Article Text

Electrolytes in sick neonates – which sodium is the right answer?
  1. Richard I King1,
  2. Richard J Mackay1,
  3. Christopher M Florkowski1,
  4. Adrienne M Lynn2
  1. 1Department of Clinical Biochemistry, Canterbury Health Laboratories, Christchurch, New Zealand
  2. 2Neonatal Services, Christchurch Women's Hospital, Christchurch, New Zealand
  1. Correspondence to Richard I King, Clinical Biochemistry Unit, Canterbury Health Laboratories, Cnr Hagley Ave and Tuam Street, PO Box 151, Christchurch 8011, New Zealand; richard. king{at}


Introduction Hypoproteinaemia leads to spuriously high-sodium values when measured by indirect ion-selective electrodes (ISE) as used in main laboratory analysers compared with direct ISE employed in point-of-care analysers (POCT). The authors, therefore, investigated the occurrence of hypoalbuminaemia and its effect on measured sodium from POCT and the main laboratory analyser of neonatal intensive-care samples.

Method Sodium, in paired retrospective samples, measured by the main laboratory and neonatal unit blood-gas (POCT) analysers were compared.

Results Hypoalbuminaemia (<30 g/l) was present in 1400/2420 paired results. Sodium was higher when measured by laboratory analyser, the difference increased with decreasing albumin; sodium (laboratory – POCT)=7.6 (±1.1)–0.22 (±0.04)×albumin. A difference >3 mmol/l was present in 31% and consequently underestimated (9.4%) hyponatraemia and overestimated (3.8%) hypernatraemia.

Conclusion Hypoalbuminaemia is common in sick neonates and monitoring electrolytes using POCT and laboratory analysers frequently yield significantly different results with consequent misclassification. In these patients, measurement of electrolytes by direct ISE (blood-gas analyser) may be more accurate.

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What is already known on this topic

  • Pseudonormonatraemia and pseudohypernatraemia can arise in hypoproteinaemic states when electrolytes are measured by an indirect ion-selective electrode.

  • This artefact arises from the ‘ion exclusion’ effect.

  • The International Federation of Clinical Chemists recommends measuring electrolytes by direct ion-selective electrode in samples with altered plasma water volumes (hypo- or hyper-proteinaemia and lipaemia).

What this study adds

  • This study confirms the relationship between hypoproteinaemia and the sodium measurement artefact observed with indirect ion-selective electrodes is also seen in neonatal patients.

  • This study supports the recommendation that a single sample type be used in monitoring electrolytes if small changes in serial values are to be detected.


Electrolytes are frequently monitored in neonatal intensive-care units (NICU) by using point-of-care testing (POCT) and through the hospital laboratory. Results generated in this way often differ and this may cause concern for clinicians. A recent case in our institution illustrates this point. A sick neonate returned sodium results from concurrent samples of 123 mmol/l from a POCT blood-gas analyser and 134 mmol/l from the core laboratory main analyser. Repeat testing produced consistent results and both followed trends in their corresponding results excluding poor sample quality. The clinician sought an explanation from the laboratory; hypoalbuminaemia, with albumin 26 g/l, was thought to be responsible and we were motivated to investigate further.

Pseudohyponatraemia in hyperproteinaemic or lipaemic samples is a well-recognised artefact of indirect ion-selective electrodes (ISE) arising from the ‘ion exclusion’ effect.1 An ISE determines the activity of sodium ions present. The concentration of sodium in the plasma water is then derived and by convention reported as the concentration in the total plasma volume, plasma water plus the volume occupied by plasma proteins. ISEs may be either indirect, the sample is diluted before analysis or direct, no dilution. Indirect ISEs are popular in main laboratory analysers because dilution allows smaller sample volumes to be used. The plasma water volume is assumed to remain constant – comprising 93% of the total volume. This assumption fails in hyperproteinaemic or lipaemic samples resulting in pseudohyponatraemia. A similar error, but in the opposite direction, can arise in hypoproteinaemic states and leads to pseudonormonatraemia or pseudohypernatraemia when using an indirect ISEs.2

Total protein is seldom measured in neonates but albumin provides a suitable surrogate as high immunoglobulin concentrations are rarely encountered in the neonatal period.3 We sought to establish the occurrence of hypoalbuminaemia in samples sent from the NICU and to investigate if there was a clinically significant difference in reported results derived from POCT and laboratory testing.


We performed a retrospective search for laboratory results from patients in the NICU between 1st January 2005 and 31st December 2009. Plasma electrolyte results and albumin performed on the laboratory analyser were matched with electrolyte results obtained from the NICU's blood-gas analyser. Results registered within 30 min of each other were considered matched and representative of concurrent samples.

Sodium was measured by indirect ISE on the Abbott Architect main laboratory analyser (Abbott Laboratories, Abbott Park, Illinois, USA), between run coefficient of variation (CV) 0.67% at 136 mmol/l. Albumin was measured on the same instrument, CV 0.69% at 27 g/l. The NICU used a Corning 860 (Bayer Diagnostics, Fernwald, Germany) blood-gas analyser until June 2009 when it was replaced by a Radiometer ABL 800 (Radiometer Medical Aps, Copenhagen, Denmark). Both instruments use a direct ISE with CVs 0.89% at 134.5 mmol/l and 0.62% at 127.9 mmol/l, respectively. Agreement between POCT and laboratory methods was assessed by comparing regular patient samples throughout the analysis period.

For matched results the difference between indirect and direct ISE sodium results was calculated and correlated with the albumin concentration using least squared regression. Statistical analysis was performed by SigmaPlot 11.0 (Systat Software Inc, San Jose, California, USA) and p<0.05 was taken as significant.

A clinically significant difference between paired results was defined as >3 mmol/l, the Royal College of Pathologists of Australasia Quality Assurance Program (RCPA QAP) allowable limit of performance.


Hypoalbuminaemia, albumin <30 g/l, was present in 1400 (58%) of 2420 paired results. The incidence did not correlate with patient age. The difference between the indirect and direct ISE sodium values increased with decreasing albumin concentration, figure 1 and reached significance (p<0.05) compared with the group with normal albumin for groups with albumin concentrations <23 g/l and 24–29 g/l. Least squares regression gave the relationship – sodium (main laboratory – POCT)=7.6 (±1.1)–0.22 (±0.04)×albumin, r=0.309, p<0.001.

Figure 1

Difference between laboratory analyser (indirect ion-selective electrodes (ISE)) and point-of-care testing blood-gas analyser (direct ISE) sodium with decreasing albumin concentration. Box represents the IQR, horizontal line – median and whiskers the 10th and 90th centiles.

Thirty-one per cent of samples gave an absolute difference of >3 mmol/l, resulting in misclassification of samples by indirect ISE. Hyponatraemia, sodium <135 mmol/l, was identified in 227 (9.4%) fewer samples by indirect ISE, 134 (5.3%) more results were classified as normonatraemic and 93 (3.8%) more as hypernatraemic, >145 mmol/l, table 1. χ2 For the trend was 58.1 (p<0.05).

Table 1

Classification of results according to the two methods, direct and indirect ion-selective electrodes

Quality control material showed a small positive bias in favour of the laboratory (indirect ISE) analyser with a mean difference of 0.69 mmol/l (SEM±0.22) at a mean (indirect ISE) value of 138.9 mmol/l.

Discussion and conclusion

Significant differences in sodium results may be seen when electrolytes are monitored using a combination of POCT and samples submitted to the hospital laboratory. In patients with hypoalbuminaemia (<30 g/l), present in 58% of study samples, pseudonormonatraemia or pseudohypernatraemia may arise from the ‘ion exclusion effect’ when measuring sodium by indirect ISE.

We were interested to note that clinicians in our institution placed more trust in results from the core laboratory analyser rather than the POCT instrument. The International Federation of Clinical Chemists (IFCC)4 recommends measurement of sodium and potassium in undiluted specimens (direct ISE) when plasma water volumes are altered (hypo- or hyper-proteinaemia, lipaemia).

Allowable limits of performance set by external quality assurance organisations such as the RCPA QAP define limits for imprecision and bias. For sodium this limit is 3 mmol/l and a difference greater than this is likely to be clinically significant. A potentially clinically significant difference was present in 31% of the paired samples, with the indirect ISE underestimating the number of hyponatraemic samples and overestimating the number of hypernatraemic samples; possibly having an effect on the type or rate of fluid replacement instigated.

Similar studies have previously been reported in adult intensive-care patients,5 ,6 a setting where POCT is also commonplace, but to our knowledge this is the first study in children or babies. In their study, Story et al5 reported a similar median 3 mmol/l difference in sodium at an albumin concentration of 22 g/l.

While acknowledging the ideal study would involve using the same samples for the two measurements, we minimised any effect of treatment by choosing a short-time interval between paired samples. The lower sodium (2.3%) and protein (3.3%) content of capillary blood compared with venous blood is another potential confounder.7 Measurements by POCT used whole blood predominantly from arterial or capillary supply whereas the main laboratory analyses used plasma from mainly venous or capillary blood. Although this may lead to lower POCT results, it was thought unlikely to influence the observed relationship with albumin. Loughrey et al8 have explored these effects more fully, demonstrating that using different sample types could mask true differences in electrolyte results. Capillary samples are especially prone to haemolysis and it may go undetected in most POCT instruments, this too could reduce the sodium concentrations by dilution. The large sample number helped to mitigate any effect of this confounder.

Taken together, the recommendations of the IFCC4 and those of Loughrey et al8 suggest that for monitoring electrolytes in NICU or intensive-care unit patients, a direct ISE and a single sample type should be used. If POCT were the sole testing modality, the importance of correct calibration, maintenance and adequate training along with good quality control and quality assurance cannot be overemphasised.9 Connectivity of all POCT devices to the laboratory information system should be encouraged as this serves to maintain the patient record.

In conclusion, this study shows that hypoalbuminaemia is common in samples originating from the NICU and confirms that this can have a clinically significant effect on the results obtained from the laboratory analyser compared with the POCT blood-gas analyser. Clinicians should be aware of these differences and the consequences of their effects.


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  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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