Glucose Control in Post-Cardiac Arrest Care

Hyperglycemia in critically ill patients, such as post-cardiac arrest patients, is associated with poor clinical outcomes.^1-2 Critically ill patients have an increase in the production of cortisol, catecholamines, glucagon, growth hormone, gluconeogenesis and glycogenolysis that is responsible for hyperglycemia.³ Likewise, more than 80% of these patients demonstrate insulin resistance.⁴ Hyperglycemia following trauma increases mortality, hospital length of stay, intensive care unit (ICU) length of stay and incidence of nosocomial infections.^5-8 A prospective cohort study with 1003 critically ill patients who were admitted to the ICU following trauma showed that patients with blood glucose levels greater than 200 mg/dL have significantly increased mortality (26%) when compared to patients who were normoglycemic (12%). Also, hyperglycemic patients are more prone to nosocomial infections compared with normoglycemic patients (52% vs. 32%).⁷

Hyperglycemia in the critically ill is secondary to medical and surgical etiologies and leads to an increase in mortality. A retrospective cohort study of 1826 patients showed that those patients who had died had significantly higher admission blood glucose levels (175 mg/dl versus 151 mg/dL), mean blood glucose levels (172 mg/dL vs. 138 mg/dL) and maximum blood glucose levels (258 mg/dl versus 177 mg/dL).⁹ In this study, the mortality in hyperglycemic patients with blood glucose levels of greater than 300 mg/dL is 43%, whereas only 10% of normoglycemic patients died.

It is common to correct hyperglycemia in post-cardiac arrest patients to improve outcomes; however, the approach is not straightforward. The optimal blood glucose range is still a contentious issue. To provide a better understanding of the management of post-cardiac arrest glycemic control, we describe the following important clinical trials:

Surgical Trials

1. Leuven surgical trial¹⁰ – randomly assigned surgical ICU patients who were critically ill (n= 1548) to receive either intensive insulin therapy (IIT) or conventional blood glucose management. IIT’s goal was to maintain blood glucose levels of 80 mg/dL to 110 mg/dL, while the conventional blood glucose management goal was to maintain a blood glucose level of 180 mg/dL to 200 mg/dL through the use of conventional oral antidiabetic medications and/or an insulin infusion if the blood glucose level was greater than 215 mg/dl. They determined the following results: the IIT group had significantly lower mean blood glucose levels (103 mg/dL versus 153 mg/dL); ICU and hospital mortality in the IIT group was significantly lower (4.6% versus 8.0% and 7.2% versus 10.9% respectively); IIT decreased the incidence of polymyoneuropathy, acute renal failure, transfusion requirements, and blood stream infections; and hypoglycemia was more frequent in the IIT group.What is controversial about this study is that both groups were initially given 200 to 300 grams of intravenous glucose, which may have caused higher mortality rates when compared to other, similar studies done previously (mortality in the Leuven study is 8% and 11% versus 1.3% to 3.5% in the 2006 Likosky study and 2007 Becker study). It was argued that an intravenous infusion of glucose was harmful to the control group but not the IIT group because they were treated with the more aggressive insulin regimen.
2. Agus Study¹³ – This study contradicts the findings in the Leuven study. The administration of exogenous glucose was not performed in this study. This study involved 989 pediatric patients undergoing cardiopulmonary bypass. Patients were randomly assigned to a tight glycemic control group to maintain a blood glucose range of 80 mg/dl to 110 mg/dl or to standard care. Results showed that there was no difference in mortality, length of ICU stay, healthcare-associated infections, or several organ specific end-points. Severe hypoglycemia occurred in 3% of patients in the tight glycemic control group and only in 1% of patients in the standard care group.

Medical Trials

1. Leuven Medical Trial¹⁴ – Study protocols were the same as in the Leuven surgical trials, where 1200 ICU patients were randomly assigned to IIT or conventional blood glucose management. The results showed that IIT resulted in a lower mean blood glucose (105 mg/dL versus 160 mg/dL); IIT did not change the overall hospital mortality of 37.3 % versus 40% in the control group; IIT significantly reduced ICU length of stay, duration of mechanical ventilation, and acute kidney failure; and hypoglycemia in the IIT group was more common compared to the control group.
2. Corticosteroids and Intensive Insulin Therapy for Septic Shock (COIITSS)¹⁵ – This study utilized the IIT or conventional blood glucose management protocols of the Leuven study and randomly assigned 509 septic shock patients to these groups. The results showed no significant difference in mortality, ICU length of stay, ventilator-free days, or vasopressor-free days.

Surgical/Medical Patients

1. Normoglycemia in Intensive Care Evaluation Survival Using Glucose Algorithm Regulation (NICE-SUGAR) Trial¹⁶ – This study utilized the IIT and conventional glucose control protocol and randomly assigned 6104 medical or surgical ICU patients to each group. The IIT group had lower time-weighted blood glucose (115 mg/dL versus 144 mg/dL); the IIT group had higher 90-day mortality (27.5% versus 24.9%, odds ratio 1.14, 95% CI 1.02-1.28); and the IIT group had a higher incidence of severe hypoglycemia (6.8% versus 0.5%). Operative patients (n= 2232) showed that IIT had significantly higher mortality compared to conventional glycemic control (24.4% versus 19.8%, odds ratio 1.31, 95% CI 1.07-1.61).
2. The Volume Substitution and Insulin Therapy in Severe Sepsis Trial (VISEP)¹⁷ – An important issue in this study was that 488 patients undergoing IIT experienced increased rates of hypoglycemia and severe adverse events. Because of this, the study was interrupted. IIT and conventional glucose management outcomes were compared to medical and surgical patients, as well as comparing two methods of volume resuscitation. The results showed that morning blood glucose was significantly lower in the IIT group (112 mg/dL versus 151 mg/dL); hypoglycemia was more common in the IIT group (17% versus 4.1%); there was no significant difference in 28-day mortality, morbidity, or organ failure; and the 90-day mortality increase in the IIT group (39.7%) versus the control group (35.4%) was not statistically significant.
3. Glucontrol Trial¹⁸ – This was another controversial trial that was terminated due to numerous protocol violations. They studied 1101 critically ill medical and surgical patients that were randomly assign to IIT or conventional glucose control. Results showed that IIT increased the rate of hypoglycemia (8.7% versus 2.7%); there was no significant difference in ICU mortality.

Iatrogenic hypoglycemia in these trials is the most common adverse effect in patients who were assigned to undergo IIT. This could be problematic because hypoglycemia leads to seizures, brain damage, depression, cardiac arrhythmias and death. Other indicators to improve outcomes either are not significant or controversial. Hence, the American Heart Association guidelines of post-cardiac arrest care for hyperglycemic control is to maintain a blood glucose level of 144 mg/dL to 180 mg/dL (Class IIb). The more stringent target of 80 mg/dL to 110 mg/dL is not recommended in order to prevent iatrogenic hypoglycemia. Also, a more liberal target of 180 mg/dL to 200 mg/dL is to be avoided to prevent marked hyperglycemia.

References:

• Longstreth WT Jr., Cobb LA, et al. Neurologic outcome and blood glucose levels during out-of-hospital cardiopulmonary resuscitation. Neurology 1986; 36:1186.
• Skrifvars MB, Pettila V, Rosenberg PH, Castren M. A multiple logistic regression analysis of in-hospital factors related to survival at six months in patients resuscitated from out-of-hopital ventricular fibrillation. Resuscitation 2003; 59:319.
• McCowen KC, Malhotra A, Bistrian BR. Stress-induced hyperglycemia. Crit Care Clin 2001; 17:107.
• Saberi F, Heyland D, Lam M. et al. Prevalence, incidence, and clinical resolution of insulin resistance in critically ill patients: an observational study. JPEN J Parenter Enteral Nutr 2008; 32:227.
• Yendamuri S, Fluda GJ, Tinkoff GH. Admission hyperglycemia as a prognostic indicator in trauma patients. J Trauma 2003; 53:33.
• Laird AM, Miller PR, Kilgo PD, et. al. Relationship of early hyperglycemia to mortality in trauma patients. J Trauma 2004; 56:1058.
• Sung J, Bochicchio GV, Josh M, et. al. Admission hyperglycemia is predictive of outcome in critically ill trauma patients. J Trauma 2005; 59:80.
• Bochicchio GV, Sung J, Joshi M. et. al. Persistent hyperglycemia is predictive of outcome in critically ill trauma patient. J Trauma 2005; 58:921.
• Krinsley JS. Association between hyperglycemia and increased hospital mortality in heterogeneous population of critically ill patients. Mayo Clin Proc 2003; 78:1471.
• van den Berghe G, Wouters P, Weekers F, et. al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001; 345:1359.
• Likosky DS, Nugent WC, Clough RA, et. al. Comparison of three measurements of cardiac surgery mortality for Northern New England Cardiovascular Disease Study Group. Ann Thorac Surg 2006; 81:1393.
• Becker ER, McPherson MA, Rahimi A. Influence of source and type of admission on in-hospital mortality for coronary artery bypass surgery patient: national results from 1.7 million CABG patients, 1998 to 2002. J Card Surg 2007; 22:203.
• Agus MS, Steil GM, Wypij D, et. al. Tight glycemic control versus standard care after pediatric cardiac surgery. N Engl J Med 2012; 367:1208.
• van den Berghe G, Wouters P, Weekers F, et. al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006; 354:449.
• COIITTSS Study Investigators, Annane D, Cariou A, et. al. Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial. JAMA 2010; 303:341.
• NICE-SUGAR Study Investigators, Finfer S, Chittock DR, et. al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009; 360:1283.
• Brunkhorst FM, Engel C, Bloos F. et. al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis.N Engl J Med 2008; 358:125.
• Preiser JC, Devos P,A prospective randomized multi-centre controlled trial on tight glucose control by intensive insulin therapy in adult intensive care units: the Glucontrol study. Intensive Care Med 2009; 35:1738.
• 2016 American Heart Association Basic Life Support Provider Manual

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