Correspondence

Insulin and Pentastarch for Severe Sepsis

N Engl J Med 2008; 358:2071-2075May 8, 2008

Article

To the Editor:

Brunkhorst and colleagues (Jan. 10 issue)1 report that the Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) study established “that intensive insulin therapy has no measurable, consistent benefit in critically ill patients” in a medical intensive care unit (ICU). This interpretation appears too conclusive, since the Supplementary Appendix of the article (available with the full text of the article at www.nejm.org) indicates that the goal of normoglycemia was reached in less than 50% of the patients in the intensive insulin-therapy group. In addition to the intrinsic properties of an intensive insulin-therapy protocol, heterogeneity in the extrinsic factors (e.g., the level of training of nurses in the protocol and their workload) among centers participating in multicenter trials further influences the risk of failure to achieve normoglycemia.1,2 The intensive-therapy protocol used by Brunkhorst et al. was previously used in two single-center trials, with a 70% rate of successful glycemic control.3-5 To assess, in large multicenter trials, whether normoglycemia influences outcomes, the newly implemented protocol should first be cautiously adapted to ensure that normoglycemia is reached at each participating center. Otherwise, the concept of strict glycemic control in critically ill patients might be abandoned prematurely.

Jean-Claude Lacherade, M.D.
Hervé Outin, M.D.
Bernard De Jonghe, M.D.
Poissy Saint-Germain Hospital, 78300 Poissy, France
jclacherade@chi-poissy-st-germain.fr

5 References

1
Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008;358:125-139
Full Text | Web of Science | Medline

2
National Institutes of Health. Glucontrol study: comparing the effects of two glucose control regimens by insulin in intensive care unit patients. (Accessed April 18, 2008, at http://www.clinicaltrials.gov/ct/show/NCT00107601.)

3
Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359-1367
Full Text | Web of Science | Medline

4
Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006;354:449-461
Full Text | Web of Science | Medline

5
Van den Berghe G, Wilmer A, Milants I, et al. Intensive insulin therapy in mixed medical/surgical intensive care units: benefit versus harm. Diabetes 2006;55:3151-3159
CrossRef | Web of Science | Medline

To the Editor:

Several issues raised by the VISEP study deserve further discussion. The trial was discontinued prematurely because of an excessive rate of hypoglycemia in patients in the intensive-therapy group as compared with the conventional-therapy group (17.0% vs. 4.1%). The authors used the Leuven protocol, showing an 18.7% rate of hypoglycemic episodes.1 This high rate of a preventable complication is problematic. Furthermore, a complication classified as a “serious adverse event” should encourage the authors to improve the protocol rather than discontinue the study. Another interpretation of these data is that hypoglycemia may have counteracted the benefits of insulin. In the meantime, the authors' question (Does intensive insulin therapy improve outcome?) will remain unanswered.

Massive crystalloid perfusion induces edema and hyperchloremic acidosis and worsens organ perfusion. The authors report a median perfusion of 3.8 liters (maximum, 33.5) during the first 24 hours,2 which is well above the manufacturer's limit of 40 ml per kilogram of body weight per day. Exclusive colloid resuscitation leads to renal tubular swelling and failure.3 The authors report a median perfusion of 2.4 liters (maximum, 13 during the first 24 hours), which is above the manufacturer's recommendation of 20 ml per kilogram per day. The 10% solution is hyperoncotic (37 mm Hg), leading to a hyperoncotic syndrome (as in myeloma or paraproteinemia). A strategy of fluid resuscitation with the exclusive use of crystalloids or the exclusive use of colloids should be discouraged.

David Bracco, M.D., F.C.C.M.
Thomas Schricker, M.D.
George Carvalho, M.D.
McGill University Health Center, Montreal, QC H3G 1A3, Canada
david.bracco@mcgill.ca

3 References

1
Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006;354:449-461
Full Text | Web of Science | Medline

2
Zander R, Boldt J, Engelmann L, Mertzlufft F, Sirtl C, Stuttmann R. The design of the VISEP trial: critical appraisal. Anaesthesist 2007;56:71-77
CrossRef | Web of Science | Medline

3
Schortgen F, Lacherade JC, Bruneel F, et al. Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study. Lancet 2001;357:911-916
CrossRef | Web of Science | Medline

To the Editor:

In the VISEP study, intensive insulin therapy was associated with serious adverse events related to hypoglycemia (glucose level, ≤40 mg per deciliter), and 10% hydroxyethyl starch (HES 200/0.5) was associated with renal toxicity. The coprimary end points (death and the mean of the Sequential Organ Failure Assessment score) were similar in the two groups. Concerning the secondary end points, the rate of nonfatal renal failure was higher in the HES group than in the Ringer's lactate group (34.9% vs. 22.8%), and the rate of nonfatal hypoglycemia (glucose level, ≤40 mg per deciliter) was higher in the intensive-therapy group than in the conventional-therapy group (17.0% vs. 4.1%), as previously reported.1,2 The present study was discontinued because of a higher rate of more serious hypoglycemia in the intensive-therapy group than in the conventional-therapy group (7.7% vs. 2.1%). However, this serious adverse event was assessed by a physician who could have been aware of the treatment assignments. Moreover, no actual glycemia was shown. In the HES group, more patients had heart failure or underwent emergency surgery — both of which have been shown to be predictive of postoperative renal failure.3 HES allowed a more rapid normalization of central venous pressure but led to renal toxicity, especially in patients receiving higher doses than classically recommended (>20 ml per kilogram per day). Therefore, the VISEP study cannot convince us to forgo the reasonable control of glycemia and the reasonable use of safer HES (e.g., 6% HES 130/0.4).4

Laurent Muller, M.D.
Groupe Hospitalier Universitaire Carémeau, 30029 Nîmes, France

Samir Jaber, M.D., Ph.D.
Centre Hospitalier Universitaire Saint Eloi, 34000 Montpellier, France

Jean Yves Lefrant, M.D., Ph.D.
Groupe Hospitalier Universitaire Carémeau, 30029 Nîmes, France
jean.yves.lefrant@chu-nimes.fr

4 References

1
Schortgen F, Lacherade JC, Bruneel F, et al. Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study. Lancet 2001;357:911-916
CrossRef | Web of Science | Medline

2
Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006;354:449-461
Full Text | Web of Science | Medline

3
Kheterpal S, Tremper KK, Englesbe MJ, et al. Predictors of postoperative acute renal failure after noncardiac surgery in patients with previously normal renal function. Anesthesiology 2007;107:892-902
CrossRef | Web of Science | Medline

4
Jungheinrich C, Scharpf R, Wargenau M, Bepperling F, Baron JF. The pharmacokinetics and tolerability of an intravenous infusion of the new hydroxyethyl starch 130/0.4 (6%, 500 mL) in mild-to-severe renal impairment. Anesth Analg 2002;95:544-551
CrossRef | Web of Science | Medline

To the Editor:

Intensive insulin therapy during a stay in the ICU results in an absolute reduction in in-hospital mortality of 3%, a benefit that is detectable only after 28 days and that increases with the duration of therapy.1,2 Intensive insulin therapy is not expected to reduce 28-day mortality.1,2 The enrollment of 600 patients with sepsis in the VISEP study3 therefore only permitted the detection of an unrealistically high 10% absolute reduction of the secondary end point — 90-day mortality — and was underpowered by a factor of more than 10 to evaluate the reproducibility of the Leuven findings.1,2 Discontinuation of intensive insulin therapy before discharge from the ICU was a second flaw in the study design. Third, hypoglycemia itself is not a “serious adverse event,” since the benefit with respect to the outcome has been shown to outweigh the risk of brief, transient hypoglycemia.1,2 Also, the landmark Diabetes Control and Complications Trial showed that hyperglycemia, not hypoglycemia, impairs cognitive function.4 The use of hypoglycemia as a criterion would have inadvertently led to early discontinuation of this trial. Finally, why does the 39.7% rate of death at 90 days with intensive insulin therapy differ from the earlier reported rate of 29.5%?3

Brunkhorst et al. misinterpret the existing literature. In our trial involving patients in a surgical ICU, mortality was not “unusually high” but lower than predicted by the European System for Cardiac Operative Risk Evaluation (EuroSCORE) and further lowered by intensive insulin therapy.1,5 Our results involving patients in a medical ICU showed a significant reduction in morbidity in the entire intention-to-treat population; the mortality benefit was significant only in the subgroup of patients with ICU stays more than 3 days in duration.2

Greet Van den Berghe, M.D., Ph.D.
Alexander Wilmer, M.D., Ph.D.
Roger Bouillon, M.D., Ph.D.
Catholic University of Leuven, B-3000 Leuven, Belgium
greet.vandenberghe@med.kuleuven.be

5 References

1
Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359-1367
Full Text | Web of Science | Medline

2
Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006;354:449-461
Full Text | Web of Science | Medline

3
Kompetenznetz Sepsis. VISEP Studie. (Accessed April 18, 2008, at http://webanae.med.uni-jena.de/WebObjects/DSGPortal.woa/WebServerResources/sepnet/visep.html.)

4
The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Long-term effect of diabetes and its treatment on cognitive function. N Engl J Med 2007;356:1842-1852
Full Text | Web of Science | Medline

5
Ingels C, Debaveye Y, Milants I, et al. Strict blood glucose control with insulin during intensive care after cardiac surgery: impact on 4-years survival, dependency on medical care, and quality-of-life. Eur Heart J 2006;27:2716-2724
CrossRef | Web of Science | Medline

To the Editor:

The interpretation of the data on intensive insulin therapy from the VISEP trial raises serious concerns. One might wonder why the data differ markedly from extensively discussed numbers that were released earlier in an abstract1 (247 patients in the intensive-therapy group; mortality at 28 days, 21.6%; mortality at 90 days, 29.5%; rate of hypoglycemia, 12.1%).

The benefits of glycemic control have been outlined in various studies and various patient populations,2,3 suggesting an effect also in patients with sepsis,4 despite an increased risk of hypoglycemia. Nevertheless, although Brunkhorst et al. state that hypoglycemia in critically ill patients during intensive insulin therapy never proved to be harmful in itself but rather marked the severity of illness, the incidence of hypoglycemia resulted in early discontinuation of the VISEP trial. We are left with a relevant study that was markedly underpowered to draw reliable conclusions regarding survival and morbidity. Moreover, since special importance was given to hypoglycemia, more information on the quality of glycemic control and adherence to the protocol would be useful. We are curious about whether an adequately powered study might paint a different picture.

Bjorn Ellger, M.D.
Ingeborg van den Heuvel, M.D.
University Hospital of Münster, 48149 Münster, Germany
ellger@anit.uni-muenster.de

Jan Poelaert, M.D., Ph.D.
Free University Hospital Brussels, 1090 Brussels, Belgium

4 References

1
Brunkhorst FM, Kuhnt E, Engel C, et al. Intensive insulin therapy in patients with severe sepsis and septic shock is associated with an increased rate of hypoglycemia -- results from a randomized multicenter study (VISEP). Infection 2005;33:Suppl 1:19-20
Web of Science

2
Van den Berghe G, Wilmer A, Milants I, et al. Intensive insulin therapy in mixed medical/surgical intensive care units: benefit versus harm. Diabetes 2006;55:3151-3159
CrossRef | Web of Science | Medline

3
Pittas AG, Siegel RD, Lau J. Insulin therapy and in-hospital mortality in critically ill patients: systematic review and meta-analysis of randomized controlled trials. JPEN J Parenter Enteral Nutr 2006;30:164-172
CrossRef | Web of Science | Medline

4
Ellger B, Westphal M, Stubbe HD, Van den Heuvel I, Van Aken H, Van den Berghe G. Glycemic control in sepsis and septic shock: friend or foe? Anaesthesist 2008;57:43-48
CrossRef | Web of Science | Medline

Author/Editor Response

In the VISEP trial, we did measure 90-day and 28-day mortality. An interim safety analysis of intensive insulin therapy showed a nominally higher 90-day mortality, which we reported in an earlier abstract1; the increased 90-day mortality with intensive insulin therapy that we report in our article is based on the entirety of the data (39.7% vs. 35.4%, P=0.31). As pointed out by Van den Berghe et al., the rates of death from cardiac causes in the Leuven trial were not elevated according to the predicted EuroSCOREs. Nonetheless, the patients in the Leuven trial, as compared with the matched patients from Australia who underwent cardiac surgery, had higher median scores on the Acute Physiology and Chronic Health Evaluation (APACHE II): 11 vs. 9. In addition, the rates of death with conventional treatment were much higher in the Leuven trial than in the Australian trial (5.1% vs. 1.0%, P<0.001).2

The survival benefit of intensive insulin therapy has been demonstrated in only one study, which was a single-center, unblinded study involving postsurgical patients.3 In a subsequent randomized, controlled trial involving patients in the medical ICU,4 intensive insulin therapy showed no survival benefit; these findings were similar to those of our VISEP study involving patients with sepsis. Episodic hypoglycemia, however, was documented in these two studies; 16 to 18% of patients, most of whom were sedated, had mean glucose levels of 31 to 32 mg per deciliter. In another randomized, controlled trial, the administration of intensive versus conventional insulin therapy during anesthesia for cardiac surgery resulted in increased strokes (8 vs. 1, P=0.02) and deaths (4 vs. 0, P=0.06).5 Our VISEP study was discontinued early because hypoglycemia was associated with a significantly increased number of serious adverse events that were classified as life-threatening, requiring prolonged hospitalization, or resulting in significant disability or incapacity. Moreover, in order to show a survival benefit, the use of our data for 80% power to detect a difference at the 0.05 level in 28-day mortality would require enrollment of more than 30,000 patients with sepsis.

The occurrence of adverse events and the failure to reproduce a survival benefit could have many explanations, as suggested in the above letters: the studies were insufficiently powered, the wrong time frame was examined, or intensive insulin therapy was not implemented correctly. Alternatively, our conclusion that the survival benefit of intensive insulin therapy is not reproducible and that there is an increased risk associated with this therapy is accurate and consistent with the findings of the two other independent studies.3,4

The small baseline differences (in heart failure and emergency surgery) referred to by Muller et al. cannot easily explain the profound adverse effects of HES on renal failure. Patients in the treatment group did not “exclusively” receive HES in order to meet hemodynamic goals, as argued by Bracco et al. Additional crystalloid therapy was required to meet hemodynamic goals in 220 patients in the HES group (84.0%). The significant increase in renal failure occurred in both the high-dose and limited-dose HES groups, and such solutions should be avoided in patients with sepsis, particularly when safe alternatives such as saline and albumin are available for resuscitation. Thus, the 6% HES solution suggested by Muller et al. should be carefully tested for safety in adequately powered, long-term studies of sepsis before it is routinely used in this patient population.

Frank M. Brunkhorst, M.D.
Konrad Reinhart, M.D.
Friedrich-Schiller University of Jena, 07747 Jena, Germany
konrad.reinhart@med.uni-jena.de

Christoph Engel, M.D.
University of Leipzig, 04107 Leipzig, Germany

5 References

1
Brunkhorst FM, Kuhnt E, Engel C, et al. Intensive insulin therapy in patients with severe sepsis and septic shock is associated with an increased rate of hypoglycemia -- results from a randomized multicenter study (VISEP). Infection 2005;33:Suppl 1:19-20
Web of Science

2
Egi M, Bellomo R, Stachowski E, et al. Intensive insulin therapy in postoperative intensive care unit patients: a decision analysis. Am J Respir Crit Care Med 2006;173:407-413
CrossRef | Web of Science | Medline

3
Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001;345:1359-1367
Full Text | Web of Science | Medline

4
Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006;354:449-461
Full Text | Web of Science | Medline

5
Gandhi GY, Nuttall GA, Abel MD, et al. Intensive intraoperative insulin therapy versus conventional glucose management during cardiac surgery: a randomized trial. Ann Intern Med 2007;146:233-243
Web of Science | Medline

Citing Articles (1)