Beneficial myocardial metabolic effects of insulin during verapamil toxicity in the anesthetized canine

Jeffrey Kline, E. Leonova, R. M. Raymond

Research output: Contribution to journalArticle

96 Citations (Scopus)

Abstract

Objective: Myocardial depression from verapamil toxicity may result from alterations in carbohydrate metabolism as well as calcium-channel antagonism. We hypothesized that pharmacologic doses of insulin may be effective in reversing both of these deficits. Design: Randomized, controlled, prospective study. Setting: Laboratory of an urban hospital. Subjects: Thirty mongrel dogs. Interventions: Thirty mongrel canines were anesthetized with α- chloralose. Toxicity was induced by the administration of 0.1 mg/kg/min iv of verapamil, until there was a 50% reduction in mean arterial pressure, for 30 mins (titration), followed by a continuous verapamil infusion of 1 mg/kg/hr. Animals (n = 6 per group) were randomized to the control group (saline only) or to one of four treatment protocols: a) calcium chloride (20 mg/kg), then 0.6 mg/kg/hr; b) hyperinsulinemia-euglycemia (4.0 U/min of recombinant insulin, with arterial glucose concentration clamped to ±10 mg/dL [±0.5 mmol/L] of the basal value); c) epinephrine, with a starting rate of 1.0 μg/kg/min, titrated to maintain left ventricular pressure at basal values; or d) glucagon, a 0.2-mg/kg bolus, followed by a 150-μg/kg/hr infusion. Animals were monitored until death or 240 mins; infusate volumes were held constant for all groups. Measurements and Main Results: During verapamil titration, the myocardial respiratory quotient increased from 0.84 ± 0.05 to 1.07 ± 0.11 (p <.05, paired t-test) and myocardial glucose uptake doubled, despite a reduction in cardiac work (p <.05, paired t-test). Net myocardial lactate uptake also increased significantly, excluding myocardial ischemia. In controls, this trend continued, indicating preferential carbohydrate metabolism during untreated verapamil toxicity. Despite hyperglycemia, the plasma insulin concentration was not significantly different in controls (basal value 11 ± 2 vs. 39 ± 21 μU/mL at 30 mins). Hyperinsulinemia- euglycemia increased both myocardial glucose and lactate uptake five-fold, and significantly increased the ratio of myocardial oxygen delivery/work, along with superior improvements in maximal left ventricular elastance at end systole compared with other treatments (p <.05 vs. other treatments, contrast analysis). Conclusions: Verapamil toxicity renders the heart dependent on carbohydrate metabolism. Inasmuch as the positive inotropic effects of all treatments were coincident with increased indices of myocardial carbohydrate uptake, adequate treatment of verapamil toxicity appeared to require maximal myocardial carbohydrate utilization. Hyperinsulinemia-euglycemia allows larger increases in myocardial carbohydrate metabolism and myocardial contractility than calcium chloride, epinephrine, or glucagon, resulting in improved survival rates during severe verapamil toxicity.

Original languageEnglish (US)
Pages (from-to)1251-1263
Number of pages13
JournalCritical Care Medicine
Volume23
Issue number7
DOIs
StatePublished - 1995
Externally publishedYes

Fingerprint

Verapamil
Canidae
Insulin
Carbohydrate Metabolism
Hyperinsulinism
Calcium Chloride
Glucagon
Glucose
Epinephrine
Lactic Acid
Carbohydrates
Chloralose
Systole
Urban Hospitals
Ventricular Pressure
Calcium Channels
Clinical Protocols
Hyperglycemia
Myocardial Ischemia
Arterial Pressure

Keywords

  • calcium chloride
  • calcium-channel blocker
  • critical illness
  • drug toxicity
  • epinephrine
  • glucagon
  • glucose
  • insulin
  • lactate
  • myocardial metabolism
  • verapamil

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Beneficial myocardial metabolic effects of insulin during verapamil toxicity in the anesthetized canine. / Kline, Jeffrey; Leonova, E.; Raymond, R. M.

In: Critical Care Medicine, Vol. 23, No. 7, 1995, p. 1251-1263.

Research output: Contribution to journalArticle

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title = "Beneficial myocardial metabolic effects of insulin during verapamil toxicity in the anesthetized canine",
abstract = "Objective: Myocardial depression from verapamil toxicity may result from alterations in carbohydrate metabolism as well as calcium-channel antagonism. We hypothesized that pharmacologic doses of insulin may be effective in reversing both of these deficits. Design: Randomized, controlled, prospective study. Setting: Laboratory of an urban hospital. Subjects: Thirty mongrel dogs. Interventions: Thirty mongrel canines were anesthetized with α- chloralose. Toxicity was induced by the administration of 0.1 mg/kg/min iv of verapamil, until there was a 50{\%} reduction in mean arterial pressure, for 30 mins (titration), followed by a continuous verapamil infusion of 1 mg/kg/hr. Animals (n = 6 per group) were randomized to the control group (saline only) or to one of four treatment protocols: a) calcium chloride (20 mg/kg), then 0.6 mg/kg/hr; b) hyperinsulinemia-euglycemia (4.0 U/min of recombinant insulin, with arterial glucose concentration clamped to ±10 mg/dL [±0.5 mmol/L] of the basal value); c) epinephrine, with a starting rate of 1.0 μg/kg/min, titrated to maintain left ventricular pressure at basal values; or d) glucagon, a 0.2-mg/kg bolus, followed by a 150-μg/kg/hr infusion. Animals were monitored until death or 240 mins; infusate volumes were held constant for all groups. Measurements and Main Results: During verapamil titration, the myocardial respiratory quotient increased from 0.84 ± 0.05 to 1.07 ± 0.11 (p <.05, paired t-test) and myocardial glucose uptake doubled, despite a reduction in cardiac work (p <.05, paired t-test). Net myocardial lactate uptake also increased significantly, excluding myocardial ischemia. In controls, this trend continued, indicating preferential carbohydrate metabolism during untreated verapamil toxicity. Despite hyperglycemia, the plasma insulin concentration was not significantly different in controls (basal value 11 ± 2 vs. 39 ± 21 μU/mL at 30 mins). Hyperinsulinemia- euglycemia increased both myocardial glucose and lactate uptake five-fold, and significantly increased the ratio of myocardial oxygen delivery/work, along with superior improvements in maximal left ventricular elastance at end systole compared with other treatments (p <.05 vs. other treatments, contrast analysis). Conclusions: Verapamil toxicity renders the heart dependent on carbohydrate metabolism. Inasmuch as the positive inotropic effects of all treatments were coincident with increased indices of myocardial carbohydrate uptake, adequate treatment of verapamil toxicity appeared to require maximal myocardial carbohydrate utilization. Hyperinsulinemia-euglycemia allows larger increases in myocardial carbohydrate metabolism and myocardial contractility than calcium chloride, epinephrine, or glucagon, resulting in improved survival rates during severe verapamil toxicity.",
keywords = "calcium chloride, calcium-channel blocker, critical illness, drug toxicity, epinephrine, glucagon, glucose, insulin, lactate, myocardial metabolism, verapamil",
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T1 - Beneficial myocardial metabolic effects of insulin during verapamil toxicity in the anesthetized canine

AU - Kline, Jeffrey

AU - Leonova, E.

AU - Raymond, R. M.

PY - 1995

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N2 - Objective: Myocardial depression from verapamil toxicity may result from alterations in carbohydrate metabolism as well as calcium-channel antagonism. We hypothesized that pharmacologic doses of insulin may be effective in reversing both of these deficits. Design: Randomized, controlled, prospective study. Setting: Laboratory of an urban hospital. Subjects: Thirty mongrel dogs. Interventions: Thirty mongrel canines were anesthetized with α- chloralose. Toxicity was induced by the administration of 0.1 mg/kg/min iv of verapamil, until there was a 50% reduction in mean arterial pressure, for 30 mins (titration), followed by a continuous verapamil infusion of 1 mg/kg/hr. Animals (n = 6 per group) were randomized to the control group (saline only) or to one of four treatment protocols: a) calcium chloride (20 mg/kg), then 0.6 mg/kg/hr; b) hyperinsulinemia-euglycemia (4.0 U/min of recombinant insulin, with arterial glucose concentration clamped to ±10 mg/dL [±0.5 mmol/L] of the basal value); c) epinephrine, with a starting rate of 1.0 μg/kg/min, titrated to maintain left ventricular pressure at basal values; or d) glucagon, a 0.2-mg/kg bolus, followed by a 150-μg/kg/hr infusion. Animals were monitored until death or 240 mins; infusate volumes were held constant for all groups. Measurements and Main Results: During verapamil titration, the myocardial respiratory quotient increased from 0.84 ± 0.05 to 1.07 ± 0.11 (p <.05, paired t-test) and myocardial glucose uptake doubled, despite a reduction in cardiac work (p <.05, paired t-test). Net myocardial lactate uptake also increased significantly, excluding myocardial ischemia. In controls, this trend continued, indicating preferential carbohydrate metabolism during untreated verapamil toxicity. Despite hyperglycemia, the plasma insulin concentration was not significantly different in controls (basal value 11 ± 2 vs. 39 ± 21 μU/mL at 30 mins). Hyperinsulinemia- euglycemia increased both myocardial glucose and lactate uptake five-fold, and significantly increased the ratio of myocardial oxygen delivery/work, along with superior improvements in maximal left ventricular elastance at end systole compared with other treatments (p <.05 vs. other treatments, contrast analysis). Conclusions: Verapamil toxicity renders the heart dependent on carbohydrate metabolism. Inasmuch as the positive inotropic effects of all treatments were coincident with increased indices of myocardial carbohydrate uptake, adequate treatment of verapamil toxicity appeared to require maximal myocardial carbohydrate utilization. Hyperinsulinemia-euglycemia allows larger increases in myocardial carbohydrate metabolism and myocardial contractility than calcium chloride, epinephrine, or glucagon, resulting in improved survival rates during severe verapamil toxicity.

AB - Objective: Myocardial depression from verapamil toxicity may result from alterations in carbohydrate metabolism as well as calcium-channel antagonism. We hypothesized that pharmacologic doses of insulin may be effective in reversing both of these deficits. Design: Randomized, controlled, prospective study. Setting: Laboratory of an urban hospital. Subjects: Thirty mongrel dogs. Interventions: Thirty mongrel canines were anesthetized with α- chloralose. Toxicity was induced by the administration of 0.1 mg/kg/min iv of verapamil, until there was a 50% reduction in mean arterial pressure, for 30 mins (titration), followed by a continuous verapamil infusion of 1 mg/kg/hr. Animals (n = 6 per group) were randomized to the control group (saline only) or to one of four treatment protocols: a) calcium chloride (20 mg/kg), then 0.6 mg/kg/hr; b) hyperinsulinemia-euglycemia (4.0 U/min of recombinant insulin, with arterial glucose concentration clamped to ±10 mg/dL [±0.5 mmol/L] of the basal value); c) epinephrine, with a starting rate of 1.0 μg/kg/min, titrated to maintain left ventricular pressure at basal values; or d) glucagon, a 0.2-mg/kg bolus, followed by a 150-μg/kg/hr infusion. Animals were monitored until death or 240 mins; infusate volumes were held constant for all groups. Measurements and Main Results: During verapamil titration, the myocardial respiratory quotient increased from 0.84 ± 0.05 to 1.07 ± 0.11 (p <.05, paired t-test) and myocardial glucose uptake doubled, despite a reduction in cardiac work (p <.05, paired t-test). Net myocardial lactate uptake also increased significantly, excluding myocardial ischemia. In controls, this trend continued, indicating preferential carbohydrate metabolism during untreated verapamil toxicity. Despite hyperglycemia, the plasma insulin concentration was not significantly different in controls (basal value 11 ± 2 vs. 39 ± 21 μU/mL at 30 mins). Hyperinsulinemia- euglycemia increased both myocardial glucose and lactate uptake five-fold, and significantly increased the ratio of myocardial oxygen delivery/work, along with superior improvements in maximal left ventricular elastance at end systole compared with other treatments (p <.05 vs. other treatments, contrast analysis). Conclusions: Verapamil toxicity renders the heart dependent on carbohydrate metabolism. Inasmuch as the positive inotropic effects of all treatments were coincident with increased indices of myocardial carbohydrate uptake, adequate treatment of verapamil toxicity appeared to require maximal myocardial carbohydrate utilization. Hyperinsulinemia-euglycemia allows larger increases in myocardial carbohydrate metabolism and myocardial contractility than calcium chloride, epinephrine, or glucagon, resulting in improved survival rates during severe verapamil toxicity.

KW - calcium chloride

KW - calcium-channel blocker

KW - critical illness

KW - drug toxicity

KW - epinephrine

KW - glucagon

KW - glucose

KW - insulin

KW - lactate

KW - myocardial metabolism

KW - verapamil

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JO - Critical Care Medicine

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