Chapter 12: Hypoglycemia
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11/1/2017 at 12:24:15 PM GMT
Posts: 40
Chapter 12: Hypoglycemia

Dear ISPAD member/friend,

The 2014 ISPAD Clinical Practice Consensus Guidelines were much appreciated. We are happy to announce that preparations for the 2018 Guidelines are now well underway and that the first draft chapter is now ready for your comments and input. We look forward to hearing your thoughts and ideas on the Hypoglycemia chapter here below!

Kind regards,

David Maahs
ISPAD Secretary General

 Attached Files: 

Last edited Tuesday, February 20, 2018
11/6/2017 at 1:36:47 PM GMT
Posts: 5
Thank you, very nice chapter!
A few aspects:
1.Please use mmol/mol as a HbA1c value as well.
2.The spelling of "analogs" or "analogues" should be consequent in the paper.
3.Reference 15 lacks authors.
4.To me it locks strange to write 2.15 hours (p17) - we usually do not think we divide an hour into centesimals?
Best wishes, gun forsander

11/8/2017 at 1:37:19 PM GMT
Posts: 1
Dear colleagues,
Thank you, nice piece of work!
just a few comments/suggestions:

**p4** Treatment of hypoglycemia should increase the blood glucose by nearly 3 to 4 mmol/L (54 to 70 mg/dL). This can be accomplished by giving glucose tablets or sweetened fluids.
Approximately 9 grams of glucose is needed for a 30 kg child and 15 grams for a 50 kg
child (approximately 0.3 g/kg).(C) --> comment: (1) any need to distinguish hypo-treatment in CSII vs MDI? (2) should a maximal glucose intake be advised in order to prevent reactive hyperglyc?

** p4** Blood glucose monitoring should be performed prior to exercise, and extra carbohydrates
should be consumed based on the blood glucose level and the expected intensity and
duration of exercise (B). --> comment: please also mention insulin dose reduction prior to sports

Suggestion to add a paragraph (or refer to the specific ISPAD chapter) on technical issues in the measurement of hypo by glucose meters, sensors, FSL etc: what are common pitfalls, how about reliability and precision of the different systems in the hypo-region.

Sincely, Dick Mul,

12/2/2017 at 4:13:04 AM GMT
Posts: 1
Nice update and very important chapter,

As a Pediatrician/physician from LIC, I have following comments/curiosity.

1. As Dr. Mul mentioned, the maximum dose of ? anhydrous glucose (0.3 gm/kg) is better to be mentioned.
2. I have seen my colleagues using NG tube in severe hypogycemia to administer glucose when IV access is difficult, especially in remote places. And i have heard that some of the health personnel are using IV dextrose(5%/10%) via NG tube when IV access is not available. Is it justified??. I think ,this should be clearly mentioned in recommendation whether to use or not.
3. We don't have glucagon, glucose tablet or gel available in our country. we have only anhydrous glucose packet and IV dextrose available in our market. So, itz better to mention the NG route as well coz sometym itz difficult for IV access, especially in remote health care facilities.
4. Evidence regarding repeat dose of glucagon in persistent hypoglycemia and its use in malnourished child with diabetes.
Best wishes

Dr. Dipak Muktan

Dr. Dipak Muktan,
Pediatrician, Nepal

12/2/2017 at 9:46:17 AM GMT
Posts: 2
hypothyroidism as co morbidity in hypoglycemia

Very nice  & updated review for hypos in  diabetic children .

My comments to add hypothyroidism as co morbidity in hypoglycemia in these children 

I saw few cases of severe hypoglycemia  in diabetic children & adolescents  ,associated with hypothyroidism .



Dr Majida Noori

Pediatric Endocrinologist 


12/14/2017 at 7:52:12 PM GMT
Posts: 1
Thanks for a great updated chapter!
A couple of minor comments:
- To adapt to more politically correct language, I suggest replacing "developed countries" (page 10) with "high-income countries" and "developing countries" (p. 26) with "low- and middle income countries", or probably even better, with "resource-limited settings".
- Following up on Dr. Muktan's comment, I think it would be great to include alternatives for hypoglycemia treatment including glucagon alternatives for settings where this is not available.
1. Alternatives for hypoglycemia treatment where child is conscious include locally available hard candies, table sugar (1 tsp = 4g), sugar cane (1/3 stick = ~15g), sugar cane juice (4oz = ~15g), any other locally produced juice, ripe mango (1/2 small mango = ~15g),
2. For severe hypoglycemia if glucagon or a nearby health care facility are not available, regular table sugar can be "crushed" to make powdered sugar which, if mixed with a bit of water can be made into a paste (similar to thick cake icing) that can be applied to the child's gums (similar to glucose gel). 1 unsifted tbsp of powdered sugar corresponds to 8g of glucose
3. NG tube can be inserted and D10-50% given per NG


12/17/2017 at 10:36:26 PM GMT
Posts: 6
Dear David- thanks for this and congratulations on the chapter.

I have a couple of queries-

1) In the text it says that “Acute hypoglycaemia has been attributed in 4-10% of deaths in a population-based cohorts and international registries”. The supporting reference is that of Seaquist et al. The Seaquist et al paper is simply a report of a consensus statement and does not supply primary data. Instead the Seaquist et al paper cites the following primary sources:

Patterson CC, Dahlquist G, Harjutsalo V, et al . Early mortality in EURODIAB population-based cohorts of type 1 diabetes diagnosed in childhood since 1989. Diabetologia 2007;50:2439–2442
141 deaths in 219,061 person-years of follow-up from 1989 to 2005. 73 deaths occurred prior to 2003. Of the 141 deaths there was data on 134. Of the 134 deaths, 47 were attributable to diabetes. Of the 47 deaths attributable to diabetes, 27 were said to be caused by DKA and 5 due to hypoglycaemia. No clarity as to how the ‘death due to hypoglycaemia’ statement was arrived at (the investigators did not review the case notes as far as I can tell). Putting this aside the 5/147 gives 3% incidence rate in a cohort that is arguably not at all representative of today’s clinical context of paediatric care.

Jacobson AM, Musen G, Ryan CM, et al.; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group. Long-term effect of diabetes and its treatment on cognitive function. N Engl J Med 2007;356:1842–1852
The focus of this paper is upon cognitive function and hypoglycaemia. In passing it mentions 53 deaths in the DCCT/EDIC study period of which 3 were attributable to hypoglycaemia (all 3 deaths occurred in the EDIC phase). There is no mention whether these 3 are adults or adolescents at the time of death but given it was during the EDIC phase it would appear likely they were adults. There is also no mention as to how the cause of death was ascertained. This was not a population based cohort.

Feltbower RG, Bodansky HJ, Patterson CC, et al . Acute complications and drug misuse are important causes of death for children and young adults with type 1 diabetes: results from the Yorkshire Register of Diabetes in Children and Young Adults. Diabetes Care 2008;31:922–926
This paper analysed all-cause mortality in all ages in West Yorkshire 1978-2004. Thirty two deaths (25 = male) were said to occur from acute diabetes complications and of these 8 deaths were said to be due to hypoglycaemia (no mention as to how this diagnosis was ascertained). It is not stated what ages these patients were but given the preponderance of males (25/32) and the lack of association between acute complications and gender during childhood, one could assume they were mostly adults.

Skrivarhaug T, Bangstad HJ, Stene LC, Sandvik L, Hanssen KF, Joner G. Long-term mortality in a nationwide cohort of childhood-onset type 1 diabetic patients in Norway. Diabetologia 2006;49:298–305.
This paper follows up patients from 1973 until the end of 2002. Causes of death were reviewed by a Clinic Review Committee. There was 1 cause of death attributable to hypoglycaemia in people aged < 19 years over the study period (out of a total number of 26 deaths in this age group).

In summary the data cited is inexact and inappropriate in terms of ages germaine to childhood/adolescence and the current therapeutic era.

Sorry to bang on about this but figures such as the ‘4-10% of deaths due to hypoglycaemia’ can have an enormous impact upon patients, parents and policy makers. For a start I was taught never to cite percentages when the ‘n’ is less than 100- it implies a greater gravitas to the data than it deserves. Inaccurate statements about risk of hypo-related death feed into the angst of parents who resist tightening up metabolic control.

I would think a more accurate statement would be “In the pre- and immediate post-DCCT period, acute hypoglycaemia was been associated with a handful of deaths in several population-based paediatric cohorts. Data from contemporary cohorts are lacking”. I wouldn’t cite the Jacobsen or the Seaquist paper but would cite the other 3 primary references.

2) Under the “dead in bed’ section.

“.. there is increasing evidence that a combination of severe nocturnal hypoglycaemia (42) and autonomic neuropathy can cause changes in cardiac repolarisation (43) and result in this devastating complication (43, 44).

Reference #42 is a well-known case report of a single patient. As far as I am aware this is the only published case report of an episode of hypoglycaemia associated with a diabetic death (in a non-suicide context). I’m not sure that n=1 amounts to ‘increasing evidence’

Reference #44 is a two page mini-review article. I’m not sure that it merits being cited in a consensus guidelines. Notwithstanding this caveat, the authors canvass the possibility that the finding that some forms of ‘more complete’ autonomic neuropathy associated with severe hypoglycaemia are less likely to result in QT changes (Lee et al Diabetes 2004; 53:1535-42). The review also goes on to state that the association between a history severe hypoglycaemia and prior to a dead in bed event is an epidemiologic finding. A history of severe hypoglycaemia is simply an epidemiologic risk factor equal to being male, Caucasian, higher HbA1C, overall glycaemic instability and lower BMI.

As I understand it there are currently three main theories about ‘dead in bed’ syndrome:

i) ? Hypoglycaemia causing a fatal heart arrhythmia
Subtle ECG changes with hypoglycaemia occur equally during the daytime and night-time (Novodvorsky et al epub Feb 17)
-> My comment: we see plenty of day-time hypoglycaemia so why don’t we see day-time arrhythmia?

ECG changes appear to be greater if hypoglycaemia is induced in a clamp study compared to real world ambulant conditions (Christensen et al J Diabet Complic 2014; 28:723-8)
-> My comment: the clamp data (cited in reference #43 and elsewhere) probably over-estimates the actual link between hypoglycaemia and arrhythmia.

At best I think it only fair to say that the potential mechanistic link between a hypoglycaemic episode and a fatal arrhythmia remains unclear.

ii) ? Autonomic neuropathy leading to arrhythmic death.
Recent meta-analysis found enormous variability in published incidence rates of autonomic neuropathy in kids (Tang et al Pediatr Diabetes 2013; 14:239-48)
->My comment: This does not explain why most dead-in-bed episodes occur in younger (not older) adults, who have greater rates of autonomic neuropathy.

iii) ? Hypoglycaemia leading to a seizure and hypoxia
Classically no sign of any disturbance in DIB cases

There is a recent mini-review paper published on International Hypoglycemia study Group website: by Phillip Cryer and Simon Heller.

I guess the 7th paragraph of this paper says it all for me- the confusion between ‘association’ vs ‘causation’ and that if one is to attempt to extrapolate from associative data to a potential causative process there has to be a plausible biological mechanistic link. The references I cited above show that the biologic studies linking arrhythmias to hypoglycaemia as a potential biologic link are far from clear cut. It is pretty clear still that the data between hypoglycaemia and death is overwhelmingly just associative and originates mostly from the adult T2D literature. Cryer and Heller cite the review by Goto et al (their ref #23) as the strongest support for a causal link. In the context of T1D in youth the Goto et al review is not helpful as a) the review is of T2D in adults and b) in the review the major cause of cardiovascular death are infarctions, coronary vascular disease and congestive cardiac failure, not arrhythmias. Given that the ISPAD guidelines are around T1D in youth and that nobody has found myocardial infarcts/CCF as a cause of sudden death in youth, I can’t see that Goto et al review is relevant or that the case for a causative link is any stronger.

Apologies for being perhaps overly pedantic, but the guidelines will be an important reference document and read by many. It is important that where the evidence is robust it is acknowledged and where the evidence is speculative/associative at best, this too is acknowledged. For all of the reasons above I feel that the evidence suggesting that severe hypoglycaemia causes dead in bed is debatable and that this should be acknowledged. I do not think that there is ‘increasing evidence”.



12/17/2017 at 11:06:25 PM GMT
Posts: 40
Dear Fergus and all,

Thank you very much for your feedback and comments! We welcome more to make these the best guidelines possible.

The chapter authors and editors will work to incorporate responses to all comments for the final drafts.

Please stay tuned for additional chapters to be posted.


1/13/2018 at 1:58:17 AM GMT
Posts: 3
Prevent hypoglycemia before driving
It is a comprehensive work. I have a request for adding a paragraph of " prevent hypoglycemia before driving " which should be educated and emphasized to patients. Thanks for hard work. S. Likitmaskul

1/24/2018 at 10:42:40 AM GMT
Posts: 7
Thank you for these new guidelines, which read very well. I have a few comments:

P. 2: Severe hypoglycemic coma is defined as a subgroup of severe hypoglycemia, as an event associated with loss of consciousness with or without seizures.

p. 4, bullet #2: “Do not routinely follow rapid acting glucose by additional carbohydrates as this often causes rebound hyperglycemia. However, in some cases (ie continued exercise, too high insulin dose), this may be necessary to prevent recurrence of hypoglycemia.

Bullet #3: Blood glucose will increase by approximately 3 to 4 mmol/L (54 to 70 mg/dL) 10-15 min. after giving 0.3 g/kg of glucose (approximately 9 grams of glucose is needed for a 30 kg child and 15 grams for a 50 kg child). The treatment of hypoglycemia should increase the blood glucose to be safely above 4.0 mmol/l (70 mg/dl). A common mistake is to give more (ie eat until symptom relief occurs), which will contribute to a “roller coaster” glucose pattern.

p. 25, glucagon dose: 0.1 and 0.2 mg/kg has been shown to be effective (Aman J, Wranne L. Hypoglycaemia in childhood diabetes. II. Effect of subcutaneous or intramuscular injection of different doses of glucagon. Acta Paediatr Scand 1988;77:548-53.)

I am missing text specifically on hypoglycemic seizures.
Hypoglycemic seizure activity during childhood may be a risk factor for later cognitive impairment in children with diabetes (1). Although older studies do not show an increased prevalence of epilepsy and diabetes (2, 3), newer find a two- to six-fold increase (4, 5). Children with diabetes may be more prone to euglycemic seizures (2), although this has not been systematically evaluated. However, antiepileptic drugs may prevent seizures (5), also during hypoglycemia (2). Antiepileptic drug treatment has been associated with a reduced number of severe hypoglycemic events (3). Some (many?) centers recommend antiepileptic treatment if a child has had repeated hypoglycemic seizures. A subgroup seem to have seizures at modest hypoglycemia levels of 2-3 mmol/l, and respond well to antiepileptic therapy, ie can treat hypoglycemia without having a seizure and without progressing to severe hypoglycemia.
1.    Kaufman FR, Epport K, Engilman R, Halvorson M. Neurocognitive functioning in children diagnosed with diabetes before age 10 years. J Diabetes Complications. 1999; 13:31-8.
2.    O'Connell MA, Harvey AS, Mackay MT, Cameron FJ. Does epilepsy occur more frequently in children with Type 1 diabetes? Journal of paediatrics and child health. 2008; 44:586-9.
3.    Schober E, Otto KP, Dost A, Jorch N, Holl R, German/Austrian DPVI, et al. Association of epilepsy and type 1 diabetes mellitus in children and adolescents: is there an increased risk for diabetic ketoacidosis? J Pediatr. 2012; 160:662-6 e1.
4.    Fazeli Farsani S, Souverein PC, van der Vorst MM, Knibbe CA, de Boer A, Mantel-Teeuwisse AK. Chronic comorbidities in children with type 1 diabetes: a population-based cohort study. Arch Dis Child. 2015; 100:763-8.
5.    Ramakrishnan R, Appleton R. Study of prevalence of epilepsy in children with type 1 diabetes mellitus. Seizure. 2012; 21:292-4.

Last edited Wednesday, January 24, 2018

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