Problem-Based Review: a Patient with Metabolic Acidosis

Acute Medicine 2012 11(4): 251-256 251

Trainee Section

Problem-Based Review: A patient 251 with metabolic acidosis saf

R Allan & C Foster

Abstract Metabolic acidosis is a common metabolic derangement present in the acute medical patient. A thorough and structured investigative approach is required as there are many causes and management is reliant on identifying these. In particular calculation of the anion gap with correction for albumin level and use of the delta ratio can be helpful in complex cases especially in patients where a combination of metabolic derangements may be present. Keywords metabolic acidosis, anion gap, delta ratio, renal tubular acidosis, bicarbonate

Key points • Calculation of the anion gap is crucial in identifying the cause of metabolic acidosis. • Metabolic acidosis is often multi-factorial and the delta ratio calculation can be useful in identifying situations where a normal gap acidosis coexists with a raised anion gap cause. • Identification of the specific cause(s) of metabolic acidosis is vital as this will usually guide treatment. • Bicarbonate treatment has a role in some cases but adverse effects should be considered.

Case Vignette Although the anion gap calculation will narrow A 37 year old male with no past medical history presents our differential (Table 2), many possible explanations to the acute medical unit (AMU) with a history of general for the acidosis remain, especially when the gap is deterioration in health over the last 8 months. He has lost 10 high. The mnemonic MUDPILERS (Methanol, kg of weight and has severe fatigue. More recently he describes a Uraemia, Diabetic Ketoacidosis or other causes Table 1. arterial blood gas of patient in case vignette Table 2. Causes of Metabolic Acidosis according to Anion Gap1,2,3,4,5 pH 7.2 Raised anion gap Normal anion gap pCO 2.6kPa 2 - Renal failure HCO3 loss HCO3 8mmol/l Ketoacidosis GI – diarrhoea, ileus, pO 15kPa (on room air) 2 (DKA,sarvation,alcohol) pancreato- or uretero fistula feeling of breathlessness. A blood gas is performed (see Table 1). Paraldyhyde, Toluene, Type 2 – Renal Tubular Iron,Tricyclics, Isoniazid Acidosis (RTA) What are the potential causes of this acidosis and how can these be further classified? Ethylene Glycol, Ethanol, Acetazolamide Methanol The low bicarbonate and low carbon dioxide is consistent with a metabolic acidosis with an attempt Lactate (type A or B), D Addition of chloride at respiratory compensation. The differential for lactate (short bowel) (e.g. 0.9% saline use) Russell Allan ST5 Acute Medicine, a diagnosis that explains this finding remains large Rhabdomyolysis Failure to secrete H+ Western Infirmary, but can be narrowed significantly by calculating the Type 1 RTA Glasgow anion gap using the following equation: Email: russellallan@doctors. Type 4 RTA org.uk + + - - Type 3 RTA Anion gap (AG) = (Na + K ) – (HCO3 + Cl ) Hypoaldosteronism Christopher Foster [Normal range – 10-20 (on old colorimetry (1o/2o), Consultant Acute Medicine, Royal Alexandra Hospital, measurements); 3-11 (on modern ion-selection electrode Tubulo-interstital renal Paisley. measurements)] disease Email: cjfoster@doctors. org.uk © 2012 Rila Publications Ltd. 252 Acute Medicine 2012; 11(4): 251-256

Problem-Based Review: A patient with metabolic acidosis

of ketoacidosis, Paraldyhyde, Iron/Isoniazid, expressed by the delta gap and delta ratio, calculated Lactate, Ethylene glycol/Ethanol, Rhabdomyolysis, using the following formulae: Salicylate) may be helpful.

What else can influence the anion gap? Delta gap (ΔAG) = (Calculated AG – 12) –

The anion gap can also be expressed as: (24 – measured HCO3) Delta ratio = (Calculated AG – 12) / (24 –

Unmeasured anions – Unmeasured cations measured HCO3)

This demonstrates how an anion gap can be high The delta ratio should be approximately balanced if or low in the absence of an acidosis. The major a pure raised anion gap (AG) acidosis exists (ratio of anion that can act in this way is albumin. A low or between 1-2) high anion gap will result, depending on whether A delta gap > 6 (or ratio > 2) suggests a concurrent the albumin level is lower or higher than normal, metabolic alkalosis (or chronic respiratory acidosis), respectively. When calculating an anion gap we A delta gap < -6 (or ratio <1) suggests there is also can adjust for an abnormal albumin by using the a concurrent normal AG metabolic acidosis4,5 following equation:6 His corrected anion gap is calculated at 20 and the cause Corrected anion gap = 0.25 x (40 – albumin (g/l)) of this elevation is found to be due to ketones identified in + anion gap (AG) his urine. His blood glucose is elevated at 28mmol/l and as a result, a diagnosis of type 1 diabetes is made with a Any other ion not represented in the AG equation first presentation of DKA. His delta ratio is calculated at can influence the gap but this is usually to a lesser 0.5 suggesting the co-existing presence of a normal anion degree than that seen with albumin. As well as gap acidosis. The treating physicians are aware that there the anion, phosphate, and cations, magnesium is a potential connection between diabetes and renal tubular and calcium, we must consider the presence of acidosis and plan to explore this possibility. other charged particles not present in normal What is meant by the term renal tubular acidosis circumstances. Paraproteins seen in myeloma and (RTA)? other gammopathies can be positively or negatively RTAs by definition are a group of disorders with charged and lithium has a positive charge resulting dysfunction of renal tubule acidification mechanisms in a low AG when taken in excess. Rarely the AG but well preserved glomerular filtration rate. Table 3 can even become negative, a phenomenon that is describes the RTA types and the differential causes most likely to be seen with lab errors – for example, for a normal anion gap acidosis,highlighting any chloride level can be over-estimated in the presence differences which will aid diagnosis. of bromide containing drugs, hyperlipidaemia or In type 2 RTA, it is the proximal tubule HCO – salicylate poisoning. 3 reabsorption that malfunctions. Clearly this results in - How will we know if there is more than one disorder a high loss of HCO3 in the urine. However, distal present? tubular reabsorption does still occur, resulting in a – When a raised AG cause is found we should continue serum acidosis with a [HCO3 ] that rarely falls below – to explore for other metabolic derangements. This 12. When the serum [HCO3 ] falls it means less is will involve testing for other anions that may have filtered and, as a result, less is present in the tubular accompanied an acid (e.g. lactate, ketones etc.) and lumen. For this reason, the high urinary pH and high – also calculating the delta ratio. [HCO3 ] in the urine may not be obvious until the – serum [HCO3 ] is normalised. In fact, the urine pH What is the Delta ratio and how can it be calculated? can be <5.3 when an equilibrium has been established. It should be appreciated that where the AG is The proximal tubular reabsorption defect may not – increased, the degree of change from a normal gap be unique to HCO3 and often is accompanied by reflects the quantity of non-chloride anion added. that of glucose, phosphate, urate, potassium and This anion will have an accompanying H+, each of others. The obvious treatment for this should be to which will be buffered by a bicarbonate ion. It follows replace the deficit using high doses of bicarbonate. that the change in the anion gap (ΔAG) from that The correction of the acidosis can be problematic as - individual’s normal and the change in the HCO3 it will cause the already hypokalaemic state to worsen - concentration (ΔHCO3 ) from that individual’s further. Potassium must therefore always be replaced normal should be approximately the same. Where along with alkalinization therapy. In adults, the most the ΔAG is significantly less than the measured common cause of type 2 RTA is myeloma and this - 6 ΔHCO3 , a coexistent normal AG acidosis should should therefore always be considered . be considered. Where the ΔAG is significantly more In type 1 RTA, the deficient mechanism is at - + than the measured ΔHCO3 , the coexisting presence the terminal tubule involving the excretion of H . – of a metabolic alkalosis may be present. This can be In comparison to type 2 RTA, the serum [HCO3 ]

Problem-Based Review: A patient with metabolic acidosis

Table 3.1,7Classification and causes of Renal Tubular Acidosis

Type 1 RTA Type 2 RTA GI HCO3 loss Tubulo- RTA T4 interstital disease Mechanism Defect exists at Defect exists Gastrointestinal In renal Aldosterone the distal tubule in the proximal loss of failure, failure resistance/ preventing H+ tubule preventing bicarbonate ions to filter deficiency - secretion. reabsorption of HCO3 sulphuric acid (+/-glucose, amino is the main acids,phosphate,K+etc) mechanism for acidosis (high AG). When glomerulus intact but tubules affected only H+ secretion fails (i.e. normal AG) Causes Autoimmune Usually Myeloma in Gastroenteritis, Multiple Hypoadrenalism disease (esp. adults IBD, causes (1oor2oto Sjögrens (Fanconi syndrome in Ureteric or hyporeninaemia), syndrome), children) pancreatic fistula, CKD (esp. Renal transplant, Endocrinecasues Diabetic obstructive nephropathy), uropathy, Sickle Congenital cell disease, resistance cirrhosis Serum [K+] Low and Low and worsens as Low Often low High improves as acidosis is corrected acidosis does (can be high)

Serum Very low ~12-20 Mild decrease Mild decrease [HCO3] (Often <10) only (usually > 17) Urinary pH Always > 5.5. Often < 5.5. Increases to < 5.3 Variable < 5.5 Can’t acidify >7.5 when bicarbonate urine infused

Associations Nephrocalcinosis, Rickets/ osteomalacia Features of calcium stones cause Renal Usually normal Usually normal Can be Often Normal unless function deranged if also deranged cause is hypovolaemic CKD causing aldosterone resistance

can fall significantly and be less than 10. Even at this idiopathic, type 1 RTA can be related to connective stage the urinary pH can never acidify below a pH tissue diseases, particularly Sjögrens, rheumatoid of 5.3. Due to the Henderson-Hasselbach equation, arthritis and SLE, which must always be excluded. + - when the urinary [H ]falls the [HCO3 ] increases An incomplete form of type 1 RTA also exists and therefore treatment involves the replacement of which, like the complete form, puts the individual bicarbonate. As with type 2 RTA, the serum [K+] is at risk of calcium renal stones due to alkaline urine. usually lowlow. However, it may be high, depending However, the incomplete form generally gives a on the specific acid secreting mechanism failure. normal plasma pH and HCO3 and is often diagnosed Unlike type 2 RTA, hypokalaemia may improve when investigating the cause of recurrent renal with alkalinization due to reduction of potassium calculi (urinary hypocitraturia and failure to acidify secretion at the distal tubule. Although often urine)7.

Problem-Based Review: A patient with metabolic acidosis

Type 4 RTA, in comparison to type 1 and • After acidification therapy (e.g. ammonium 2, will usually be associated with hyperkalaemia. chloride), loop diuretics and/or fludrocortisone These derangements occur due to a lack of In conditions where kidneys have normally mineralocorticoid effects on the distal tubule. This functioning distal tubules, the urine will become can result from aldosterone deficiency or resistance. more acidic due to increased H+ secretion; in RTA The [HCO -] is usually only mildly low (>17) and 3 type 1, the urinary pH will remain >5.3.10 the urine pH is usually < 5.3. It is most commonly due to hyporeninaemic hypoaldosteronism which is 2. Assess the ammonium content of the urine frequently seen in mild to moderate chronic kidney This reflects acid secretion (after it combines disease (especially if due to diabetic nephropathy). with ammonia). Unfortunately this can not be Alternatively, a hyporeninaemic hypoaldosteronism measured directly in many labs and instead should be state (e.g. adrenal failure, lead poisoning, ACE estimated. This can be done in two ways.11 inhibitor, rifampicin, heparin or antifungal use) or (i) Urine anion gap (UAG) hyperaldosteronaemic state (with tubular resistance Measured on a random urine specimen and to its effect i.e. pseudohypoaldosteronism) could is calculated using the following equation: – exist. Renin and aldosterone levels can be measured. UAG = Urine [Na+K-Cl] However, results will not usually alter treatment and Since ammonium and chloride are excreted it is more common simply to treat empirically.1 together (as NH4Cl), where there is a Type 3 RTA is rare and has features of type 1 higher ammonium concentration, the [Cl-] and 2 RTA. It results from carbonic anhydrase II rises too, resulting in a lower/more negative deficiency and is seen in association with cerebral UAG. Therefore, where a distal tubular calcification, developmental delay, craniofacial defect exists,the UAG will never show the 8 disproportion and osteopetrosis . normal response of becoming negative, Although strictly not a RTA owing to the loss even if acid is infused.11 of preserved glomerular filtration, chronic kidney The use of UAG does become inaccurate disease (CKD) can result in a normal anion gap and unhelpful in states where ammonium acidosis (in comparison to the more usual raised anion is secreted with an anion (or cation) other gap that it causes). As well as the raised creatinine this than chloride which is not reflected in the can be differentiated from type 1 RTA by a urinary above equation. This situation occurs in pH < 5.3 and from type 2 RTA by the low levels of conditions such as ketoacidosis, toluene 9 ammonium in the urine . inhalation or D-lactic acidosis (all of How should we investigate a normal AG acidosis to which can be seen with a normal gap – see find the specific cause? potential bicarbonate loss below). For this When a normal gap acidosis is found we should reason, the alternative way of estimating follow the following steps to establish the cause. urinary ammonium level, urinary osmolar 1. Measure the urinary pH gap, is more useful.12 In a normally functioning kidney,urine pH (ii) Urinary osmolar gap (UOG) should be less than 5.3 when a serum acidosis is This is the difference between the measured present. To prevent misleading results it is important and calculated urinary osmolarity (i.e. takes that before this measurement is performed, any into account the alternative anions/cations existing hypokalaemia and hypovolaemia is corrected that can invalidate the UAG). It therefore and that urinary infection (particularly with urease largely represents ammonium (reflecting acid containing organisms) is excluded. If the pH is secretion) and a relatively accurate estimate > 5.3 this confirms the presence of renal tubular of urinary [NH4] can be made dividing the dysfunction and when < 5.3, excludes the presence UOG by two (in mmol/l). In the presence of type 1 RTA. of acidosis, an estimated urinary [NH4] of + • After alkalinization therapy (e.g. sodium < 20meq/l indicates impaired H excretion bicarbonate) (i.e. type 1or type 4 RTA). When calculating UAG or UOG, any As noted above, in type 2 RTA, when equilibrium hypovolaemia, hypokalaemia or urease has been reached, the urinary pH may be less than producing UTI should have been treated to 5.3. When alkalinization therapy is administered, the avoid an erroneous result13. urinary pH will increase significantly (often to > 7.5) Given the possible association between type 1 diabetes and the fractional excretion of HCO3 will be > 15- and autoimmune adrenal failure our patient undergoes a 20%.Fractional excretion of HCO3 can be calculated using the following equation:.10 short synacthen test to exclude adrenal insufficiency. His adrenal function is confirmed to be normal. His urine is Fractional Excretion = Urine HCO Plasma Cr × 100 then investigated as above. He has an appropriately low 3× of HCO3 Plasma HCO Urine Cr urinary pH with a urinary anion gap which is positive and 3 a urinary osmolar gap that is high. Given these findings the © 2012 Rila Publications Ltd. Acute Medicine 2012; 11(4): 251-256 255

Problem-Based Review: A patient with metabolic acidosis

treating team decide that the low delta ratio is most likely to delivery resulting in less anaerobic respiration and be explained by potential bicarbonate loss. lactic acid formation). When used in such a way,the following equation can be used to help guide What is meant by the term ‘potential bicarbonate requirement: bicarbonate loss’? The idea of potential bicarbonate loss should Bicarbonate deficita (mmol/l) = bicarbonate also be considered when faced with a normal gap spaceb × acidosis. This situation arises when a classical cause bicarbonate of elevated anion gap acidosis (particularly lactate, deficit per litrec ketones and toluene) has been present and treatment has begun. To understand this we must appreciate a. Bicarbonate deficit = amount of alkali that the new anion is excreted in the urine in the - required to raise the [HCO3 ] to target presence of normal renal function. This therefore - b. Bicarbonate space = {0.4 + 2.6 ÷ [HCO3 reduces the anion gap which often becomes - ]} x lean body weight (since the [HCO3 ] normal despite persistence of the metabolic will change with treatment, an average of acidosis. This normal gap acidosis is explained by the bicarbonate space calculated using the the fact that the anion excreted in the urine would - - target [HCO3 ] and the starting[HCO3 ] otherwise have been metabolised to produce should be used) - HCO3 and therefore a potential bicarbonate loss is c. Bicarbonate deficit per litre = target present.13,14 This potential loss may result in a delta - - [HCO3 ] – starting [HCO3 ] ratio of less than 1 when the added anions are only - Target [HCO3 ] = 12mmol/l partially cleared. Consideration should also be given to the When should sodium bicarbonate be used and what continuing production of acid and regeneration of are the concerns? bicarbonate and therefore this calculation is not a When bicarbonate is being lost as in RTA type 2, substitute for frequent repeat sampling. Once the pH the treatment is intuitive and involves administration has returned to>7.20 or bicarbonate to > 12mmol/l, of sodium bicarbonate. As noted above, this is also no further bicarbonate treatment is required.14 helpful in RTA type 1 however in an undefined Due to the problems outlined in Table 4, alternatives metabolic acidosis, the precise cause of the metabolic to bicarbonate have been considered. THAM (tris- acidosis should first be established and, where hydroxymethylaminomethane) and carbicarb are two possible, treated. This emphasizes the importance such alternatives which may result in less CO2production of the diagnostic approach and knowledge of the as a result of an amine group and a carbonate addition various causes highlighted above. For example, respectively which can bind to CO2 and produce - it is the insulin and fluid therapy in our patient’s HCO3 . Despite these theoretical advantages, neither case that will improve the acidosis. In conjunction of these treatments has yet established a place in the with this treatment, the normal kidneys should be clinical treatment of acidosis.14,16 responding by increasing the excretion of acid. Use Table 4. Potential side effects of intravenous sodium of bicarbonate therapy in addition to fluids and bicarbonate16,17 insulin in DKA is controversial.14,15 In lactic acidosis and ketoacidosis, most experts Adverse effects of intravenous sodium bicarbonate therapy would suggest that the acidaemia must be severe (e.g. pH <7.00) prior to consideration of IV Production of CO2 bicarbonate. It is prudent to consider the problems Cerebral acidosis (as a result of lipophilic CO2rapidly associated with bicarbonate therapy (see table 4). crossing the blood brain barrier) Bicarbonate therapy is sometimes indicated when Hypervolaemia the severity of the metabolic acidosis is leading to Hypernatraemia cardiac dysfunction and vasodilatation, creating a o vicious cycle of worsening acidosis. In this situation, Reduced cardiac contractility (2 to reduction in bicarbonate may have a beneficial effect, both ionized/unbound calcium due to excess alkalinization) directly (by increasing serum pH) and indirectly Post-recovery alkalosis (as a result of regeneration of HCO - from the anion present in excess) (by increasing myocardial contractility and oxygen 3

Problem-Based Review: A patient with metabolic acidosis

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