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The definition of hypoglycaemia
2 The definition of hypoglycaemia J. W. GREGORY
A. AYNSLEY-GREEN
There are difficulties in defining hypoglycaemia, which have led to much controversy and confusion particularly in paediatric medicine, as has been demonstrated by the analysis of a recent survey of the definition of hypoglycaemia in newborn babies. Thirty-six text books of paediatrics and the replies to questionnaires sent to 242 paediatricians in charge of neonatal intensive care cots in the United Kingdom were analysed (Koh et al, 1988a). This survey showed that there was no universally accepted definition of hypoglycaemia, with suggested blood glucose concentrations ranging from less than 1 mmol/1 to less than 4 mmol/1. There was also a trend to define Tower blood glucose values in small-for-dates and preterm infants than in those born at term (Figure 1). Blood glucose estimations may be affected by the clinical circumstances in which the blood was sampled, the site of blood sampling, the fraction used for analysis and the duration of fasting before the blood was obtained. Thus, blood glucose values in venous blood are approximately 10% below those in capillary or arterial blood, and because the glucose concentration is relatively lower within red blood cells, glucose concentrations in whole blood are approximately 15% below those in plasma or serum. Blood glucose values in normal young children decrease significantly during fasting, with glucose values conforming to a Gaussian pattern of distribution (Chaussain, 1973), which is in contrast to adults, who rarely become hypoglycaemic even during prolonged starvation. Finally, blood glucose concentrations may also be affected by the method of collection and analysis. Hypoglycaemia may be defined in four ways, though all these approaches to the definition of hypoglycaemia have their limitations. (1) Hypoglycaemia may be defined statistically (for example, all subjects with values below the fifth centile derived from normative data obtained under predefined circumstances). However, blood glucose values below or above a 'fifth centile' are not always associated with the presence or absence of neuroglycopenic symptoms. (2) A functional definition relates hypoglycaemia to evidence of concurrent physiological counterregulatory hormone (e.g. glucagon, adrenaline, growth hormone and cortisol) responses or to evidence of neurological 587 Copyright © 1993, by Bailli~re Tindall All rights of reproduction in any form reserved
Bailli~re' s Clinical Endocrinology and Metabolism--
Vol. 7, No. 3, July 1993 ISBN 0-7020-1700-0
588
J.W. GREGORYAND A. AYNSLEY-GREEN 70~
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Blood glucose concentration (mmol/I)
Figure 1. Analysis of questionnaires sent to 242 paediatricians in the UK concerning their perception of the definition of neonatal hypoglycaemia in (a) full-term, appropriate-forgestational-age infants and (b) preterm and small-for-gestational-ageinfants. The horizontal axis represents the blood glucosevalues identifiedby medicalstaff to indicate hypoglycaemia. The solidpart of each histogram represents the responsesfrom consultantsin charge of regional referral units (Koh et al, 1988a). dysfunction. In neither case will the patient necessarily be symptomatic. There are, however, either very limited (Hawdon et al, 1992) or conflicting (Amiel et al, 1987, 1988; Mitrakou et al, 1991) data on the counterregulatory h o r m o n e responses to specific blood glucose levels in different groups of subjects (e.g. strict glycaemic control in subjects with insulin-dependent diabetes mellitus lowers the blood glucose level at which counterregulatory hormone release occurs (Amiel et al, 1988)). However, abnormal electrophysiological studies are more closely associated with the presence of blood sugar values less than 2.6 mmol/1 than the occurrence of overt symptoms (Koh et al, 1988b). (3) A symptomatic definition of hypoglycaemia depends on the presence of symptoms due to either the autonomic responses caused by hypoglycaemia or the consequences of neurological dysfunction secondary to the effects of neuroglycopenia. The presence or absence of neurological symptoms, especially in neonates, is not a good discriminatory predictor of blood glucose concentration (Koh et al, 1988b). (4) Finally, hypoglycaemia may be defined in relation to the frequency of
THE DEFINITION OF HYPOGLYCAEMIA
589
adverse long-term neurodevelopmental sequelae in the context of previous experiences of hypoglycaemia (Lucas et al, 1988). The predictive value of the neurodevelopmental tests performed at 18 months in children who have previously experienced hypoglycaemia in infancy is not, however, well established, nor is the capacity for such subjects to demonstrate catch-up development thereafter (Lucas et al, 1988). In neonates, a range of values, dependent on the gestation and postnatal age of the infant have previously been used to describe and define hypoglycaemia (Cornblath and Reisner, 1965; Chance and Bower, 1966; Lubchenco and Bard, 1971; Fluge, 1974; Sexson, 1984; Srinivasan et al, 1986; Heck and Erenberg, 1987). In term infants, Cornblath and Schwartz (1991) have suggested the definition of hypoglycaemia in the first 24 h at a value of 2.22mmol/1, increasing to a value of 2.78 mmol/1 after this age. Neurophysiological studies at the time of hypoglycaemia (Koh et al, 1988b) and studies based on retrospective outcome analysis (Lucas et al, 1988) have both suggested that the definition of hypoglycaemia be at a blood glucose value of 2.6 mmol/1 or less. Above this value, adverse neurophysiological consequences seem unlikely. In practical terms, a blood glucose of 2.6 mmol/1 is the value used by our unit in children of all ages to define hypoglycaemia and at which investigations as to its cause are considered. However, it is important to recognize that while guidelines are important for clinical management, rigid definitions are inadequate and should be avoided; for example, it is not necessarily recommended that all asymptomatic term infants with a blood glucose value below 2.6 mmol/1 require therapy, as there is clear evidence that many of them can produce alternative fuels (e.g. ketone bodies) for cerebral metabolism (Hawdon et al, 1992). Furthermore, there is clear evidence from studies in healthy adults that there is a distinct hierarchy of responses to decreasing plasma glucose (Mitrakou et al, 1991). The threshold for counterregulatory hormone secretion occurs at a higher level than that for the initiation of autonomic warning symptoms, which in turn occur at higher plasma glucose levels than those that are associated with the onset of acute neuroglycopenic symptoms and deteriorating cerebral function (Mitrakou et al, 1991). In adults, there has also been controversy over the definition of hypoglycaemia. Some authors have suggested that significant hypoglycaemia be defined at plasma glucose values less than 2.22 mmol/1 in adults under the age of 60 years and below 2.78 mmol/1 in those aged over 60 years (Marks, 1976). Others have defined hypoglycaemia at plasma glucose levels below 2.78 mmol/1 at all ages (Marks and Rose, 1981; Service, 1983; Field, 1989). It is, however, clearly important that the circumstances in which hypoglycaemia is being assessed are defined (e.g. in relation to fasting or feeding). It has been suggested that after a 72-h fast, normal plasma glucose values should not fall below 2.5 mmol/1 in men, though in normal women the plasma glucose concentration has been observed to fall below 2.0retool/1 (Merimee and Tyson, 1974; Ross, 1992). However, in the majority of both male and female patients with insulin-secreting tumours, values less than
590
J.w.
GREGORY AND A. AYNSLEY-GREEN
2.2 m m o l / 1 w i l l b e s e e n a f t e r o n l y 2 4 - 3 6 h o f f a s t i n g w h e n s u c h i n d i v i d u a l s u n d e r t a k e m o d e r a t e e x e r c i s e ( F r e r i c h s a n d C r e u t z f e l d t , 1976).
REFERENCES
Amiel SA, Simonson DC, Tamborlane WV et al (1987) Rate of glucose fall does not affect counterregulatory hormone responses to hypoglycemia in normal and diabetic humans. Diabetes 36: 518-522. Amiel SA, Sherwin RS, Simonson DC & Tamborlane WV (1988) Effect of intensive insulin therapy on glycemic thresholds for counterregulatory hormone release. Diabetes 37: 901-907. Chance GW & Bower BD (1966) Hypoglycaemia and temporary hyperglycaemia in infants of low birth weight for maturity. Archives of Disease in Childhood 41: 279-285. Chaussain JL (1973) Glycemic response to 24 hour fast in normal children and children with ketotic hypoglycemia. Journal of Pediatrics 82: 438-443. Cornblath M & Reisner SH (1965) Blood glucose in the neonate and its clinical significance. New England Journal of Medicine 273: 378-381. Cornblath M & Schwartz R (1991) Disorders of Carbohydrate Metabolism in Infancy, 416pp. Cambridge: Blackwell Scientific Publications. Field JB (1989) Hypoglycemia: definition, clinical presentations, classification, and laboratory tests. Endocrinology and Metabolism Clinics of North America 18: 27-43. Fluge G (1974) Clinical aspects of neonatal hypoglycaemia. Acta Paediatrica Scandinavica 63: 826-832. Frerichs H & Creutzfeldt W (1976) Hypoglycaemia. 1. Insulin secreting tumours. Bailli~re's Clinical Endocrinology and Metabolism 5: 747-767. Hawdon JM, Ward Platt MP & Aynsley-Green A (1992) Patterns of metabolic adaptation for preterm and term infants in the first neonatal week. Archives of Disease in Childhood 67: 357-365. Heck LJ & Erenberg A (1987) Serum glucose levels in term neonates during the first 48 hours of life. Journal of Pediatrics 110: 119-122. Koh THHG, Eyre JA & Aynsley-Green A (1988a) Neonatal hypoglycaemia--the controversy regarding definition. Archives of Disease in Childhood 63: 1386-1388. Koh THHG, Aynsley-Green A, Tarbit M & Eyre JA (1988b) Neural dysfunction during hypoglycaemia. Archives of Disease in Childhood 63: 1353-1358. Lubchenco LO & Bard H (1971) Incidence of hypoglycemia in newborn infants classified by birth weight and gestational age. Pediatrics 47: 831-838. Lucas A, Morley R & Cole TJ (1988) Adverse neurodevelopmental outcome of moderate neonatal hypoglycaemia. British Medical Journal 297: 1304--1308. Marks V (1976) The measurement of blood glucose and the definition of hypoglycemia. In Hypoglycemia: Proceedings of the Rome Symposium, p 1. Stuttgart: Georg Thieme Verlag. Marks V & Rose FC (1981) Hypoglycaemia, p 51. Oxford: Blackwell Scientific Publications. Merimee TJ & Tyson JE (1974) Stabilization of plasma glucose during fasting. New England Journal of Medicine 291: 1275-1278. Mitrakou A, Ryan C, Veneman T et al (1991) Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. American Journal of Physiology 260 (Endocrinol. Metab. 23): E67-E74. Ross RJM (1992) Protocols for common endocrine tests. In Grossman A (ed.) Clinical Endocrinology, pp 1015-1032. Oxford: Blackwell Scientific Publications. Service FJ (1983) Hypoglycemic Disorders. Boston: GK Hall Medical Publishers. Sexson WR (1984) Incidence of neonatal hypoglycemia: a matter of definition. Journal of Pediatrics 105: 149-150. Srinivasan G, Pildes RS, Cattamanchi G e t al (1986) Plasma glucose values in normal neonates: a new look. Journal of Pediatrics 109: 114--117.
A. AYNSLEY-GREEN
There are difficulties in defining hypoglycaemia, which have led to much controversy and confusion particularly in paediatric medicine, as has been demonstrated by the analysis of a recent survey of the definition of hypoglycaemia in newborn babies. Thirty-six text books of paediatrics and the replies to questionnaires sent to 242 paediatricians in charge of neonatal intensive care cots in the United Kingdom were analysed (Koh et al, 1988a). This survey showed that there was no universally accepted definition of hypoglycaemia, with suggested blood glucose concentrations ranging from less than 1 mmol/1 to less than 4 mmol/1. There was also a trend to define Tower blood glucose values in small-for-dates and preterm infants than in those born at term (Figure 1). Blood glucose estimations may be affected by the clinical circumstances in which the blood was sampled, the site of blood sampling, the fraction used for analysis and the duration of fasting before the blood was obtained. Thus, blood glucose values in venous blood are approximately 10% below those in capillary or arterial blood, and because the glucose concentration is relatively lower within red blood cells, glucose concentrations in whole blood are approximately 15% below those in plasma or serum. Blood glucose values in normal young children decrease significantly during fasting, with glucose values conforming to a Gaussian pattern of distribution (Chaussain, 1973), which is in contrast to adults, who rarely become hypoglycaemic even during prolonged starvation. Finally, blood glucose concentrations may also be affected by the method of collection and analysis. Hypoglycaemia may be defined in four ways, though all these approaches to the definition of hypoglycaemia have their limitations. (1) Hypoglycaemia may be defined statistically (for example, all subjects with values below the fifth centile derived from normative data obtained under predefined circumstances). However, blood glucose values below or above a 'fifth centile' are not always associated with the presence or absence of neuroglycopenic symptoms. (2) A functional definition relates hypoglycaemia to evidence of concurrent physiological counterregulatory hormone (e.g. glucagon, adrenaline, growth hormone and cortisol) responses or to evidence of neurological 587 Copyright © 1993, by Bailli~re Tindall All rights of reproduction in any form reserved
Bailli~re' s Clinical Endocrinology and Metabolism--
Vol. 7, No. 3, July 1993 ISBN 0-7020-1700-0
588
J.W. GREGORYAND A. AYNSLEY-GREEN 70~
e-
(a)
7Or-
60
60
5O
50
(b)
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Blood glucose concentration (mmol/I)
Figure 1. Analysis of questionnaires sent to 242 paediatricians in the UK concerning their perception of the definition of neonatal hypoglycaemia in (a) full-term, appropriate-forgestational-age infants and (b) preterm and small-for-gestational-ageinfants. The horizontal axis represents the blood glucosevalues identifiedby medicalstaff to indicate hypoglycaemia. The solidpart of each histogram represents the responsesfrom consultantsin charge of regional referral units (Koh et al, 1988a). dysfunction. In neither case will the patient necessarily be symptomatic. There are, however, either very limited (Hawdon et al, 1992) or conflicting (Amiel et al, 1987, 1988; Mitrakou et al, 1991) data on the counterregulatory h o r m o n e responses to specific blood glucose levels in different groups of subjects (e.g. strict glycaemic control in subjects with insulin-dependent diabetes mellitus lowers the blood glucose level at which counterregulatory hormone release occurs (Amiel et al, 1988)). However, abnormal electrophysiological studies are more closely associated with the presence of blood sugar values less than 2.6 mmol/1 than the occurrence of overt symptoms (Koh et al, 1988b). (3) A symptomatic definition of hypoglycaemia depends on the presence of symptoms due to either the autonomic responses caused by hypoglycaemia or the consequences of neurological dysfunction secondary to the effects of neuroglycopenia. The presence or absence of neurological symptoms, especially in neonates, is not a good discriminatory predictor of blood glucose concentration (Koh et al, 1988b). (4) Finally, hypoglycaemia may be defined in relation to the frequency of
THE DEFINITION OF HYPOGLYCAEMIA
589
adverse long-term neurodevelopmental sequelae in the context of previous experiences of hypoglycaemia (Lucas et al, 1988). The predictive value of the neurodevelopmental tests performed at 18 months in children who have previously experienced hypoglycaemia in infancy is not, however, well established, nor is the capacity for such subjects to demonstrate catch-up development thereafter (Lucas et al, 1988). In neonates, a range of values, dependent on the gestation and postnatal age of the infant have previously been used to describe and define hypoglycaemia (Cornblath and Reisner, 1965; Chance and Bower, 1966; Lubchenco and Bard, 1971; Fluge, 1974; Sexson, 1984; Srinivasan et al, 1986; Heck and Erenberg, 1987). In term infants, Cornblath and Schwartz (1991) have suggested the definition of hypoglycaemia in the first 24 h at a value of 2.22mmol/1, increasing to a value of 2.78 mmol/1 after this age. Neurophysiological studies at the time of hypoglycaemia (Koh et al, 1988b) and studies based on retrospective outcome analysis (Lucas et al, 1988) have both suggested that the definition of hypoglycaemia be at a blood glucose value of 2.6 mmol/1 or less. Above this value, adverse neurophysiological consequences seem unlikely. In practical terms, a blood glucose of 2.6 mmol/1 is the value used by our unit in children of all ages to define hypoglycaemia and at which investigations as to its cause are considered. However, it is important to recognize that while guidelines are important for clinical management, rigid definitions are inadequate and should be avoided; for example, it is not necessarily recommended that all asymptomatic term infants with a blood glucose value below 2.6 mmol/1 require therapy, as there is clear evidence that many of them can produce alternative fuels (e.g. ketone bodies) for cerebral metabolism (Hawdon et al, 1992). Furthermore, there is clear evidence from studies in healthy adults that there is a distinct hierarchy of responses to decreasing plasma glucose (Mitrakou et al, 1991). The threshold for counterregulatory hormone secretion occurs at a higher level than that for the initiation of autonomic warning symptoms, which in turn occur at higher plasma glucose levels than those that are associated with the onset of acute neuroglycopenic symptoms and deteriorating cerebral function (Mitrakou et al, 1991). In adults, there has also been controversy over the definition of hypoglycaemia. Some authors have suggested that significant hypoglycaemia be defined at plasma glucose values less than 2.22 mmol/1 in adults under the age of 60 years and below 2.78 mmol/1 in those aged over 60 years (Marks, 1976). Others have defined hypoglycaemia at plasma glucose levels below 2.78 mmol/1 at all ages (Marks and Rose, 1981; Service, 1983; Field, 1989). It is, however, clearly important that the circumstances in which hypoglycaemia is being assessed are defined (e.g. in relation to fasting or feeding). It has been suggested that after a 72-h fast, normal plasma glucose values should not fall below 2.5 mmol/1 in men, though in normal women the plasma glucose concentration has been observed to fall below 2.0retool/1 (Merimee and Tyson, 1974; Ross, 1992). However, in the majority of both male and female patients with insulin-secreting tumours, values less than
590
J.w.
GREGORY AND A. AYNSLEY-GREEN
2.2 m m o l / 1 w i l l b e s e e n a f t e r o n l y 2 4 - 3 6 h o f f a s t i n g w h e n s u c h i n d i v i d u a l s u n d e r t a k e m o d e r a t e e x e r c i s e ( F r e r i c h s a n d C r e u t z f e l d t , 1976).
REFERENCES
Amiel SA, Simonson DC, Tamborlane WV et al (1987) Rate of glucose fall does not affect counterregulatory hormone responses to hypoglycemia in normal and diabetic humans. Diabetes 36: 518-522. Amiel SA, Sherwin RS, Simonson DC & Tamborlane WV (1988) Effect of intensive insulin therapy on glycemic thresholds for counterregulatory hormone release. Diabetes 37: 901-907. Chance GW & Bower BD (1966) Hypoglycaemia and temporary hyperglycaemia in infants of low birth weight for maturity. Archives of Disease in Childhood 41: 279-285. Chaussain JL (1973) Glycemic response to 24 hour fast in normal children and children with ketotic hypoglycemia. Journal of Pediatrics 82: 438-443. Cornblath M & Reisner SH (1965) Blood glucose in the neonate and its clinical significance. New England Journal of Medicine 273: 378-381. Cornblath M & Schwartz R (1991) Disorders of Carbohydrate Metabolism in Infancy, 416pp. Cambridge: Blackwell Scientific Publications. Field JB (1989) Hypoglycemia: definition, clinical presentations, classification, and laboratory tests. Endocrinology and Metabolism Clinics of North America 18: 27-43. Fluge G (1974) Clinical aspects of neonatal hypoglycaemia. Acta Paediatrica Scandinavica 63: 826-832. Frerichs H & Creutzfeldt W (1976) Hypoglycaemia. 1. Insulin secreting tumours. Bailli~re's Clinical Endocrinology and Metabolism 5: 747-767. Hawdon JM, Ward Platt MP & Aynsley-Green A (1992) Patterns of metabolic adaptation for preterm and term infants in the first neonatal week. Archives of Disease in Childhood 67: 357-365. Heck LJ & Erenberg A (1987) Serum glucose levels in term neonates during the first 48 hours of life. Journal of Pediatrics 110: 119-122. Koh THHG, Eyre JA & Aynsley-Green A (1988a) Neonatal hypoglycaemia--the controversy regarding definition. Archives of Disease in Childhood 63: 1386-1388. Koh THHG, Aynsley-Green A, Tarbit M & Eyre JA (1988b) Neural dysfunction during hypoglycaemia. Archives of Disease in Childhood 63: 1353-1358. Lubchenco LO & Bard H (1971) Incidence of hypoglycemia in newborn infants classified by birth weight and gestational age. Pediatrics 47: 831-838. Lucas A, Morley R & Cole TJ (1988) Adverse neurodevelopmental outcome of moderate neonatal hypoglycaemia. British Medical Journal 297: 1304--1308. Marks V (1976) The measurement of blood glucose and the definition of hypoglycemia. In Hypoglycemia: Proceedings of the Rome Symposium, p 1. Stuttgart: Georg Thieme Verlag. Marks V & Rose FC (1981) Hypoglycaemia, p 51. Oxford: Blackwell Scientific Publications. Merimee TJ & Tyson JE (1974) Stabilization of plasma glucose during fasting. New England Journal of Medicine 291: 1275-1278. Mitrakou A, Ryan C, Veneman T et al (1991) Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. American Journal of Physiology 260 (Endocrinol. Metab. 23): E67-E74. Ross RJM (1992) Protocols for common endocrine tests. In Grossman A (ed.) Clinical Endocrinology, pp 1015-1032. Oxford: Blackwell Scientific Publications. Service FJ (1983) Hypoglycemic Disorders. Boston: GK Hall Medical Publishers. Sexson WR (1984) Incidence of neonatal hypoglycemia: a matter of definition. Journal of Pediatrics 105: 149-150. Srinivasan G, Pildes RS, Cattamanchi G e t al (1986) Plasma glucose values in normal neonates: a new look. Journal of Pediatrics 109: 114--117.