Anesth Analg 2002;95:1823-1824
© 2002 International Anesthesia Research Society
LETTERS TO THE EDITOR
On the Failure of Insulin to Affect Hyperglycemia During Cardiac Surgery
Thomas Schricker, MD PhD
Department of Anesthesia, Royal Victoria Hospital McGill University, Montreal, QC, Canada
To the Editor: I read with great interest the manuscript by Rassias et al. reporting a positive effect of insulin infusion on neutrophil phagocytic capacity after coronary artery bypass surgery (1). Notwithstanding the potential immunological significance of their results, the authors’ strategy to maintain normoglycemia and patient selection criteria deserve further comment.
Table 1 in the article shows that an average of 16.3 U of insulin was given and that the mean bypass time was 95 min in the study group. Accordingly, the authors’ statement in the discussion that insulin was infused at 10 U/h during extracorporal circulation can only be true if insulin was discontinued after separation from bypass. The methodology and algorithm shown in the appendix do not provide this information. If, contrary to the protocol published by Chaney et al., who continued insulin treatment until sternal closure (2), insulin was stopped immediately post bypass, why was the plasma glucose concentration on arrival in the ICU, more than 1 h later, lower than in the control group? In this context one would further appreciate information about how insulin was infused, i.e., centrally or peripherally and if corresponding tubing was preconditioned with albumin, blood or insulin prior to administration (to avoid delayed insulin delivery due to its binding to tubing material).
In order to better understand the failure of insulin to reduce hyperglycemia in this protocol, the reader also needs to know if the two groups were comparable with respect to preoperative medication, in particular ß-adrenergic blocker therapy, actual blood loss and transfusion requirements, fluid replacement, cardioplegia, absolute temperatures during bypass, end-tidal isoflurane concentrations (isoflurane has a strong hyperglycemic effect) (3), antibiotic treatment (were antibiotics diluted in dextrose 5%?), and the amount and type of catecholamines that were actually used as well as the total doses of protamine and heparin. Heparin stimulates lipoprotein lipase in vivo leading to an increase in free fatty acids, which subsequently impair glucose utilization by the so called Randle mechanism (4). Assuming that heparin dosing was based on body weight, which appeared to be greater in the treatment group, one would expect that patients in the insulin group received more heparin.
By setting the upper body mass index (BMI) limit at 37 kg/m2 the authors admitted obese patients (BMI > 28 kg/m2) to their study protocol, thereby voluntarily accepting subjects, who likely have glucose intolerance and insulin resistance (5). Although the mean BMI in the insulin group at 29.8 kg/m2 was significantly greater than in the control group (25.7 kg/m2, P = 0.0043), which per se may account for the failure of insulin to affect hyperglycemia, the discussion totally ignores this important issue.
Finally, in light of the long-recognized detrimental effects of acute hyperglycemia in surgical patients and the most recent finding of a 40% reduction in mortality by maintaining plasma glucose concentration between 80 and 110 mg/dL in critically ill patients (60% after cardiac procedures) (6), it is surprising that patients in the control group had to develop severe hyperglycemia (400 mg/dL) in order to receive insulin treatment.
References
- Rassias AJ, Givan AL, Marrin CAS, et al. Insulin increases neutrophil count and phagocytic capacity after cardiac surgery. Anesth Analg 2002; 94: 1113–9.[Abstract/Free Full Text]
- Chaney MA, Nikolov MP, Blakeman BP, Bakhos M. Attempting to maintain normoglycemia during cardiopulmonary bypass with insulin may initiate postoperative hypoglycemia. Anesth Analg 1999; 89: 1091–5.[Abstract/Free Full Text]
- Horber FF, Krayer S, Miles J, et al. Isoflurane and whole body leucine, glucose and fatty acid metabolism in dogs. Anesthesiology 1990; 73: 82–92.[Web of Science][Medline]
- Baron AD, Brechtel G, Edelman SV. Effects of free fatty acids and ketone bodies on in vivo non-insulin-mediated glucose utilization and production in humans. Metabolism 1989; 38: 1056–61.[Web of Science][Medline]
- Tighe AP, Allison DB, Kral JG, Heymsfield SB. Nutritional support of obese patients. In: Rombeau JL, Caldwell MD, eds. Clinical nutrition: parenteral nutrition. Philadelphia: WB Saunders, 1993: 716–36.
- Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. New Engl J Med 2001; 345: 1359–67.[Abstract/Free Full Text]
Response
Athos J. Rassias, MD, and
Mark P. Yeager, MD
Department of Anesthesiology, Dartmouth Medical School, Lebanon, NH
In Response: We greatly appreciate Dr. Schricker’s comments concerning our study (1) and the interesting topic of control of intraoperative hyperglycemia during cardiac surgery with cardiopulmonary bypass (CPB). His questions centered on our methodology and the observations that our protocol did not affect intraoperative glucose, although postoperative glucose was lower in the group that received insulin.
As Dr. Schricker surmised, the duration of insulin administration was limited to time on CPB. Insulin was administered centrally through tubing that was not preconditioned to decrease binding. The patients were comparable with regards to preoperative medications, intraoperative fluid replacement, blood product transfusions, amount of cell saver blood replaced, and catecholamine administration. Five patients in the control group and three patients in the insulin group received catecholamine infusions during the time of separation from CPB, for an average time duration of 30 and 45 min, respectively. The anesthetic agents were comparable between groups. The initial heparin dose that was administered was indeed weight-based, but the two groups received similar doses overall (32,439 U and 33,071 U on average for the control and insulin groups, respectively, P = 0.869). This likely reflects the subsequent doses administered in response to activated clotting times, as it is well known that the response to heparin dosing is highly variable. While the group receiving insulin did indeed have a greater body mass index (BMI), upon multivariate analysis this factor did not affect glucose levels.
Our study is in agreement with previously published observations by Chaney et al. that an intraoperative insulin infusion leads to lower postoperative glucose levels but unchanged intraoperative levels (2). As Dr. Schricker observes, Chaney et al. continued their insulin protocol through the period of sternal closure (2) and our protocol ceased insulin at the time of separation from CPB. It should be noted that the primary stimulus for hyperglycemia during cardiac surgery is CPB (3). Hence, once this profound stimulus ceases, it is not surprising that normal glucose control returns quickly, and the exogenous insulin administered will have an additive effect. This would be expected to lead to lower postoperative glucose levels.
We strongly agree with Dr. Schricker’s concerns against allowing patients to remain hyperglycemic, especially given the recent exciting findings of Van den Berghe et al. (4). It must be noted that CPB is a potent stimulus for hyperglycemia (3), as well as an activator of the inflammatory response (5). While the hyperglycemia associated with CPB has been recognized for many years, the impact of this transient alteration in glucose control in the face of the activation of the systemic inflammatory response is poorly understood. We previously found that diabetic patients undergoing CPB have improved neutrophil phagocytosis and improved intraoperative glycemic control with an aggressive insulin infusion (6). However, the issue of hyperglycemia associated with CPB and nondiabetic patients is incompletely understood. Indeed, we were prompted to study this issue in light of the lack of consensus as to the importance of hyperglycemia during CPB in this patient population.
References
- Rasslas AJ, Givan AL, Marrin CA, Whalen K, Pahl J, Yeager MP. Insulin increases neutrophil phagocytic capacity in non-diabetic cardiac surgical patients. Anesthesia and Analgesia 2002; 94: 1113–9.
- Chaney MA, Nikolov MP, Blakeman , et al. Attempting to maintain normoglycemia during cardiopulmonary bypass with insulin may initiate postoperative hypoglycemia. Anesth Analg 1999; 89: 1091–5.
- Lehot J, Piriz H, Villard J, et al. Glucose homeostasis - comparison between hypothermic and normothermic cardiopulmonary bypass. Chest 1992; 102: 106–11.[Abstract/Free Full Text]
- Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001; 345: 1359–67.
- Knudsen F, Andersen LW. Immunological aspects of cardiopulmonary bypass. J Cardiothorac Anesth 1990; 4: 245–58.[Medline]
- Rassias AJ, Marrin CA, Arruda J, Whalen PK, Beach M, Yeager MP. Insulin infusion improves neutrophil function in diabetic cardiac surgery patients. Anesthesia and Analgesia 1999; 88: 1011–6.[Abstract/Free Full Text]
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