Very immature babies often become hyperglycemic during the first few days of life. How to respond (or prevent) this has been uncertain.
One problem in deciding on the best course of action is the multiple possible approaches that need to be compared:
One could: ignore the problem and do nothing directly to the blood sugar; reduce glucose intake; switch the calorie intake to another form; start insulin to prevent the most severe hyperglycemia, with various possible thresholds; or start insulin and aim for a normal blood sugar.
There is no standard approach, but I think that ignoring it isn’t an option, some babies become very severely hyperglycemic and as a result severely hyperosmolar, they occasionally develop osmotic diuresis. However, at what threshold you need to address the issue is quite unclear. Many of us start to react when the blood sugar is significantly elevated, in order to avoid either reducing the calorie intake too much or the risks of hypoglycemia if we start insulin.
Is this the right approach? We really don’t have a good answer in the preterm newborn. Even in adults where there are a number of important studies, the response is not exactly clear. A series of controlled studies from Leuven seemed to show a survival advantage of adults treated aggressively to achieve normoglycemia. This was followed by a pivotal multi-center trial (using a somewhat different protocol) that showed a survival disadvantage to aggressive maintenance of normoglycemia Nearly a 3% excess in mortality in the intervention group. And a few other trials also showing either no effect or a survival disadvantage.
So we come to one of the publications that have triggered this posting, a secondary analysis of that pivotal study, showing that hypoglycemia is a major risk factor for mortality . The NICE-SUGAR Study Investigators. Hypoglycemia and Risk of Death in Critically Ill Patients. New England Journal of Medicine 2012, 367(12):1108-1118. (Risk factor meaning, as usual, a characteristic which is significantly associated with the adverse outcome, not necessarily the cause of the adverse outcome.) This analysis showed that the increased risk of death with hypoglycemia occurred in both groups in the study (in fact the hazard ratio for death was greater in the controls than the insulin group). There is a nice review article accompanying the publication.
One of the other publications that interested me recently was the publication of a standard protocol for insulin therapy in pediatric patients (Chima RS, Schoettker PJ, Varadarajan KR, Kloppenborg E, Hutson TK, Brilli RJ, Repaske DR, Seid M: Reduction in hypoglycemic events in critically ill patients on continuous insulin following implementation of a treatment guideline. Quality management in health care 2012, 21(1):20-28). This before and after study showed much less hypoglycemia when a standard pre-printed protocol was introduced than in the historical controls. (3% compared to 36%).
The final recent paper that this post will refer to is the very well done small trial (n=88) by Jane Alsweiler and Colleagues in Auckland, New Zealand Alsweiler JM, Harding JE, Bloomfield FH: Tight Glycemic Control With Insulin in Hyperglycemic Preterm Babies: A Randomized Controlled Trial. Pediatrics 2012. They randomized very preterm infants of less than 1500 grams birth weight who became hyperglycemic (2 blood sugars more than 8.5 (that’s in modern units: millimoles per litre, for the americans)) to a target blood sugar of 4 to 6 or a target of 8 to 10, the ‘control group’ who were only treated with insulin if they met all of the following criteria: sugar > 10 mmol/L or persistent glycosuria >2+; tolerating <100 kcal/kg per day; >72 hours. 64% of the controls received insulin. So this is really an RCT comparing early to late insulin, and in the control group the authors were trying to get up to 100 kcal despite hyperglycemia, using insulin if they couldn’t get up to 100 kcal and have a blood sugar less than 10. The results showed more hypoglycemic episodes in the tight control group (more than 1/2 had at least one sugar below 2.6) than the controls (but 1/4 the controls still had hypoglycemia), the other differences between the groups were a greater growth in weight and head circumference in the tight control group, and a greater linear growth in the controls.
If I try to put this in the context of other literature (which is one big reason I write this blog) there are several other trials that have looked at blood sugar management in the preterm. The unsinkable Jack Sinclair (who is supposed to be retired, but you wouldn’t know it from his production of Cochrane Reviews) has co-authored 2 systematic reviews, one of prevention of hyperglycemia, the other of treatment. As for prevention of hypoglycemia, the only studies of insulin therapy appear to be the 2 trials of low dose routine insulin infusion accompanied by 20% glucose by Kathryn Beardsall (the first being a small pilot trial, the 2nd including nearly 200 babies per group). In neither of those studies was there a clinical benefit found, and there was much more hypoglycemia in the intervention group. The other studies are not very informative for clinically important outcomes.
As for the trials investigating how to treat hyperglycemia, Collins and co-workers compared giving insulin to not doing so, and Meetze compared giving insulin to reducing the glucose intake. Both small trials showed short term advantages of giving insulin, in terms of energy balance, growth, and in one trial reduced infections. Overall survival advantages or other clinically important outcomes are not available from these small studies.
So what makes most sense, given a lack of good evidence about clinically important outcomes? It doesn’t seem that ignoring the sugars is appropriate, infants with very high sugars will be hyperosmolar which opens the blood brain barrier to bilirubin and is a reported risk factor for intra-ventricular haemorrhage. In addition they lose many of their precious calories in the urine. We can reduce the chances of hyperglycemia a little by giving less sugar, but very preterm babies will still become hyperglycemic, and in addition will be less well nourished. If we give more lipid, starting earlier in life we can probably reduce the adverse effects of giving too little calories, but exceeding the basic metabolic requirements (between 70 to 80 kcal/kg/day) as fast as possible is appropriate and an aim to reach 100 calories/kg/day needed for growth is also reasonable. As we do this many very preterm infants will become hyperglycemic, over 6, and many will become very hyperglycemic, over 10. However, trying to prevent this with routine insulin therapy is risky and has not been shown to improve any outcomes.
Treating infants who have become very hyperglycemic with insulin rather than reducing their calorie intake seems to be generally well tolerated, and has growth benefits. Trying to reduce the glucose to normal with insulin is risky in terms of hypoglycemia, and doesn’t seem to do much good, compared to leaving the glucose a little high, say 8 to 10, which might be a better idea. Pre-printed standardised insulin protocols help older children to avoid hypoglycemia, and should be developed for the preterm infant, and trialed to see if we can safely reduce hypoglycemia, and control hyperglycemia.