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June 2002

Glucose and lactate in neonatology (clinical focus)

Both high and low blood glucose levels may be dangerous to the newborn baby. Measurement of blood or plasma lactate concentrations gives an indication of the adequacy of oxygen delivery to tissues, and blood and CSF lactate levels are essential investigations in the diagnosis of inborn errors of metabolism (IEM).  

The requirement for frequent tests and rapid results suggests that near-patient testing is the ideal. However, most near-patient testing devices do not have the sufficient accuracy required given the limited range of optimal blood glucose and lactate values. Neonatal unit laboratory instruments now appear to hold the solution.

THE CLINICAL SIGNIFICANCE OF CIRCULATING GLUCOSE AND LACTATE CONCENTRATIONS

Glucose

It has been recognized for many years that both high and low blood glucose levels may be dangerous to the newborn baby [1]. Therefore, in at-risk groups (see below) it is essential to have accurate and regular monitoring of blood glucose concentrations so that prolonged periods of disordered blood glucose homeostasis may be prevented. 

However, one cannot define single cut-off values above or below which damage may occur and, as with all aspects of neonatology, our aim is to treat the baby’s clinical condition and not a number (the blood glucose concentration).

At-risk groups:

  • Moderately preterm or growth-retarded babies - blood glucose monitoring is an adjunct to the support and optimization of breast feeding and along with clinical assessment may indicate when formula supplements are necessary.
  • A baby presenting with an acute illness - measurement of blood glucose concentration is important to identify hypoglycemia as either the cause or an association of the collapse, and to guide subsequent intravenous fluid management. Unexpected hypoglycemia should alert clinicians to an inborn error of metabolism and appropriate blood and urine samples should be taken immediately, as it is often difficult to diagnose metabolic conditions in normoglycemic, unstressed infants.
  • Babies cared for on neonatal units who have known co-existing clinical complications - low blood glucose concentrations indicate that energy provision (intravenous or enteral) should be increased, and monitoring should be continued to assess the effects of changes in management. High blood glucose concentration may be an early marker of infection or other stress which cause metabolic perturbation, and thus alert attending staff to carry out further investigations.

In summary, the determination of blood glucose concentration is essential for the prevention of severe and prolonged hypoglycemia and hyperglycemia, the diagnosis of underlying disorders in sick infants and in guiding feeding and fluid prescriptions for small, vulnerable or sick neonates.

Lactate

Lactate accumulates in tissues, blood and CSF as a result of anaerobic metabolism. Thus, measurement of blood or plasma lactate concentrations gives an indication of the adequacy of recent or current oxygen delivery to tissues which may be reduced during hypoxemia, cardiac failure, or peripheral vascular shutdown. 

Whilst bedside monitoring provides an immediate indication of hypoxemia, measurement of lactate concentrations may alert clinicians to problems with oxygen delivery to tissues, for example in neonatal septicemia or persistent ductus arteriosus [2]. 

High plasma lactate concentrations have been associated with adverse outcome after perinatal hypoxia-ischemia and in neonates undergoing extracorporeal membrane oxygenation [3,4,5,6] .

Finally, measurement of blood and CSF lactate levels is an essential investigation in the diagnosis of inborn errors of metabolism (IEM).

THE REQUIREMENT FOR ACCURACY AND REPRODUCIBILITY

Glucose

There is now extensive literature regarding the numerical definition of neonatal hypoglycemia, which has been succinctly summarized by Halamek et al [7]: “As of 1997 no consensus exists in the normal newborn nursery, NICU, or the courtroom as to the definition of hypoglycemia in the neonate”.

Although there can be no single defining values for hypoglycemia and hyperglycemia, many neonatal units aim to maintain blood glucose levels above 2-3 mmol/L and below 10-15 mmol/L in low-birthweight or sick babies. 

This range of optimal blood glucose values necessitates accuracy of monitoring, as management may be changed if blood glucose measurements are perceived to change by as little as 1 mmol/L at either end of the optimal range. Inaccurate monitoring may also lead to overtreatment or undertreatment, which may in turn harm the baby.

Lactate

Similarly, blood and CSF lactate concentrations are normally within a narrow range. Mean ± 2SD for blood lactate concentration for healthy, full-term infants has been reported as 0.22-2.98 mmol/L and 0.26-2.21 mmol/L [8,9]. 

Therefore, small deviations from this range may be of clinical significance and methods of measurement must be accurate.

PREVIOUS DIFFICULTIES

Glucose

Leaving aside any controversy regarding definition, it is of greater clinical importance to discuss issues of accuracy of measurement.

Differences arise when comparing plasma and whole blood measurements of glucose, even using accurate laboratory measures [10]. This difference is greater at high hematocrits. 

However, as long as either plasma or blood values are consistently used for an individual subject, and method of measurement is reported, the difference between plasma and whole-blood measurements is of lesser clinical significance than the potential inaccuracies of measurement described below.

The most common method used for blood glucose monitoring has been by reagent strip at the cotside, using heelprick capillary blood samples. The perceived advantages of this method are cost, ease of use, accessibility and need for minimal training. 

The reagent strips are designed for the detection of hyperglycemia in diabetic patients, for which purpose they are sufficiently accurate. However, it has been demonstrated and the manufacturers themselves acknowledge that reagent sticks have no role in the diagnosis of hypoglycemia because of inherent inaccuracies at low blood glucose concentrations [11,12,13]. 

These problems have been highlighted by the UK Department of Health and the American Academy of Pediatrics [14,15]. Attempts to introduce more accurate (and more expensive) methods of near-patient glucose monitoring have proved equally disappointing in neonatal practice [16,17,18].

If samples are sent to hospital laboratories for accurate measurement to confirm cotside readings, there is the inevitable decline in glucose in a whole-blood sample during transit and delay in reporting a result [18].

Lactate

Until recently, the clinical significance of blood and CSF lactate concentrations has not been widely appreciated by neonatologists, and there has been little commercial drive to produce methods of measurement which may be used outside of specialized or research laboratories. 

Therefore, practical limitations of transfer of specimens and reporting time have mitigated against the use of regular lactate monitoring in neonatal practice.

As for glucose, lactate concentrations will change over time in a whole-blood sample because of red-cell metabolism, levels will increase if there is delay in measurement [9,18]. 

Recently, methods have been introduced for more immediate and accessible monitoring of lactate concentrations, but these measurements may be available either in isolation or in parallel only with blood glucose measurements. 

This limits the value of a single lactate measurement, and the ability to report a lactate concentration alongside simultaneous measurements of glucose, blood gases, and electrolytes (especially chloride) would aid interpretation and add more to the clinical picture.

FUTURE SOLUTIONS

Neonatologists would not consider embarking upon the care of an infant with respiratory problems without access to rapid and accurate measurement of blood gas values with on-site blood gas analyzers. 

In the same way, they would wish to have available an on-site facility for measurement of electrolytes, glucose and lactate in addition to blood gas analysis. Neonatal unit laboratory-based glucose analyzers have been evaluated and have proved preferable to the near-patient methods discussed above [19]. 

The ability to perform immediate, accurate, and simultaneous analysis of blood gases, electrolytes, glucose, lactate, bilirubin, and hemoglobin or hematocrit would optimize the management of fluid, salt and energy provision to the smallest and sickest babies in particular.

Analyzers that provide this facility must be:

  • Sufficiently robust to handle multiple specimens (and users) and able to function around the clock, with short breaks for maintenance and calibration. 
  • Have a facility for daily quality control (QC) checks with high and low QC samples appropriate for the neonatal range of concentrations.
  • Designed for ease of operation by a multidisciplinary team.
  • Amenable to maintenance and basic “troubleshooting” by local medical physicists or biochemists.
  • Able to carry out analysis on small specimens.

Clinicians should satisfy themselves that performance data indicate:

  • Accuracy, using a recognized “gold standard” measure and employing Bland-Altman plots to interpret data, rather than regression or correlation fits [20].
  • The range of measurement is appropriate for the subject group.
  • Accuracy at the upper and lower ends of the range of measurement.
  • Reproducibility.
  • Minimal effects of hematocrit and other factors such as bilirubin concentration.
References
1. Hawdon JM, Aynsley-Green A. Disorders of blood glucose homeostasis in the neonate. In: Roberton, Rennie, eds. Textbook of Neonatology. 3rd ed. Edinburgh: Churchill Livingstone, 1999, 939-56. 
2. Fitzgerald MJ, Goto M, Myers TF, Zeller WP. Early metabolic effects of sepsis in the preterm infant: Lactic acidosis and increased glucose requirement. J Pediatr 1992; 121: 951-55. 
3. Cheung P, Finer NN. Plasma lactate concentration as a predictor of death in neonates with severe hypoxemia requiring ECMO. J Pediatr 1994; 125: 753-58. 
4. Cheung P, Robertson CMT, Finer NN. Plasma lactate as a predictor of early childhood developmental outcome of neonates requiring extracorporeal membrane oxygenation. Arch Dis Child 1996; 74: F47-50. 
5. Chou YH, Tsou Yau K-I, Wang P-J. Clinical application of the measurement of cord plasma lactate and pyruvate in the assessment of high risk neonates. Acta Paediatr 1998; 87: 764-68. 
6. Deshpande SA, Ward Platt MP. Association between blood lactate and acid-base status and mortality in ventilated babies. Arch Dis Child 1997; 76: F15-20. 
7. Halamek LP, Benaron DA, Stevenson DK. The value of neurophysiologic approaches in the anticipation and evaluation of neonatal hypoglycaemia. Acta Paediatr Japonica 1997; 39: S33-43. 
8. Hawdon JM, Ward Platt A, Aynsley-Green A. Patterns of metabolic adaptation for preterm and term infants in the first neonatal week. Arch Dis Child 1992; 67: 357-65. 
9. Nielsen J, Ytrebo LM, Bond O. Lactate and pyruvate concentrations in capillary blood from newborns. Acta Paediatr 1994; 83: 920-22. 
10. Kaplan M, Blondheim O, Alon I, Eylath U, Trestian S, Eidelman O. Screening for hypoglycaemia with plasma in neonatal blood of high haematocrit value. Crit Care Med 1989; 17: 279-82. 
11. Lin HC, Maguire C, Oh W, Cowett R. Accuracy and reliability of glucose reflectance meters in the high risk neonate. J Pediatr 1989; 115: 998-1002. 
12. Reynolds GJ, Davies S. A clinical audit of cotside blood glucose measurement in the detection of neonatal hypoglycaemia. J Paediatr Child Health 1993; 29: 289-91. 
13. Sharief N, Hussein K. Comparison of two methods of measurement of whole blood glucose in the neonatal period. Acta Paediatr 1997; 86: 1246-52. 
14. Department of Health. Extra laboratory use of blood glucose meters and test strips: contraindications, training and advice to the users. Medical Devices Agency Safety Notice 9616 (MDA SN 9616). London: Department of Health, Medical Devices Agency, 1996. 
15. American Academy of Pediatrics Committee on the Fetus and Newborn. Routine evaluation of blood pressure, hematocrit and glucose in the newborn. Pediatrics 1993; 92: 474-76. 
16. Ellis M, Manandhar DS, Manandhar N, Land JM, Patel N, Costello AM de L. Comparison of two cotside methods for the detection of hypoglycaemia among neonates in Nepal. Arch Dis Child 1996; 75: F122-25. 
17. Leonard M, Chessall M, Manning D. The use of Hemocue blood glucose analyser in a neonatal unit. Ann Clin Biochem 1997; 34: 287-90. 
18. Elimann A, Horal M, Bergstrom M, Marcus C. Diagnosis of hypoglycaemia: effects of blood sample handling and evaluation of a glucose photometer in the low glucose range. Acta Paediatr 1997; 96: 474-78. 
19. Conrad PD, Sparks, JW, Oxberg I, Abrams L, Hay WW. Clinical application of a new glucose analyser in the neonatal intensive care unit: Comparison with other methods. J Pediatr 1989; 114: 281-87. 
20. Bland J, Altman DG. Statistical methods for assessing agreement between two methods of clinical agreement. Lancet 1986; I: 307-10.
References
1. Hawdon JM, Aynsley-Green A. Disorders of blood glucose homeostasis in the neonate. In: Roberton, Rennie, eds. Textbook of Neonatology. 3rd ed. Edinburgh: Churchill Livingstone, 1999, 939-56. 
2. Fitzgerald MJ, Goto M, Myers TF, Zeller WP. Early metabolic effects of sepsis in the preterm infant: Lactic acidosis and increased glucose requirement. J Pediatr 1992; 121: 951-55. 
3. Cheung P, Finer NN. Plasma lactate concentration as a predictor of death in neonates with severe hypoxemia requiring ECMO. J Pediatr 1994; 125: 753-58. 
4. Cheung P, Robertson CMT, Finer NN. Plasma lactate as a predictor of early childhood developmental outcome of neonates requiring extracorporeal membrane oxygenation. Arch Dis Child 1996; 74: F47-50. 
5. Chou YH, Tsou Yau K-I, Wang P-J. Clinical application of the measurement of cord plasma lactate and pyruvate in the assessment of high risk neonates. Acta Paediatr 1998; 87: 764-68. 
6. Deshpande SA, Ward Platt MP. Association between blood lactate and acid-base status and mortality in ventilated babies. Arch Dis Child 1997; 76: F15-20. 
7. Halamek LP, Benaron DA, Stevenson DK. The value of neurophysiologic approaches in the anticipation and evaluation of neonatal hypoglycaemia. Acta Paediatr Japonica 1997; 39: S33-43. 
8. Hawdon JM, Ward Platt A, Aynsley-Green A. Patterns of metabolic adaptation for preterm and term infants in the first neonatal week. Arch Dis Child 1992; 67: 357-65. 
9. Nielsen J, Ytrebo LM, Bond O. Lactate and pyruvate concentrations in capillary blood from newborns. Acta Paediatr 1994; 83: 920-22. 
10. Kaplan M, Blondheim O, Alon I, Eylath U, Trestian S, Eidelman O. Screening for hypoglycaemia with plasma in neonatal blood of high haematocrit value. Crit Care Med 1989; 17: 279-82. 
11. Lin HC, Maguire C, Oh W, Cowett R. Accuracy and reliability of glucose reflectance meters in the high risk neonate. J Pediatr 1989; 115: 998-1002. 
12. Reynolds GJ, Davies S. A clinical audit of cotside blood glucose measurement in the detection of neonatal hypoglycaemia. J Paediatr Child Health 1993; 29: 289-91. 
13. Sharief N, Hussein K. Comparison of two methods of measurement of whole blood glucose in the neonatal period. Acta Paediatr 1997; 86: 1246-52. 
14. Department of Health. Extra laboratory use of blood glucose meters and test strips: contraindications, training and advice to the users. Medical Devices Agency Safety Notice 9616 (MDA SN 9616). London: Department of Health, Medical Devices Agency, 1996. 
15. American Academy of Pediatrics Committee on the Fetus and Newborn. Routine evaluation of blood pressure, hematocrit and glucose in the newborn. Pediatrics 1993; 92: 474-76. 
16. Ellis M, Manandhar DS, Manandhar N, Land JM, Patel N, Costello AM de L. Comparison of two cotside methods for the detection of hypoglycaemia among neonates in Nepal. Arch Dis Child 1996; 75: F122-25. 
17. Leonard M, Chessall M, Manning D. The use of Hemocue blood glucose analyser in a neonatal unit. Ann Clin Biochem 1997; 34: 287-90. 
18. Elimann A, Horal M, Bergstrom M, Marcus C. Diagnosis of hypoglycaemia: effects of blood sample handling and evaluation of a glucose photometer in the low glucose range. Acta Paediatr 1997; 96: 474-78. 
19. Conrad PD, Sparks, JW, Oxberg I, Abrams L, Hay WW. Clinical application of a new glucose analyser in the neonatal intensive care unit: Comparison with other methods. J Pediatr 1989; 114: 281-87. 
20. Bland J, Altman DG. Statistical methods for assessing agreement between two methods of clinical agreement. Lancet 1986; I: 307-10.
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May contain information that is not supported by performance and intended use claims of Radiometer's products. See also Legal info.

Jane M. Hawdon Jane M. Hawdon

 

MA MBBS FRCP FRCPCH PhD 
Consultant neonatologist, 
University College London Hospitals 
UK

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