Say hello to the latest wonder drug-insulin. It can reduce morbidity and mortality in critically ill patients. It tackles sepsis head-on. It's cost-effective and can reduce length of stay. It's got nurses begging to perform more point-of-care testing. How crazy is that?

More specifically, tight-really tight, tighter than you ever thought possible-glycemic control of patients in ICUs, maintained by hourly bedside glucose monitoring and IV insulin infusions, is transforming the hospital landscape, undoing generations of training and practice and exploding the myth that for critically ill patients, high blood sugars are just fine, thank you very much. Researchers are taking aim, with numerous studies either recently completed or underway. And late last year experts issued the first-ever guidelines for managing in-hospital blood sugar levels.

These changes are nothing short of revolutionary, say endocrinologists. But like most revolutions, it's been a long time in the making. The change should have come sooner, say many.

"We always knew, in our heart of hearts, that it was a bad idea to let patients' sugars be high in the hospital," says David Baldwin, MD, acting director, endocrinology, Rush University Medical Center, Chicago. "We would work to keep sugars well controlled in the hospital, but there was never an institutional or programmatic approach to it."

"We've always known to keep sugars low," agrees Irl Hirsch, MD, professor of medicine, University of Washington School of Medicine, Seattle. The real issue, he says, was a lack of outcomes data, which they needed to convince highly skeptical colleagues.

The DIGAMI (Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction) study should have provided that data. Published in the late 1990s, in a series of articles, it broke new ground but fell short of touchstone status. "They took 600 patients having an acute MI, and they randomized them to either really intensive glucose control with intravenous insulin versus letting them have the standard care they'd always gotten in the past," Dr. Baldwin says. The researchers showed a 30 percent reduction in mortality in patients whose blood sugar levels were tightly controlled with IV insulin. "That was striking. But years later, that still had not become the standard of care anywhere in the world, for reasons that are just unclear."

It's possible the DIGAMI trial was disregarded because it was novel. "It stood by itself," Dr. Baldwin says. "There was nothing else out there that showed this kind of approach would be beneficial."

The study also was assailed by critics who rightfully pointed out it tried to do too much. In the active treatment arm, patients not only had their glycemic levels tightly controlled in the hospital via intravenous insulin, but also for at least three months after discharge, during which they received daily insulin injections to maintain normal levels. The obvious question arose: What was responsible for saving lives, the IV insulin or the subcutaneous insulin? Both?

Or was it something entirely different? As Dr. Baldwin points out, many of the patients in the study were diabetics who were already taking oral antidiabetic agents—including one pill associated with cardiac toxicity. "Maybe some patients who got insulin got better because they were no longer taking the pills that may have been harmful," he says.

A second DIGAMI study now underway should address the shortcomings of the first one. The newer study is larger and delineates those receiving IV and subcutaneous insulin from those who receive only the in-hospital infusions; it's also looking more carefully at the types of oral agents patients may be taking. "So they're doing it in a bigger and hopefully more definitive way," says Dr. Baldwin. "Because their first study, even though the results were very clear, had enough question marks that it could never have the impact that they hoped it would-and that it deserved to have."

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That impact would have to wait until 2001. November 11, 2001, to be exact, when another stand-alone trial appeared. Unlike the DIGAMI study, however, this one is staring down all challengers.

"Everything started in November 2001," says Dr. Baldwin, referring to the publication of "Intensive Insulin Therapy in Critically Ill Patients" (N Engl J Med. 2001; 345: 1359-1357) by Greet Van den Berghe, MD, PhD, et al. "It was a real sentinel article for this whole field, a huge wake-up call" that has since sent physicians in an "amazing new direction of focusing our attention on controlling blood sugar in inpatients."

The researchers, noting that hyperglycemia and insulin resistance are common in critically ill patients, embarked on a one-year study involving 1,548 adults in the surgical ICU who were receiving mechanical ventilation. Patients were randomly assigned to receive intensive insulin therapy (maintaining blood glucose between 80 and 110 mg/dL) or conventional treatment (insulin infusion only if the blood glucose level exceeded 215 mg/dL, maintaining a level between 180 and 200 mg/dL).

The intensive therapeutic approach reduced mortality during ICU stay, from eight percent with conventional treatment to 4.6 percent with the tighter control. The greatest reduction in mortality involved deaths due to sepsis-related multiple-organ failure. Intensive therapy reduced overall in-hospital mortality by 34 percent, bloodstream infections by 46 percent, acute renal failure (requiring dialysis or hemofiltration) by 41 percent, the median number of red-cell transfusions by 50 percent, and critical-illness polyneuropathy by 44 percent. Patients whose blood glucose levels were tightly controlled were also less likely to need prolonged mechanical ventilation and intensive care.

The results gave endocrinologists a flag to rally around. "Their study was totally inspirational for thousands of other people," Dr. Baldwin says. "You could never say enough about how important it was." Here at last was solid data showing physicians that a different approach worked.

"I've noticed over the years that many of our surgical patients get infections of their wounds after surgery, seemingly in association with blood sugars that are quite high after surgery, but I'd never been able to do much about it," Dr. Baldwin says. A big part of the problem, he says, was simply trying to persuade his non-endocrinologist colleagues to consider the link. "They want to know, Where's the proof? Where's the study that really shows it's going to make a difference? And there really wasn't one."

Dr. Hirsch calls the Van den Berghe study the biggest, most important randomized study to look at the importance of tight glycemic control. "It did two things: It made people look at what they were doing in the hospital, but it also made people look at the other evidence that was already out there."

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Until the Van den Berghe study started shaking things up, in-hospital glycemic control had been a rather clumsy affair.

For decades physicians have used a sliding scale to evaluate insulin levels and administration. "Of course, that's really silly, because you're treating what happened in the last four hours, but doing so in the next four hours," says Harrison G. Weed, MD, associate professor, internal medicine, Ohio State University. "You're treating the past instead of the future." That approach doesn't benefit patients and can be dangerous.

At the University of Washington School of Medicine, physicians moved away from the sliding-scale approach to an insulin infusion protocol in 1991. "We were very much in the minority," Dr. Hirsch says. The shift wasn't prompted by outcomes data—because there wasn't any. "It was based on safety," Dr. Hirsch says. "Because when you look at how we train residents in the hospital, we don't do a good job of teaching them how to manage diabetes. Disasters were just waiting to happen, simply because people were so intimidated by the use of insulin."

Certainly hypoglycemia is nothing to sneeze at. But that fear has made physicians fainthearted when it comes to insulin, and their dread has been passed along to residents and medical students for years. "What we've done is taught people how to avoid insulin for as long as possible," says Dr. Hirsch. "If you look at the big, giant studies in the United States, you'll see that the average patient starts insulin with an average A_1C of 10.4 percent, because we're trying to avoid insulin use—even though it may have been indicated years earlier."

"People are afraid," says Kwame Osei, MD, professor of medicine and exercise physiology and director of the Division of Endocrinology, Diabetes, and Metabolism at OSU.

Trying to fight that has been a tall order. "The typical American doctor is happy enough if the sugars are in the 200s," says Dr. Baldwin. "'200, that's OK. 300s, that's maybe too high. 100s—uh-oh, I'm a little worried, maybe it's too low.' That was always the fear of the general doctor—'Oh my God, the sugar's going to go too low, they're going to crash.'"

That sort of thinking has been especially hard on ICU nurses, who typically have had to try managing their patients with only the vaguest of orders. Dr. Baldwin gives a classic example: Start IV insulin infusion if the sugar goes above 200, and titrate to keep the sugar less than 200. "That would be the entire order. So the poor nurse had no guideline. You were pretty much telling her 'Fly by the seat of your pants.'" As a result, sugars were reflexively kept around 200 by nurses afraid to go lower.

Given all that, the idea of keeping ICU patients' blood sugar levels between 80 and 110 mg/dL is nothing short of shocking. Think of it as insulin's four-minute mile.

When Dr. Baldwin began rolling out new insulin infusion protocols at Rush two years ago, 110 mg/dL seemed a little scary even to him. "Our target is between 80 and 120—because 110 made me nervous at the time. But now, looking back, we could easily do 110. It's no big deal."

"Our nurses are not afraid of it at all anymore," he continues. "But you can be sure they started out afraid, as did all the doctors."

Starting with the surgical ICU, Rush began instituting an insulin infusion protocol April 1, 2002, making it mandatory for all patients who had undergone any type of cardiovascular surgery, as well as for all organ transplant patients. Since they were acting primarily on the Van den Berghe study, Dr. Baldwin and his colleagues chose to have their early efforts take the form of research studies, so they could collect their own data and determine whether it confirmed her results.

Within six months, Dr. Baldwin reports, the protocol had spread to nearly all other surgical patients, primarily through nurses and the rotation of residents into different teams throughout the hospital. "The nurses in the neurosurgical unit heard about it through the grapevine, and then they came to me and said, 'We want this too. We're tired of bad glucose control.' So we taught them, and they got it up and running," he says. About eight months ago the protocol was put into place in the medical ICU. "It's been a gradual thing creeping through the institution," he says. "Once the nurses start doing something, the residents catch on."

The nurses love the protocol, he says, even though it means they're performing more bedside tests. "It means they can safely have the sugars be running totally in the normal range, which is something that was totally foreign to them. ICU patients' sugars never run in the normal range, or at least had not up to then."

This summer the protocol will take another leap, when Rush will begin using it for every patient with a myocardial infarction and elevated blood sugar. "The stress of having a heart attack often makes your sugars go up, whether you're diabetic or not," Dr. Baldwin explains. When that takes hold, every ICU at Rush will be using the protocol.

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In Washington, Dr. Hirsch and his colleagues adjusted their approach in summer 2002, using a protocol published by Lawrence J. Markovitz, MD (Endocr Pract. 2002; 8: 10-18). (It's also published in an article coauthored by Dr. Hirsch: J Clin Endocrinol Metab. 2003; 88: 2430-2437). They have not yet published their data, "but we feel it's very safe, and it's adaptable to someone with any type of diabetes on any floor in the hospital," Dr. Hirsch says. "In fact, we use that protocol on every floor except psychiatry."

When Dr. Baldwin and his colleagues analyzed the data from their first year's use of the protocol in the SICU, they found them to be "a little disappointing," he says. In the heart patients, "we did not find any change in the rate of infections compared to the year before, when only about half the patients got insulin and the sugars were not nearly as low."

But he remains convinced of the protocol's usefulness, and chalks up the less-than-dramatic results to the relatively small patient population they evaluated?. "I think we weren't able to show a difference because we're looking at events that happen only one, two, three percent of the time," he says. "You need a large number of patients before you can show a statistically significant difference."

They did find that atrial fibrillation, a common complication after open-heart surgery, dropped by about 30 percent, and postsurgical infection rates dropped in the transplant patients.

Other, larger studies may bolster his views. A study by Anthony Furnary, MD (J Thorac Cardiovasc Surg. 2003; 125: 1007-1021), involving more than 3,000 patients over 10 years showed that giving perioperative insulin drips to coronary artery bypass graft patients who are diabetic reduced in-hospital mortality as well as infections, Dr. Baldwin reports.

The Van den Berghe study recently had its first confirmation, presented at the Society of Critical Care Medicine's annual meeting in Orlando in late February. James Krinsley, MD, director of critical care at The Stamford (Conn.) Hospital, reported that using an intensive protocol in a medical-surgical ICU, aimed at maintaining levels between 80 and 140 mg/dL, resulted in a six percent reduction in in-hospital mortality, for a relative risk reduction of 29 percent. The year-long study compared 800 consecutive admissions with 800 historical controls. "The data showed almost exactly the same thing as what Dr. Van den Berghe showed in 2001," says Dr. Hirsch. "So I don't think any of this is fluke." (Dr. Krinsley also published a study in Mayo Clinical Proceedings [2003; 78: 1471-1478], involving 1,826 ICU patients with a wide range of medical and surgical diagnoses, that showed hyperglycemia increased the patient's chance of death.)

In addition to the second DIGAMI study, Dr. Baldwin points to a large, multicenter study underway in England, the GIST study (Glucose Insulin in Stroke Trial), which is looking at tighter glycemic control in patients with acute stroke. "There's a lot of indirect data that indicate if you let patients' blood sugars be high when they're having a stroke, that the extent of the permanent damage to their brain is far greater than if you gave them insulin right away and kept their sugars normal," he says.

More immediately, there are new guidelines on managing blood sugars in hospitalized patients, whether diabetic or not. The guidelines emerged from a consensus conference held in December that was sponsored and attended by "every possible interested party of doctors, nurses, and specialties," Dr. Baldwin says. The guidelines are available on the Web site of the American Association of Clinical Endocrinologists (www. aace. com/). In addition, the February issue of Diabetes Care (http:// care. diabetesjournals. org/ content/vol27 / issue2/ index.shtml) contains a technical review (authored in part by Dr. Hirsch) of the literature from which the guidelines were derived. "It's the bible on the subject," says Dr. Baldwin.

The guidelines can be summed up in two numbers: 110 and 180, the former being the maximum for all ICU patients, and the latter the maximum for all non-ICU hospitalized patients. "Below 180 is the target for the postprandial glucose level for those patients who are eating," Dr. Hirsch clarifies. "Before eating, the number is 110." With these guidelines, says Dr. Baldwin, the whole mentality that OK'd higher levels "has been formally written off."

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The how-low-can-you-go limbo dance is likely to continue. "The line between abnormal and normal has been drifting down," says Dr. Baldwin. "And it may very well go down in the future as we learn more." Though 80 is likely to remain the low range of normal, the upper range is definitely in flux, he says.

It's only a matter of time before other institutions see the light. "We're going to see change," Dr. Hirsch says, if for no other reason than fear of litigation. "What has driven a lot of hospitals is the threat of disaster and, quite frankly, the attorneys. And I know of two hospitals in the last year where there have been deaths from sliding-scale insulin." He adds that the December consensus conference included a representative of the JCAHO, and while it's difficult to say how the guidelines will be translated into hospital accreditation, "the fact they were there suggests to me that there will be greater emphasis on appropriate diabetes care."

Tight controls will also spread well beyond the ICU. Dr. Baldwin is particularly excited about a recently published study in Circulation, which evaluated tight glycemic control in patients with acute MI who received TPA (Chaudhuri A, et al. 2004; 109: 849-854). Those who received IV insulin had smaller infarctions—the area of dead heart muscle was reduced by 30 percent. "That's just mind-boggling," Dr. Baldwin says.

It may even be enough to pressure cardiologists to adhere to tighter controls, though that group of specialists has been tough to budge. At Rush, however, they're beginning to buy into it. "Cardiology has had so much clinical success with lytic therapy, angioplasty, and stents that the benefits of insulin therapy have been under their radar screen," says Dr. Baldwin. "Intensive therapy with insulin hasn't been within their usual realm of training or expertise." But, he says, he and the Rush cardiologists recently formed a plan to adopt the insulin protocol for diabetic MI patients. "And the nurses are in-serviced and ready to go."

A big step in convincing others is to alleviate their fears about hypoglycemia. As it turns out, it's not that hard.

In trying to reduce high blood sugars at his institution, reports Dr. Weed, "we also dramatically reduced the episodes of low blood sugar. The episodes of hypoglycemia dropped from 15 per month to one per month." These figures come from one-month trials, done at separate times—not a perfectly controlled experiment. "Nonetheless, it's a really dramatic drop," he says. "And since we did a good job of avoiding hypoglycemia, people have agreed to tighten up the protocol." Like other hospitals, OSU began its efforts in the SICU, moved to the MICU, and is gradually adding other wards.

Dr. Weed and his colleagues are also making sure the protocol is maintained when critically ill patients leave the ICU to have procedures done in other areas of the hospital. "We now have the equipment for doing the blood glucose testing in the radiology and cardiology procedure suites, so they can continue to have their sugars checked and their insulin infusion rate adjusted as needed," he says.

Hypoglycemia simply isn't the big concern that it was 10 years ago, adds Dr. Hirsch, pointing to the availability of insulin analogues. "We can get blood sugars under excellent control with very little risk of hypoglycemia."

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As fears about insulin and hypoglycemia recede, a clearer picture should emerge about why insulin works so well in so many settings.

There's no end to the theories, but Dr. Baldwin boils them down to several essential points. First, he notes, high blood sugars paralyze portions of the immune system. "If you look at why patients didn't die in the Van den Berghe study, the only cause of death that was reduced across the board was sepsis."

In heart attack and stroke patients, insulin may keep penumbra tissue from a buildup of destructive acid levels, thereby limiting the volume of dead tissue. It may also help maintain metabolism in healthy tissue despite lower levels of oxygenated blood.

Insulin also turns out to have a huge number of anti-inflammatory properties, inhibiting inflammatory growth factors such as activator protein 1 and early growth response gene-1. "Insulin acts in these areas [affected by MI or stroke] to preserve and let the tissue survive the insult," Dr. Baldwin says.

There's more—insulin appears to have considerable anticoagulant properties. That could make it a potent ally in reducing tissue death from stroke and MI, even more so than risky and expensive clot busters and emergency angioplasties. "What does insulin cost? Pennies. Pennies! And all you have to do is check the sugar every hour," says Dr. Baldwin.

All enthusiasm aside, plenty of questions remain. "What are the longer term results?" asks David Gurka, MD, PhD, director of the section of critical care medicine and director of the MICU at Rush. "They've shown that patients do better in the ICU, but how do they do when they get out? Do they need tighter monitoring? There hasn't been enough time for that followup to happen—maybe we'll start to see that data in the next year or so."

Dr. Osei raises other questions that may have a bearing on the laboratory's role. "Is the benefit due to insulin per se, or to tighter controls? What is insulin's impact independent of glucose?" Monitoring insulin levels, hardly routine now, may become important. So might monitoring proinflammatory markers and free fatty acids.

It will also be important, he notes, to coordinate the transition between IV insulin and subcutaneous insulin as patients move out of ICUs. "Just giving them insulin in the ICU and then sending them to the ward without continuation of the protocol is a disservice."

But the larger disservice will be failing to keep tighter glycemic control in hospitalized patients. While the focus has been on hypoglycemia for years, "it turns out the real disaster is on the other end," says Dr. Baldwin.