Preliminary Report of the NICE-SUGAR study: Hypoglycemia and what it may mean for patient safety

The optimal treatment for the hyperglycemic patient in an ICU setting has been hotly debated for many years. On one side are those who propose that normoglycemia is the goal of treatment of hyperglycemia, and on the other side those who propose that the case has not yet been proven – that the risk of trying to do so, particularly the higher risk of hypoglycemia, may outweigh the benefits. Perhaps the strongest evidence in favor of using insulin infusions and setting goals of normoglycemia is from Greet Van Den Berghe and her colleagues in Belgium, who performed a large randomized controlled trial to assess the optimal treatment of hyperglycemia in the SICU setting¹. They found that maintenance of a goal of normoglycemia on patients in SICU settings for five or more days reduced mortality by 32% overall, 44% in those with sepsis, and significant reductions in both morbidity and hospital costs also occurred. A very recent study in Lancet by her team, Vlasselaers et al, published in The Lancet on February 14th, 2009, extends their evaluation by finding a significant benefit in reducing morbidity in the pediatric age group, but with a significant increase in the frequency of hypoglycemia².

The hypoglycemia appears to be the main barrier to widespread adoption of intensive glycemic control in inpatient care. There are many questions still unanswered. Can we reduce the high incidence of hypoglycemia noted in so many published studies? Are we using the wrong tools? Are the instruments we use to measure glucose introducing errors which result in their suboptimal accuracy and precision? These questions and others will be the subject of this and subsequent editorials.

Two important studies have weighed in on this topic in the past weeks. The most important, but perhaps the most preliminary information is from the NICE-SUGAR study group . Their preliminary report of the first 100 hypoglycemic events can be found on the ANZCA website, athttp://www.anzca.edu.au/jficm/resources/ccr/2007/september/niceSugar.html/?searchterm=NICE-SUGAR.

The NICE-SUGAR study is a large multinational study that evaluated 1838 patients in ICU settings. They compared an intensive glycemic control strategy, which utilized continuous insulin infusions, with a strategy that was less intensive, with less stringent glycemic goals. Their findings were a surprise to many. The most common explanation for the adjudicated causes of the hypoglycemic events was clinician error, defined as failure to follow the computerized treatment algorithm, as for example, inappropriately infrequent blood glucose monitoring. Clinical errors alone explained 37% of the hypoglycemic events. The next most common cause was decreased nutritional intake, which explained 24% of the hypoglycemic events.

Put another way, their preliminary data indicates that although their algorithms to achieve normoglycemic were sound, if they were not implemented correctly, hypoglycemia commonly resulted. It is yet another example as to why it is not enough to have an excellent plan, but we need to make sure the implementation of this is correct. Without adequate training and monitoring of how the plan is delivered, suboptimal results often occur. This data provides a potential answer to the question as to why others have not duplicated van Den Berghe’s results. The failure to do so may be more a systems problem than a failure of concept.

Another study, published online on February 5, 2009 in Diabetes Care by Blaha and colleagues, may also be relevant. In this study, performed in Prague, the authors compared three protocols for tight glycemic control in cardiac surgery patients. They noted a relatively lower rate of hypoglycemic events overall in the three choices of algorithms, and made a point that the experience of the ICU staff with the protocols and the appropriate implementation period may have been one of the reasons why the quality and safety of glucose control in their study was significantly better than most of the previously published studies. However, by design, this study focused only on their chosen outcomes, glycemic control and freedom from hypoglycemia. It is therefore not comparable to the NICE-SUGAR study due to the lack of morbidity and mortality data.

Nevertheless, both the data from Blaha study and the preliminary data from the NICE-SUGAR study strongly suggest that failure to duplicate the positive findings of the Van Den Berghe studies may often be due to a failure to pay adequate attention to the need to adequately train and monitor the work of the personnel who are managing the insulin infusions. Creating adequate systems of care for this complicated therapy is a must, and results may be much better once there is more consistent attention to this important aspect of care.

References:

Van den Berghe G, et al. Intensive Insulin Therapy in Critically Ill Patients, NEJM 345: 1359-1367
Vlasselaers D, et al. Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomized controlled study, Lancet 373:547-556

Leave a Comment

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.