which potential pitfalls associated with citrate usage has lead to the sensible will be missed if information on plasma protein concentration is not suggestion from proponents of this technique to insist on the use of sought for evaluation of the acid-base status. This has lead to the local protocols [29]. various refinements of the equation over the years with possibly the Similar complications associated with citrate administration simplest shown below [36]: are seen in massive blood transfusion where the banked blood is + + - - anticoagulated with acid citrate dextran and in therapeutic plasma ([Na ] + [K ]) - ([C1 ] + [HCO3 ] + [0.25 x (40-albumin]) = AGc exchange where the administration of fresh frozen plasma as a (3) replacement fluid is used in large quantities. Clinical presentation of metabolic alkalosis c) Liver transplantation i) Signs and symptoms Orthotopic liver transplantation is often associated with a metabolic These are non-specific and in the ventilated sedated patient will be alkalosis in the early postoperative period with up to 50% of missed. Mild to moderate metabolic alkalosis may be asymptomatic patients exhibiting such an acid-base disturbance. Interestingly, unless hypokalaemia is significant, in which case neuromuscular the development of a metabolic alkalosis in this patient group does signs and symptoms predominate including weakness and not appear to be associated with an adverse outcome, unlike that myalgia. Hypokalaemia also increases myocardial irritability and

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may precipitate cardiac arrhythmia and potentiate digitalis toxicity i) Correction of volume depletion for example. Associated decreased ionised calcium concentration Where the presumed aetiology is volume depletion through whatever contributes to peri-oral parasthaesia, tingling, numbness and mechanism, the alkalosis can be corrected through administration muscle spasms and in extreme metabolic alkalosis signs of tetany of saline replacement. This will result in both increased bicarbonate manifest. The compensatory hypoventilation which develops due secretion and decreased reabsorption of bicarbonate by the kidney. to the depression of the medullary respiratory centre may lead to Restoration of the circulating volume removes the drive to retain hypercapnia and hypoxaemia, and in severe cases this is followed by sodium which in turn, reduces the amount of bicarbonate reabsorbed. headache, lethargy, stupor, delirium and seizures. Furthermore, the resulting increase in chloride delivery to the distal tubule will promote chloride passage intracellularly, hence leading to ii) History increased bicarbonate secretion in the cortical collecting tubule and a The history is very important as it may point to the underlying aetiology significant rise in urinary bicarbonate excretion. of the metabolic alkalosis. For example, a history of excess ingestion of alkali, calcium supplements or potassium containing resins may ii) Correction of chloride depletion be found. A history of renal failure, gastro-intestinal losses through The importance of chloride replacement has been demonstrated in whatever cause (diarrhoea, vomiting, gastric suction and bulimia) studies of both acute and chronic chloride depletion [15]. Chloride- or diuretic use (loop or thiazide) can point the clinician toward an depletion alkalosis has been completely corrected by administration underlying mechanism for the maintenance of metabolic alkalosis. of several non-sodium chloride salts even in circumstances that An important factor to consider is also signs and symptoms suggestive would maintain or generate an alkalosis. However, alkalosis was of glucocorticoid excess (Cushing’s syndrome) or mineralocorticoid not corrected without chloride replacement [39]. Chloride depletion excess which may be present and can be easily missed. In practice, appears to decrease GFR through tubuloglomerular feedback which on the intensive care most cases are due to disturbances in volume may be a protective mechanism to prevent excessive fluid and sodium status or through compensation of a respiratory acidosis and rarely losses [40]. Normal functioning of the proximal tubule is essential to through exogenous agents. permit appropriate bicarbonate reabsorption but during metabolic alkalosis the collecting duct appears to play a major role in electrolyte Diagnosis and proton transport. During the maintenance of metabolic Diagnosis of a metabolic alkalosis in the intensive care unit is rarely alkalosis, bicarbonate secretion does not occur because insufficient a problem given the regularity of blood tests, particularly arterial chloride is available for bicarbonate exchange but following chloride blood gas analyses, that our patients are exposed to. As indicated, administration luminal or cellular chloride concentration increases metabolic alkalosis may be suspected based on symptoms, but often and bicarbonate is promptly excreted and alkalosis is corrected. may not be noticeable. A pH on arterial blood gas greater than 7.45 Where volume depletion is present, isotonic saline should be given confirms the diagnosis. Levels of other electrolytes like potassium, which corrects both volume status and chloride deficiency. In severe sodium, and chloride are also often outside the normal range for the volume contraction the administration of a minimum of 3-5L of reasons described. The level of bicarbonate in the blood will be high, 150 mmol/l NaCl is usually necessary to correct volume deficits and usually greater than 29 mmol/l and in the presence of normal renal metabolic alkalosis. If the volume status is normal then the total body function, urinary pH may rise to about 7.0 chloride deficit can be estimated from equation (4) with the caveat In patients with normal renal function, the analysis of renal that ongoing losses of fluid and electrolytes must also be accounted electrolytes particularly chloride may be of diagnostic help. As with for [3]: all measurements of urinary electrolytes they should be interpreted with caution. The presence of renal dysfunction may render the 0.2 x body weight (kg) x desired increase in plasma chloride (mmol/l) urinary chloride levels misleading and indeed, the presence of (4) profound hypokalaemia (which may well be present) will prevent maximal tubular chloride conservation from being achieved even As the chloride deficit is corrected, a brisk alkaline diuresis will occur in the presence of a low serum chloride. However, in individuals with a decrease in plasma bicarbonate toward normal. with normal renal function measuring the urinary chloride can aid the clinician in distinguishing between chloride responsive (urine iii) Correction of potassium depletion chloride <10 mEq/L) and chloride resistant (urine chloride >20 The correction of potassium depletion is also of vital importance mEq/L) metabolic alkalosis. in the treatment of metabolic alkalosis. Correction of potassium results in a movement of potassium ion into the cells together with Treatment a movement of hydrogen ions into the extracellular compartment There are several potential benefits to be achieved by correcting a through a transcellular cation exchange mechanism. This increase metabolic alkalosis and in severe cases this is a medical emergency. in extracellular proton concentration both buffers the excess Of particular relevance to those practicing in intensive care is that extracellular bicarbonate and the resultant rise in intracellular pH correction of a metabolic alkalosis increases both minute ventilation in renal tubular cells reduces hydrogen secretion and consequently and PaO2, potentially allowing patients to be weaned more rapidly bicarbonate reabsorption [12]. Because nephropathy due to potassium from mechanical ventilation [37,38]. The fundamental principles in depletion may impair free water excretion, plasma sodium should be treating metabolic alkalosis are: monitored closely during treatment, particularly if hypotonic fluids • Correct volume depletion are administered. • Correct chloride depletion • Correct potassium depletion

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Other treatment strategies for correction manifest as an overcorrection of the metabolic alkalosis potentially of metabolic alkalosis resulting in a hyperchloraemic, hypokalaemic metabolic acidosis In certain cases alternative approaches to treatment may be needed [45]. Acetazolamide enhances potassium secretion and therefore which including the use of hydrochloric acid, acetazolamide and patients should be relatively normokalaemic before commencement renal replacement. of therapy. Also, carbonic anhydrase inhibition in patients with i) Hydrochloric acid chronic respiratory acidosis may cause a small, transient, rise in the In the clinical setting of volume overload such as in congestive PCO2 . This effect is due to inhibition of carbonic anhydrase in red heart failure, the administration of large volumes of saline is clearly cells impairing CO2 transport by the red cell and the subsequent inadvisable. Although the use of KCl may be used this may also be elimination of CO2 by the lungs. Although this is a theoretical limited where an increased plasma potassium is present. Under problem, it is of little clinical significance. Although several dosing such conditions and where the alkalosis is severe (e.g. arterial pH is schedules have been used with acetazolamide one randomized greater than 7.55) hydrochloric acid can be used usually as an isotonic double-blind trial on a medical ICU compared the use of a single solution (150 mmol/l) over 8 to 24 h. The amount of HCl needed to dose of acetazolamide to multiple dosing [46]. This study concluded correct alkalosis is calculated by the formula and again continuing that a single dose of 500 mg of acetazolamide effectively reverses losses must also be replaced [3]: metabolic alkalosis for a prolonged period in mechanically ventilated asthma/COPD patients. However, in patients with severe metabolic 0.5 x body weight (kg) x desired reduction in plasma bicarbonate alkalosis due to high output losses this may not be sufficient. (mmol/l) (5) iii) Renal replacement The treatment aim is to rescue the patient from severe alkalosis Where severe, life-threatening metabolic alkalosis coexists thus it is recommended that initially the plasma bicarbonate with acute renal failure this presents additional problems. The concentration is restored to approximately halfway to normal. dialysates and replacement fluids used for both haemodialysis and Needless to say hydrochloric acid solutions must be given through a haemofiltration contain high concentrations of bicarbonate or catheter placed in a large central vein after radiographic confirmation its metabolic precursors and therefore must be modified in these that the catheter is correctly sited. Clearly frequent measurement of circumstances. An alternative approach is to correct the alkalosis arterial blood gases and electrolytes should ensue. An alternative with acid, as noted above, in tandem with renal replacement therapy. agent is ammonium chloride but this is contraindicated in renal or This requires careful consideration of fluid and electrolyte balance. hepatic insufficiency due to a potential worsening of uraemia and In milder cases,, renal replacement with CVVHD for example can acute ammonia intoxication. Minimizing continuing acid loss in this be performed as the replacement fluid will have a lower bicarbonate setting with either a H2-blocker or proton pump inhibitor may also concentration than the blood bicarbonate. In this case the filter will be beneficial [41]. act as a ‘metabolic clamp’ with eventual equilibrium being reached between plasma and replacement fluid bicarbonate concentrations. ii) Acetazolamide therapy Continual renal replacement also has the advantage that the volume The potential toxicity of ammonium chloride and hydrochloric balance desired can be easily achieved and electrolyte disturbances acid tend to limit their usage and most intensivists tend to use are readily corrected. acetazolamide as the first line of therapy to correct a metabolic alkalosis after volume and electrolyte replacement. Acetazolamide Conclusions is a carbonic anhydrase inhibitor which preferentially inhibits There are many causes of metabolic alkalosis which may present in proximal sodium bicarbonate reabsorption by up to 80%, thereby the critically ill. In most cases the cause will be apparent and may well correcting both metabolic alkalosis and where present, volume be iatrogenic. Careful attention to electrolyte and volume balance overload [42]. In several studies acetazolamide has been shown should correct the problem. In more severe cases further aggressive - to significantly decrease serum HCO3 and restore pH to normal treatment may be needed including acetazolamide therapy, within 24 hrs [43,44], however the use of acetazolamide is not hydrochloric acid infusion or renal replacement therapy. without its pitfalls particularly when multiple doses are used. This is

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