AACE Patient Safety - Editorials
The NICE-SUGAR Study on Intensive versus Conventional Glucose control-The Importance of Patient Safety in Achieving the Desired Outcomes

2009-03-25 15:56:43
By: Dr. Richard Hellman

The long-awaited NICE-SUGAR trial results have just been published on-line in the New England Journal of Medicine, together with an excellent editorial by Inzucchi and Siegel. The ADA and AACE have also released a joint statement. In their very thoughtful statement, they expressed a concern that providers of care will take the published results of the NICE-SUGAR study and conclude incorrectly that they can afford to be more complacent about uncontrolled hyperglycemia.

Their concern is justified. Some of the initial news commentary stated that the NICE-SUGAR showed that that intensive insulin therapy to achieve glucose control increases mortality in critically ill patients and may be dangerous. However, it is best to look carefully at what the actual data is.

The data provided by the NICE-SUGAR article shows that the odds ratio for death in the intensive control group was 1.14, with a 95% confidence interval of 1.02 to 1.28 and a P=0.02. The severe hypoglycemia rate (Glucose <=40mg/dl or 2.2mmol/L) was 6.8% in the intensive-control group and only 0.5% in the conventional group. On the surface it would seem that the results are unequivocal. But that would be an incorrect conclusion.

To begin with, the mean glucose level in the conventional-control group was 144mg/dl, as opposed to the intensive therapy group glucose level of 115mg/dl. The difference is not large, only a mean of 29mg%. The control in the conventional-control group was in the range of only relatively modest levels of hyperglycemia, much lower than the control groups in many other studies, which were often over 200mg%. . In addition, there were a significant number of patients, 74, whose vital status data was unknown, and a significant amount of reassignment of patients as noted in the paper. The 14% increase in death rate in the intensive group could be possibly explained by other factors not available in the analysis.

But a more compelling reason to be careful about the analysis is the fact that the NEJM article gives very little information about THE FREQUENCY THAT THE ALGORITHMS WERE DONE AS PLANNED. The algorithms used for the insulin infusions were constructed so the insulin infusion rate varied widely and the rate would change from 0 units/hr to 1, 2, and 4, units /hour in response to the glycemic levels noted. With this type of infusion algorithm, it is imperative to not let the interval in between the glucose determinations be excessively long, since otherwise the swings in glucose levels would be very rapid and large in amplitude.

In fact, in the report of their first 100 hypoglycemic events, the NICE-SUGAR study group, as reported on their ANZCA web-site, the most common adjudicated cause of hypoglycemia was clinician error, which was 37% of the group. They defined clinician error as either failure to follow the computerized treatment algorithm or inappropriately infrequent blood glucose monitoring. The next most common event, at 24 % of the adjudicated causes, was decreased nutritional intake. Each of these causes are a failure to follow the agreed upon plan.

So, is the problem of the failure of the NICE-SUAR study to show positive results in the intensive insulin therapy group that the target glucose level was set too low, or is it that the plan was good, but was carried out sub-optimally? While my opinion is that the reasons for the outcomes were complex, it is clear that in a sub-optimally conducted trial, even if the subjects were randomly assigned, a deviance from the plan of the trial weakens or limits the strength of the conclusions that should be drawn.

Yet, I think there is much about the NICE-SUGAR study that makes it an important addition to the literature. It suggests that in very ill patients, particularly patients on ventilators, and with marked severity of illness, that patients may be very vulnerable to hypoglycemia, and this much be scrupulously avoided. Also, the effects of early severe hypoglycemic episodes may be delayed, as some of the excess mortality was later, and may have represented subtle effects not initially noted in the ICU.

Also, the fact that a mean glucose level of 144mg% was associated with outcomes in an ICU that was not worse than those with lower glucose levels suggest that a target in this range may be safe.

But their own data on hypoglycemia strongly suggests that it is crucial to be sure that the algorithm is being carried out correctly for optimal results. And data from both Keukoven, 2008, Blaha, 2009, and Van Den Berghe, 2008, all point out that the training of a nursing team who is in change of actually overseeing the insulin infusions is crucial. There is a need to provide adequate numbers of trained personnel, and both education and continuing oversight. Quality improvement in this setting depends upon reviewing the work product and improving what is less than optimal. . In the editorial by Inzucchi and Siegel, they correctly point out that in many hospitals, a seamless and automatic use of insulin infusions has developed. These efforts have already resulted in a small but growing literature on the successful use of insulin infusions. More data will certainly be welcomed, for the NICE-SUGAR study is important, but far from definitive.

  1. The NICE-SUGAR Investigators, Intensive versus Conventional Glucose Control in Critically Ill Patients, NEJM, 360;13 March 26, 2009, pgs 1283-1297
  2. Inzucchi, SE, and Siegel, M., Glucose Control in the ICU-How Tight is Tight?, NEMJ, 360;13, March 26, 2009, pgs 1346-9
  3. Joint Statement of the ADA and AACE on the NICE-sugar study, Press Release, March 24, 2009, on http://media.aace.com/article_display.cfm?article_id=4886
 

There are 7 comments
Prasanna Rao-Balakrishna – UK
July 14, 2009 - 17:23
Subject: Preventing Hypoglycaemia is as important as the tight glycaemic control

Preventing hypoglycaemia is as important as the tight glycaemic control. It is important to note that glycaemic control depends on the insulin regimen, patient's own counter regulatory hormone response & insulin resistance status, the calorie intake, frequency of testing for blood glucose, interpretation and acting on the results. During acute illness it is not possible to control the counter-regulatory hormone response and the insulin resistance status, but with adequate training, frequent testing and appropriate structured response should be possible, thereby preventing a hypoglycaemia. A trial which focuses as much on hypoglycaemia avoidance as well as tight glycaemic control is needed.

Reply to Prasanna Rao-Balakrishna
Richard Hellman MD
July 16, 2009 - 11:25
Subject: RE: Preventing Hypoglycaemia is as important as the tight glycaemic control

Dr Rao-Balakrishna makes a very interesting suggestion, that preventing hypoglycemia is as important as the tight glycemic control, and suggests a trial that focuses on two end-points, the avoidance of hypoglycemia as a co-equal goal in importance to tight glycemic control.

In fact, there is a great deal we do not know about hypoglycemia in critically ill states, and it is far from clear what the short and long term consequences are of mild, moderate, or even brief periods of severe ypoglycemia for critically ill patients. We do know that severe hypoglycemia can be a marker for increased mortality, as it was clearly shown in the VADT trial, but interestingly, those deaths did not usually occur during the hypoglycemic episodes, and the relationship between severe hypoglycemia and subsequent mortality was strongest in the conventional therapy group, suggesting that the hypoglycemic events may have been a consequence of an underlying vulnerability rather than the cause of mortality.

One of the limitations of an approach focused just on the outcomes of glycemia is that from the patients' standpoint, the most important issues are their clinical outcomes: mortality, morbidity, and disability. In contrast, those outcomes may not match the relative frequency of hypoglycemia at all. For example, there is a disconnect between the very high frequency of hypoglycemia in the Van Den Berghe RCT's in critical care published in 2001, 2006, and 2009. Both the surgical ICU study of 2001 and the 2009 pediatric studies showed very excellent outcomes with respect to mortaliy and morbidity in the presence of relatively frequent hypoglycemia.

I again would like to thank Dr Rao-Blakrishna for pointing us again to this very unsettled issue of the importance of hypoglycemia prevention, for the debate as to what we can and should do rages on. There are many creative ideas that have been proposed, but we need more data to guide us as to how to obtain the best clinical outcomes with the tools we have without either unacceptably high levels of hypoglycemia or hyperglycemia.

Richard Hellman MD
Editor-In-Chief
Patient Safety Exchange Website

MRR – Texas
March 31, 2009 - 16:29
Subject: NICE_SUGAR

Several interesting points came to mind when I reviewed the NICE-SUGAR study; the degree of severe hypoglycemia, the degree of cardiovascular mortality, the conventional group’s blood glucose levels are significantly lower than the vast majority of other outcome studies, and the number of severe septic patients in the intensive control branch of the study. According to the 2008 sepsis guidelines, the glycemic control target level for the septic patient is already in question and perhaps sepsis should be an exclusion criteria?

I was tasked with the development and oversight of a Tight Glycemic Control Program pilot study from May 2006 through April 2008 for a South Texas community hospital/level 2 trauma center. This included a 14 bed CCU, 12 bed M/S ICU and 12 bed trauma ICU as well as 4 M/S wards. Clinical inertia was our most difficult element to overcome and for the most part this was never accomplished. Clinical inertia was not only evident on physician's part, but also administration, nursing, nutritional services, pharmacy, and the patients themselves. Accountability to noncompliance to protocols was lacking as well. The philosophy that inpatient glycemic control was not necessarily treating diabetes, yet acute hyperglycemia was never fully accepted. When results like ACCORD, ADVANCE, and VADT were released, I would usually take the phone off the hook and leave the hospital because those wbeepdo not support inpatient glycemic control would come out en mass wishing to compare apples to oranges. That is not necessarily the case with NICE-SUGAR. In our Trauma ICU, where support was highest, for the entire year of 2007, we had only 7% BG > 200mg/dL, less than 2% hypoglycemia under 50 mg/dL, and nearly 75% BG between 80 - 150 mg/dL.

Overall, I applaud the NICE-SUGAR research team for a job very well done and thank them for their contribution to this ongoing discussion. I do support further research to differentiate specific glycemic control target ranges for specific diagnosis, but I too fear this could cause a pendulum swing in the opposite direction resulting in less facilities participating in inpatient glycemic control resulting in less data for differentiation.

NISSIM GABAY – VENEZUELA
March 26, 2009 - 15:25
Subject: NICE -SUGAR

I think that the central goal of the ADA/AACE impatient glucose targets is safe with the protocols .
Hospitals should have protocols in place for using insulin to treat and prevent hyperglycemia.
Subcutaneous insulin may be used for both purposes in most noncritically ill patients, whereas intravenous infusion of
insulin is preferred in critically ill patients.
Be careful with this trial [NICE -SUGAR] to overcome clinical inertia.

Dr. Orlin Sergev – Charleston, SC
March 16, 2009 - 16:28
Subject:

Dear Dr Hellman:
I enjoyed all the editorials on patients' safety that you have recently published. I think that they raise questions which we as physicians are not always open about. Safety itself is frequently a topic that we love to discuss but it's never our fault. In this connection, the article about overconfidence and medical errors is timely - especially, at this time of expected health care changes. Briefly, I do not think we as physicians are different from any other specialists in different areas. Lack of adequate knowledge in a special area is always a good reason to be noisy and seemingly overconfident. Most of us agree that the more you know the more you realize how much more you do not know. Overconfident behavior in front of outsiders seem to be the cover of ignorance. I think we have to improve medical education in order to make medical decisions safer. Just remember the pilot of the plane that landed in Hudson river - quiet professional on top of his performance. We in medical profession must lead in patients' safety. In order to do that we have to lead the health care reform. We have to regain our authority, responsibility and accountability. (accountability without authority and responsibility is meaningless - see Dr Hellman's article on Medicare). We have to lead the health education of the society - most of the tragic mistakes in life happen from ignorance. First and foremost, of course, we have to maintain the superiority in medical knowledge. We must improve the quality of medical education. Instead of multiple choice questions we have to put back in place the stern professor wbeepmade clinical judgements based on knowledge, experience, and gut feeling and set up a good personal example for the next generation of physicians. Pilot "Sully" did not read the manual and the guidelines how to handle the critical situation - all his life before, however, prepared him for the right on the spot decision. Decisions based on profound knowledge and experience are the safest! Let's start the health care reform with ourselves.
Do not stop learning and teaching your team about sound and safe medical practices. When we have achieved that, we can confidently go out and regain our authority over various bureaucracies (government agencies-Medicare, insurances, medical malpractice law, etc).

james t poulos – west lafayette in
March 03, 2009 - 15:09
Subject: NICE-SUGAR

There was an article in acta scandinavia in january that showed very little hypoglycemia when intensive therapy is done right! I came across the article on medlinx in mid January, but it was actually published in October 2008. authors: Kaukonen KM et al in acta anaethesiol scandinavia and titled severe hypoglycemia in intensive insulin therapy.

Reply to james t poulos
Dr Hellman
March 04, 2009 - 16:12
Subject: Further thoughts related to the NICE-SUGAR study

Dear Dr. Poulos,

Thank you for calling attention to the study by Kaukonen KM et al. Your excellent point adds to the discussion generated by the NICE-SUGAR study. Their preliminary data analysis showed that error by provider was the most common cause of hypoglycemia. Their data implied, as I stated in my recent editorial, that improving the training and performance of those managing the insulin infusions greatly decreases the threat of hypoglycemia.

In this study by Kaukonen, done at the Helsinki University Central Hospital in Helsinki, Finland, the authors evaluated the incidence of hypoglycemia in all patients treated in two intensive care units between February 2005 and June 2006. They showed that severe hypoglycemia during intensive insulin therapy was rare in clinical practice. Analyzing data for 1124 patients and 61,203 glucose measurements, they found 36 measurements of severe (≤ 2.2mmol/L) hypoglycemia in 25 patients, with an incidence of 0.06% of severe hypoglycemia.

They commented that the frequency of blood glucose monitoring correlated inversely with the frequency and magnitude of severe hypoglycemia. In surgical patients, it is of note that five of the six instances of hypoglycemia occurred when a nurse failed to comply with the protocol.

The Helsinki group’s observations are entirely in keeping with the preliminary data from the NICE-SUGAR study and make a good deal of common sense. When the rate of decrease of glucose is rapid, for example greater than 1mg/dl/minute, simple arithmetic can tell us when the next glucose determination needs to occur to be able to safely avoid severe hypoglycemia. But if the frequency of checking of glycemic levels is arbitrary, and set too low, then hypoglycemia is to be expected much more often. The Kaukonen group avoided this by making sure the blood glucose sampling was relatively frequent.

In our clinical practice setting as well, the principles of safe handling of insulin infusions have been:

1.frequent monitoring, always at least hourly in ICU settings, more often when dealing with lower glycemic levels;
2.intensive training of nurses to make them expert in understanding how best to use algorithms;
3.specific points at which prolonged hyperglycemia or hypoglycemia necessitates immediate consultation with the responsible physician;
4.review of data to indicate variations in performance and appropriate correction and retraining when appropriate.

We too have extensive experience over many years with the safe use of insulin infusions in inpatient settings with relatively rare severe hypoglycemic episodes and little morbidity.

The NICE-SUGAR study should provide important information. We should not get too far ahead of their forthcoming data, but there is already abundant data, such as the important study from Helsinki, which show us that with a safer system of care, more ambitious glycemic control is both achievable and safe.

Kaukonen KM et al. Severe hypoglycemia during intensive insulin therapy, Acta Anaesthesiol Scand. 2009 Jan;53(1):61-65. Epub 2008 Oct 20.

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