potential candidates include l - lactate , -hydroxybutyrate , d - lactate , salicylate , formate and oxalate in toxicological situations , pyroglutamate , semisynthetic penicillins , sulphate and hippurate in renal failure , and occasionally urate and amino acids with catabolic states and total parenteral nutrition . reports of increased tricyclic acid ( tca ) cycle anions in shock are now emerging . their presence is often inferred from the anion gap ( ag ) , calculated as [ na ] + [ k ] - ( [ cl ] + [ hco3 ] ) . when its reference range is exceeded , a search for unmeasured anions should commence , irrespective of the overall metabolic acid - base status , because a competing metabolic alkalosis can mask their presence . likely culprits vary with the clinical scenario , but the search usually starts with l - lactate and -hydroxybutyrate . during this process , stoichiometry is tracked between ag ( measured ag  normal ag ) and the summed concentrations of suspect anions ( always in meq / l , because we are dealing in electrical neutrality ) . if ag both sensitivity and specificity are reduced by perturbations of albumin ( remembering that albumin negative charge forms the bulk of the normal ag ) , ph , [ ca ] , [ mg ] and [ phosphate ] . the most promising alternative is the strong ion gap ( sig )   like the ag , the sig quantifies unmeasured anions minus unmeasured cations , but unlike its predecessor it is insulated from variations in [ albumin ] , [ phosphate ] , ph , [ l - lactate ] , [ ca ] and [ mg ] . in the previous issue of critical care , bruegger and colleagues   combine sig calculations with capillary electrophoresis , and report that anions associated with the tca cycle , specifically citrate and acetate , contribute to the metabolic acidosis of canine haemorrhagic shock . their data originate from an earlier experiment designed to investigate the benefits of a perflurocarbon - based oxygen carrier during resuscitation from a predefined oxygen debt . capillary electrophoresis on specimens before shock , during shock and on resuscitation revealed maximal citrate elevations of 1.9 meq / l , whereas the peak acetate increase was 3.4 although these findings fuel ongoing speculation concerning tca anions in shock , several potential confounders are worthy of comment . during preparation , the animals acquired major metabolic perturbations , with severe baseline hypoalbuminaemia ( 1.5 g / dl ) and impressive hyperchloraemia ( 130 mmol / l ) , but ( from the parent study ) only mild anaemia ( 11 g / dl ) . most surprising in this context was a massive baseline plasma acetate ( 2.4 meq / l ) , which is 40 times the level reported from a previous study in dogs ( 0.06 mmol / l ) . the postshock acetate peaked at 5.8 meq / l , over 30 times that in the previous report ( 0.19 mmol / l ) . to our knowledge such prodigious acetate levels are unprecedented outside the setting of exogenous administration . in the parent study , ringer 's solution 15 ml / kg per hour was documented as infused during all but the shock phase . if this was ringer 's acetate , and if the animals had received both saline ( as stated by bruegger and colleagues ) and ringer 's acetate , then this would explain much . of relevance is a report that exogenous acetate can elevate hepatic citrate . although the authors acknowledge that they re - infused blood containing citrate phosphate dextrose solution during the shock phase , thus introducing exogenous citrate a final caveat is that charge and dissociation indices for human albumin used in this study differ from those for canine albumin , although the effect on sig calculations is probably small . until now , talk of unmeasured ions in critical illness has largely been speculative , based on discrepancies in ag or sig . nonetheless , since the late 1960s reports have emerged of accumulating tca cycle intermediates in shock and dysoxic states . the pattern reported by forni and colleagues   in human metabolic acidosis differed substantially from the findings reported by bruegger and coworkers , with relatively small increases in isocitrate , -ketoglutarate , malate and d - lactate , and in some cases citrate and succinate . only on aggregate were these sufficient to inflate the ag . it is insufficient to invoke ' tissue stress ' to explain such increases in tca anions . elevations must be considered within the context of anaplerosis and cataplerosis , which combine to maintain adequate concentrations of tca intermediates . ag = anion gap ; sig = strong ion gap ; tca = tricyclic acid .
evidence is emerging that elevated concentrations of the intermediates of the citric acid cycle may contribute to unmeasured anions in critical illness . 
 both the anion gap and the strong ion gap are used as scanning tools for recognition of these anions . 
 the mechanisms underlying these elevations and their significance require further clarification .