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Correspondence |

Is Intensive Insulin Therapy Safe in the Critically Ill? FREE TO VIEW

Mohamed Y. Rady, MD PhD
Author and Funding Information

Affiliations: Mayo Clinic College of Medicine, Phoenix, AZ,  University College London Foundation Hospitals, London, UK,  University of Pittsburgh School of Medicine,  Royal Children’s Hospital, Brisbane, QLD, Australia,  *Wake Forest University School of Medicine, Winston-Salem, NC

Correspondence to: Mohamed Y. Rady, MD, PhD, Professor of Critical Care Medicine, Mayo College of Medicine, Mayo Clinic Hospital, 5777 East Mayo Blvd, Phoenix, AZ 85054; e-mail: rady.mohamed@mayo.edu



Chest. 2006;130(4):1278-1281. doi:10.1378/chest.130.4.1278
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Published online

To the Editor:

Hamdulay et al1 described two similar cases of severe reversible cardiac depression, temporally related to exposure to chemotherapy agents for the treatment of lymphoma or prior to haploidentical bone marrow transplantation. Both cases required continuous venovenous hemofiltration, which had been reported to result in the reversal of septic shock and hemodynamic improvement over time because of the plasma clearance of myocardial depressant cytokines. It could be argued that the hemodynamic recovery witnessed was not related to insulin-glucose infusion but was explained by time-dependent plasma clearance of inflammatory cytokines because of the earlier initiation of continuous renal replacement therapy.

There are several studies that have indicated that indiscriminate intensive insulin therapy to maintain a blood glucose level at < 6.1 mmol/L (110 mg/dL) can result in attributable mortality. A large randomized controlled trial2in patients with acute myocardial infarction reported that insulin therapy at a blood glucose level < 7 mmol/L (126 mg/dL) increased the mortality rate to 8.3% (control mortality rate, 6.6%; p < 0.01). Murcia et al3reported that the cumulative risk for total mortality including cardiovascular mortality and morbidity increased with insulin treatment in diabetic patients with acute myocardial infarction and left ventricular failure. In a recent study by Van den Berghe et al,4intensive insulin therapy in patients with a short length of stay in the ICU and low severity of illness had a much higher mortality rate (27%) compared to patients receiving conventional insulin therapy (19%) [ie, a relative increase in mortality of 42%; p = 0.045]. The premature and indiscriminate use of intensive insulin therapy in the ICU, which is based on 2004 recommendations5 without robust scientific evidence, may have resulted in preventable death across the United States. The early resolution of stressors related to the acute illness and minimizing the iatrogenic interventions that exacerbate hyperglycemia rather than prescribing intensive insulin therapy in critically ill patients is the safest method for improved glycemic control and survival.

Dr. Rady has no affiliations or financial involvement with any organization or entity with a direct financial interest in the subject matter or materials discussed in the article.

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Table Graphic Jump Location
Table 1. Common Symptoms of Cough*
* 

FB = fiberoptic bronchoscopy; ACCP = American College of Chest Physicians; RCT = randomized controlled trial; GER = gastroesophageal reflux; GERD = gastroesophageal reflux disease.

The author has no conflicts of interest to disclose.

Hamdulay, SS, Khafaji, AA, Montgomery, H (2006) Glucose-insulin and potassium infusions in septic shock.Chest129,800-804. [CrossRef] [PubMed]
 
The CREATE-ECLA Trial Group Investigators.. Effect of glucose-insulin-potassium infusion on mortality in patients with acute ST-segment elevation myocardial infarction: the CREATE-ECLA Randomized Controlled Trial.JAMA2005;293,437-446. [CrossRef] [PubMed]
 
Murcia, AM, Hennekens, CH, Lamas, GA, et al Impact of diabetes on mortality in patients with myocardial infarction and left ventricular dysfunction.Arch Intern Med2004;164,2273-2279. [CrossRef] [PubMed]
 
Van den Berghe, G, Wilmer, A, Hermans, G, et al Intensive insulin therapy in the medical ICU.N Engl J Med2006;354,449-461. [CrossRef] [PubMed]
 
Garber, AJ, Moghissi, ES, Bransome, ED, Jr, et al American College of Endocrinology position statement on inpatient diabetes and metabolic control.Endocrine Pract2004;10,77-82
 
To the Editor:

We thank Dr. Rady on his comments regarding our review on glucose-insulin and potassium infusions in septic shock.1 However, we disagree on his suggestion that the hemodynamic improvement that occurred in our patients could be attributed to the continuous veno-venous hemofiltration (CVVH).

CVVH has been widely used for the treatment of critically ill patients with acute renal failure, and the effects of CVVH on inflammatory responses have been aggressively investigated.24 Although circulating inflammatory cytokines were removed by ultrafiltration and adsorption, studies failed to show a decrease in plasma cytokine levels,34 even with an aggressive high-volume hemofiltration.5Having said that, high-volume hemofiltration can significantly improve hemodynamic instability and decrease the vasopressor dose in septic shock patients.6 Nearly all of our patients with sepsis and renal failure are receiving CVVH, yet such dramatic reductions in vasopressor support that we described are unique to the patients in whom we used glucose-insulin-potassium infusion (GIK).

Dr. Rady mentioned that driving glucose to lower levels has been associated with adverse effects on mortality, and therefore therapies that intensively use insulin are to be avoided. It is important to differentiate between the use of GIK as an adjunct to vasopressor in hypodynamic septic shock and the much-discussed tight glucose control in intensive care. Our case reports and literature review make the case that high doses of insulin used in combination with glucose loading may yet have a role in improving hemodynamics. Finally, we agree that GIK should not be used indiscriminately, and further studies to establish its utility as an adjunct to the traditional vasopressors in patients with hypodynamic septic shock should be carried out.

References
Hamdulay, SS, Al-Khafaji, A, Montgomery, H Glucose-insulin and potassium infusions in septic shock.Chest2006;129,800-804. [CrossRef] [PubMed]
 
Ronco, C, Bellomo, R, Ricci, Z Continuous renal replacement therapy in critically ill patients.Nephrol Dial Transplant2001;16,67-72
 
Sander, A, Armbruster, W, Sander, B, et al Haemofiltration increases IL-6 clearance in early systemic inflammatory response syndrome but does not alter IL-6 and TNF plasma concentration.Intensive Care Med1997;23,878-884. [CrossRef] [PubMed]
 
Cole, L, Bellomo, R, Hart, G, et al A phase II randomized controlled trial of continuous hemofiltration in sepsis.Crit Care Med2002;30,100-106. [CrossRef] [PubMed]
 
Cole, L, Bellomo, R, Journois, D, et al High-volume haemofiltration in human septic shock.Intensive Care Med2001;27,978-986. [CrossRef] [PubMed]
 
Ronco, C, Bellomo, R, Homel, P, et al Effect of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: a prospective randomized trial.Lancet2000;356,26-30. [CrossRef] [PubMed]
 
To the Editor:

We thank Dr. Rubin for his kind comments about our study (May 2006),1which he stated was “one of the most complete studies” of its kind in the pediatric population.2 For readers unfamiliar with the literature on the common symptoms of cough, it is necessary that some points should be clarified, which are summarized in Table 1 .

We conducted a prospective cohort study investigating 108 children for the cause of their chronic cough, using an adult-based approach followed by treatment as appropriate and a defined timeframe to response of 2 weeks, given the placebo and period effect of cough. Dr. Rubin has stated that the pathway used was “radically different” from that used by Irwin and colleagues.3 As we have stated in the article,1the pathway has been modified for children as instinctively treating young children will never be the same as treating adults because children cannot tell you they have reflux symptoms as adults can, and, as Dr. Rubin himself states, diagnoses such as cystic fibrosis and tracheomalacia are an “essential part of the evaluation in children.”2 We felt it more important to ensure a thorough and complete investigation of the causes in children than to stringently adhere to the adult protocol, which was designed and tested some decades ago.

We thank Dr. Rubin for highlighting the important new diagnosis of protracted bacterial bronchitis (PBB) but feel it necessary to point out that he has misquoted the diagnostic criteria, which are, in fact, a history of chronic moist cough, the presence of at least a single species of pathogenic bacterial organism at a growth of ≥ 105 cfu/mL, and the resolution of cough with antibiotic therapy in a 2-week period. PBB was not diagnosed based on the presence of increased neutrophils in BAL fluid and was not diagnosed based on the presence of viral or nonpathogenic bacterial organisms. This is a new diagnostic entity, and much is still to be learned about the clinical features, airway inflammatory profile, and causative factors. We look forward to being able to shed further light on this condition in the near future.

References
Marchant, JM, Masters, IB, Taylor, SM, et al Evaluation and outcome of young children with chronic cough.Chest2006;129,1132-1141. [CrossRef] [PubMed]
 
Rubin, BK Pediatricians are not just small internists.Chest2006;129,1118-1121. [CrossRef] [PubMed]
 
Irwin, RS, Corrao, WM, Pratter, MR Chronic persistent cough in the adult: the spectrum and frequency of causes and successful outcome of specific therapy.Am Rev Respir Dis1981;123,413-417. [PubMed]
 
Chang, AB, Glomb, WB Guidelines for evaluating cough in pediatrics: ACCP evidence-based clinical practice guidelines.Chest2006;129(suppl),260S-283S
 
Chang, AB, Gaffney, JT, Eastburn, MM, et al Cough quality in children: a comparison of subjective vs. bronchoscopic findings. Respir Res. 2005;;6 ,.:3. [CrossRef] [PubMed]
 
To the Editor:

I appreciate Dr. Marchant and Chang’s comments on my editorial1pointing out that although their study2was an important evaluation of cough in a large number of young children, the protocol that they chose was quite different from that validated in adults as described by Irwin and colleagues.3They included a number of children with a cough of < 8 weeks duration, and more importantly, they did not evaluate for upper airway cough syndrome, asthma, or gastroesophageal reflux as the major diagnosis noted in adults with chronic cough. These were also noted to be common causes of chronic cough in pediatric studies as well.4Because they chose a radically different approach to the diagnosis, it is impossible to know whether the children in their study had gastroesophageal reflux, asthma, or upper airways cough syndrome. By choosing bronchoscopy as their principal diagnostic test in these patients, the authors determined that 40% of the children had “prolonged bacterial bronchitis” (PBB), although these children did not have increased airway secretions. This is in contradistinction to a report5 that in adults PBB is associated with a large amount of airway secretions. This suggests that the “moist cough” they heard in these children could have been from upper airway secretions in the back of the child’s throat.

These authors are internationally recognized experts regarding the evaluation and treatment of chronic cough in children. I am looking forward to further studies that might better answer the question “Are children with chronic cough really that different from adults?”

References
Rubin, BK Pediatricians are not just small internists.Chest2006;129,1118-1121. [CrossRef] [PubMed]
 
Marchant, JM, Masters, IB, Taylor, SM, et al Evaluation and outcome of young children with chronic cough.Chest2006;129,1132-1141. [CrossRef] [PubMed]
 
Irwin, RS, Madison, JM The diagnosis and treatment of cough.N Engl J Med2000;343,1715-1721. [CrossRef] [PubMed]
 
Holinger, LD, Sanders, AD Chronic cough in infants and children: an update.Laryngoscope1991;101,596-605. [PubMed]
 
Schaefer, OP, Irwin, RS Unsuspected bacterial suppurative disease of the airways presenting as chronic cough.Am J Med2003;114,602-606. [CrossRef] [PubMed]
 

Figures

Tables

Table Graphic Jump Location
Table 1. Common Symptoms of Cough*
* 

FB = fiberoptic bronchoscopy; ACCP = American College of Chest Physicians; RCT = randomized controlled trial; GER = gastroesophageal reflux; GERD = gastroesophageal reflux disease.

References

Hamdulay, SS, Khafaji, AA, Montgomery, H (2006) Glucose-insulin and potassium infusions in septic shock.Chest129,800-804. [CrossRef] [PubMed]
 
The CREATE-ECLA Trial Group Investigators.. Effect of glucose-insulin-potassium infusion on mortality in patients with acute ST-segment elevation myocardial infarction: the CREATE-ECLA Randomized Controlled Trial.JAMA2005;293,437-446. [CrossRef] [PubMed]
 
Murcia, AM, Hennekens, CH, Lamas, GA, et al Impact of diabetes on mortality in patients with myocardial infarction and left ventricular dysfunction.Arch Intern Med2004;164,2273-2279. [CrossRef] [PubMed]
 
Van den Berghe, G, Wilmer, A, Hermans, G, et al Intensive insulin therapy in the medical ICU.N Engl J Med2006;354,449-461. [CrossRef] [PubMed]
 
Garber, AJ, Moghissi, ES, Bransome, ED, Jr, et al American College of Endocrinology position statement on inpatient diabetes and metabolic control.Endocrine Pract2004;10,77-82
 
Hamdulay, SS, Al-Khafaji, A, Montgomery, H Glucose-insulin and potassium infusions in septic shock.Chest2006;129,800-804. [CrossRef] [PubMed]
 
Ronco, C, Bellomo, R, Ricci, Z Continuous renal replacement therapy in critically ill patients.Nephrol Dial Transplant2001;16,67-72
 
Sander, A, Armbruster, W, Sander, B, et al Haemofiltration increases IL-6 clearance in early systemic inflammatory response syndrome but does not alter IL-6 and TNF plasma concentration.Intensive Care Med1997;23,878-884. [CrossRef] [PubMed]
 
Cole, L, Bellomo, R, Hart, G, et al A phase II randomized controlled trial of continuous hemofiltration in sepsis.Crit Care Med2002;30,100-106. [CrossRef] [PubMed]
 
Cole, L, Bellomo, R, Journois, D, et al High-volume haemofiltration in human septic shock.Intensive Care Med2001;27,978-986. [CrossRef] [PubMed]
 
Ronco, C, Bellomo, R, Homel, P, et al Effect of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: a prospective randomized trial.Lancet2000;356,26-30. [CrossRef] [PubMed]
 
Marchant, JM, Masters, IB, Taylor, SM, et al Evaluation and outcome of young children with chronic cough.Chest2006;129,1132-1141. [CrossRef] [PubMed]
 
Rubin, BK Pediatricians are not just small internists.Chest2006;129,1118-1121. [CrossRef] [PubMed]
 
Irwin, RS, Corrao, WM, Pratter, MR Chronic persistent cough in the adult: the spectrum and frequency of causes and successful outcome of specific therapy.Am Rev Respir Dis1981;123,413-417. [PubMed]
 
Chang, AB, Glomb, WB Guidelines for evaluating cough in pediatrics: ACCP evidence-based clinical practice guidelines.Chest2006;129(suppl),260S-283S
 
Chang, AB, Gaffney, JT, Eastburn, MM, et al Cough quality in children: a comparison of subjective vs. bronchoscopic findings. Respir Res. 2005;;6 ,.:3. [CrossRef] [PubMed]
 
Rubin, BK Pediatricians are not just small internists.Chest2006;129,1118-1121. [CrossRef] [PubMed]
 
Marchant, JM, Masters, IB, Taylor, SM, et al Evaluation and outcome of young children with chronic cough.Chest2006;129,1132-1141. [CrossRef] [PubMed]
 
Irwin, RS, Madison, JM The diagnosis and treatment of cough.N Engl J Med2000;343,1715-1721. [CrossRef] [PubMed]
 
Holinger, LD, Sanders, AD Chronic cough in infants and children: an update.Laryngoscope1991;101,596-605. [PubMed]
 
Schaefer, OP, Irwin, RS Unsuspected bacterial suppurative disease of the airways presenting as chronic cough.Am J Med2003;114,602-606. [CrossRef] [PubMed]
 
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