title: Simulation and qualitative analysis of glucose variability, mean glucose, and hypoglycemia after subcutaneous insulin therapy for stress hyperglycemia.
abstract: BACKGROUND
  The critically ill can have persistent dysglycemia during the "subacute" recovery phase of their illness because of altered gene expression; it is also not uncommon for these patients to receive continuous enteral nutrition during this time. The optimal short-acting subcutaneous insulin therapy that should be used in this clinical scenario, however, is unknown. Our aim was to conduct a qualitative numerical study of the glucose-insulin dynamics within this patient population to answer the above question. This analysis may help clinicians design a relevant clinical trial.
  
  
  METHODS
  Eight virtual patients with stress hyperglycemia were simulated by means of a mathematical model. Each virtual patient had a different combination of insulin resistance and insulin deficiency that defined their unique stress hyperglycemia state; the rate of gluconeogenesis was also doubled. The patients received 25 injections of subcutaneous regular or Lispro insulin (0-6 U) with 3 rates of continuous nutrition. The main outcome measurements were the change in mean glucose concentration, the change in glucose variability, and hypoglycemic episodes. These end points were interpreted by how the ultradian oscillations of glucose concentration were affected by each insulin preparation.
  
  
  RESULTS
  Subcutaneous regular insulin lowered both mean glucose concentrations and glucose variability in a linear fashion. No hypoglycemic episodes were noted. Although subcutaneous Lispro insulin lowered mean glucose concentrations, glucose variability increased in a nonlinear fashion. In patients with high insulin resistance and nutrition at goal, "rebound hyperglycemia" was noted after the insulin analog was rapidly metabolized. When the nutritional source was removed, hypoglycemia tended to occur at higher Lispro insulin doses. Finally, patients with severe insulin resistance seemed the most sensitive to insulin concentration changes.
  
  
  CONCLUSIONS
  Subcutaneous regular insulin consistently lowered mean glucose concentrations and glucose variability; its linear dose-response curve rendered the preparation better suited for a sliding-scale protocol. The longer duration of action of subcutaneous regular insulin resulted in better glycemic-control metrics for patients who were continuously postprandial. Clinical trials are needed to examine whether these numerical results represent the glucose-insulin dynamics that occur in intensive care units; if present, their clinical effects should be evaluated.
authors.affiliation: Department of Trauma and Critical Care Surgery, San Antonio Military Medical Center, 3551 Roger Brooke Drive, Fort Sam Houston, San Antonio, TX, USA. rich.strilka.md@gmail.com.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Strilka
authors.affiliation: Department of Trauma and Critical Care Surgery, San Antonio Military Medical Center, 3551 Roger Brooke Drive, Fort Sam Houston, San Antonio, TX, USA. mamiestull@gmail.com.
authors.forename: Mamie C
authors.initials: MC
authors.lastname: Stull
authors.affiliation: Department of Trauma and Critical Care Surgery, San Antonio Military Medical Center, 3551 Roger Brooke Drive, Fort Sam Houston, San Antonio, TX, USA. michael.s.clemens@gmail.com.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Clemens
authors.affiliation: Walter Reed National Military Medical Center, 8901 Rockville Pike, Bethesda, MD, USA. stewart.mccarver@gmail.com.
authors.forename: Stewart C
authors.initials: SC
authors.lastname: McCaver
authors.affiliation: Division of Trauma, Acute Care and Critical Care Surgery, Pennsylvania State College of Medicine, 500 University Drive, Hershey, PA, USA. sarmen@hmc.psu.edu.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Armen
mesh_terms: D001786:Blood Glucose / Q000032:analysis*; D002940:Circadian Rhythm; D003198:Computer Simulation; D016638:Critical Illness; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000097:blood* / Q000188:drug therapy*; D007003:Hypoglycemia / Q000097:blood*; D007328:Insulin / Q000627:therapeutic use*; D061268:Insulin Lispro / Q000627:therapeutic use; D007333:Insulin Resistance; D008962:Models, Theoretical; D009991:Oscillometry; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D007328:Insulin; D061268:Insulin Lispro; D005947:Glucose
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