AACE Patient Safety - Editorials
A recent report in JAMA on the association of hypoglycemia and dementia in older patients with type 2 diabetes – Is the link causal? And if so, in what direction is the causation?

2009-05-11 14:05:15
By: Dr. Richard Hellman

A recent article in JAMA by Whitmer et al reports on an association between the diagnosis of severe hypoglycemia and a subsequent diagnosis of dementia1. The authors conclude that their data makes it unlikely that the reported association is due to dementia increasing the likelihood of hypoglycemia, but rather that early hypoglycemia in this population increases the later risk of dementia. They suggested caution on therapy in older patients with type 2 diabetes. Further, they point to the ACCORD trial as reporting related findings.

Their longitudinal cohort study was based on a Kaiser Permanente Database, and was conducted using data from a period of 1980-2007 on 16,667 patients with a mean age of 65 years and type 2 diabetes, who were members of an integrated health care system in northern California.

Their results showed that of the 1415 patients (8.8%) with one documented episode of severe hypoglycemia, dementia was subsequently diagnosed in 250 patients. They concluded that fully adjusted hazard ratios for one episode of hypoglycemia was (HR, 1.26; 95% confidence interval [CI], 1.10-1.49); 2 episodes (HR, 1.80; 95% CI, 1.37-2.36); and 3 or more episodes (HR, 1.94; 95% CI, 1.42-2.64). They found that the results were similar but slightly more positive when looking at ER admissions for hypoglycemia.

Unfortunately, this is a flawed and misleading study. Because it was in large part dependent upon incomplete data sources derived from hospital and outpatient and ER admissions, there is little question that the identified episodes of hypoglycemia were only a fraction of the total episodes of hypoglycemia experienced by the patients. Also, there was no baseline systematic evaluation of cognitive function of the cohort, and the standard for diagnosis of dementia was not uniformly applied. The same can be said for the diagnosis of hypoglycemia.

Additionally, the group with an episode of hypoglycemia was older at the time of the survey, had a longer duration of diabetes, and had a higher co-morbid index of heart disease, hypertension, previous stroke, and end stage renal disease. Although the statistics on the differences in duration of diabetes was not given, all of the others mentioned were statistically significant.

It should be expected that there would be a higher incidence of cognitive dysfunction in this group, as each of these are accepted risks for cognitive dysfunction in adults. On the other hand, there is no information given on the social support available for the patients with hypoglycemia, whether they lived alone, or the frequency of glucose self-monitoring, the lack of which in insulin users is associated with an increased risk for injury (D Cox, EASD Rome 2008). Neither is there information about depression in diabetes which increases the risk for hypoglycemia and cognitive dysfunction. The data does show an association, but it does not answer the question of causation.

One can easily posit a quite different explanation for the observed association of hypoglycemia and dementia. This is as follows:

Severe hypoglycemia may be a marker for patients at higher risk for dementia and in fact may be more commonly seen in patients who already have mild-to-moderate cognitive dysfunction. Those patients have poorer ability to protect themselves and provide optimal self-care, and may be more prone to both hyper and hypoglycemia. The higher glucose levels and increased glycemic variability will increase their risk for earlier and more severe complications, some of which, in turn, will increase the risk for more hypoglycemia as well as a poorer overall clinical outcome. It is no surprise that such patients have increased death rates, a common feature of patients with increasing cognitive dysfunction.

While it is true that severe brain injury can follow an episode of prolonged hypoglycemia, particularly after seizure activity, the data from the EDIC trial suggests that severe hypoglycemic episodes may not necessarily lead to long term dementia, and in fact, there is a better correlation with long term A1C values with respect to cognitive dysfunction.

But the case in older adults is not settled and the study of Whitmer et al is not the definitive answer at all. Rather, it highlights the need for us to study this vulnerable population, patients 60 years of age or greater with diabetes and co-morbid vasculopathy, and to carefully examine their baseline status regarding both depression and cognitive function. There are a variety of easy-to-use validated tools for rapid evaluation of both depression and dementia. Both the Mini-Mental Status Exam and the Beck Depression Inventory are examples of the many good tools available.

At the end of the day, by proper identification of the potential vulnerabilities of each of our at-risk populations, we can improve our ability to tailor the diabetes therapy to the actual needs of the patient and make diabetes care not only more effective, but safer as well.

REFERENCES
  1. Whitmer RA, Karter AJ, et al. Hypoglycemic Episodes and Risk of Dementia in Older Patients With Type 2 Diabetes Mellitus. JAMA, April 15, 2009; 301: 1565-1572.
 

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.

Leave a Comment



?
? ?
?

Powered by TalkBack
 

 

American Association of Clinical Endocrinologists
245 Riverside Avenue Suite 200
Jacksonville, FL 32202
904.353.7878