Nirmatrelvir/Ritonavir-Induced Calcium Channel Blocker Intoxication Successfully Treated by High Dose Insulin Therapy.

Rationale:High-dose insulin (HDI) therapy has been used as inotropic support for toxin-induced cardiogenic shock, but literature suggests that it can also be used in non-toxin-induced cardiogenic shock states. Its use has not been reported in veno-arterial extracorporeal membrane oxygenation (VA-ECMO) decannulation.Patient concerns:A 56-year-old male presented with progressive dyspnea and lower extremity edema without any reported toxic ingestion.Diagnosis:After left heart catheterization, he was diagnosed with acute biventricular nonischemic cardiac failure that ultimately required VA-ECMO support for 8 days, after which decannulation was planned.Interventions:During decannulation, he was initiated on HDI therapy via a 1 U/kg regular insulin bolus with 25 g of dextrose and a 1 U/kg/hr insulin infusion.Outcomes:During the decannulation, he was monitored with transesophageal echocardiography. Initially, left ventricular (LV) ejection fraction (EF) was estimated at 10% to 15%. Transesophageal echocardiography after HDI but prior to decannulation showed LVEF 30% to 40%. Transthoracic echocardiography 3.5 hours after HDI bolus and decannulation revealed normal LV systolic function; LVEF 50% to 55%.Lessons:While multiple interventions occurred during decannulation, HDI therapy may have assisted in transitioning off ECMO support, and HDI should be investigated as an adjunctive option in future decannulations and other non-toxin-induced cardiogenic shock states.

Introduction High dose insulin (HDI) therapy for cardiogenic shock from acute poisoning can be complicated by treatable hypoglycemia which persists following poisoning recovery. Glucose requirements post-HDI reflect supraphysiological insulin plasma concentration. A publication reported a patient treated with HDI with plasma insulin concentrations >1000 µU/mL and elimination half-life 10–18 h requiring intravenous glucose replacement for >5 days. We report two cases treated with HDI (Actrapid; soluble or regular insulin) with shorter elimination half-lives. Case reports A man ingesting diltiazem received HDI for approximately 60 h (maximum dose 10 U/kg/h) and supplemental intravenous dextrose for 44 h post-HDI. Post-HDI the maximum measured plasma insulin concentration was 6345 µU/mL and elimination half-life 5.5 h. A man ingesting propranolol received HDI for approximately 12 h (maximum dose 1.5 U/kg/h) and supplemental intravenous dextrose for 4 h post-HDI. Post-HDI the maximum measured plasma insulin concentration was 368 µU/mL and elimination half-life 2.2 h. Discussion Markedly different insulin pharmacokinetics post-HDI is observed in two cases and a previously published report, and factors contributing to the interpatient differences are poorly defined. This pharmacokinetic variability impacts on the severity and duration of treatable hypoglycemia post-HDI. Analytical factors impacting on the measured plasma insulin concentrations include appropriate sample dilution and differing analytical specificity for the type of insulin.

High dose insulin therapy has become an increasingly popular treatment for poisonings over the last two decades. It is often mistakenly considered an antidote for poisonings of multiple drug classes, including beta-blocker and calcium channel blocker overdose. This misconception has encouraged overzealous and, at times, inappropriate use, particularly in patients who have vasoplegic shock following poisonings from drugs such as dihydropyridine calcium channel blockers. High dose insulin is not an antidote, but rather an inodilator. Its relatively slow onset of action, compared to catecholamine-based inotropes, of 15-60 min makes it best suited to second-line therapy for cardiogenic shock in poisonings. It has no role in isolated vasoplegic shock where it may exacerbate toxicity. It should be used concurrently with noradrenaline to counteract insulin-induced vasodilation. High dose insulin has predictable adverse effects of hypoglycaemia and electrolyte disturbances, particularly hypokalaemia, which can persist long beyond cessation.

Introduction High-dose insulin therapy is used in patients with calcium channel blocker and beta-adrenergic antagonist overdoses. The pharmacokinetics of insulin are scantly reported following high-dose insulin therapy. We present two cases of persistently elevated insulin concentrations following high-dose insulin therapy. Case reports A 50-year-old woman and a 45-year-old man experienced hypotension after overdosing on amlodipine and atenolol. They were treated with high-dose insulin therapy for 54 hours at 2 units/kilogram/hour and 48 hours at 10 units/kilogram/hour, respectively. Following termination, serum insulin elimination was studied. Insulin concentrations remained greater than 1,000 µU/mL (fasting reference 2.6–24.9 µU/mL) for longer than 4 hours (case 1) and 11 hours (case 2) and greater than 300 µU/mL for longer than 8 hours and 21 hours, respectively. Insulin concentrations decreased with apparent first-order elimination half-lives of 13.0 hours and 6.0 hours. Discussion Following high-dose insulin therapy, insulin concentrations remained elevated for longer than expected based on normal pharmacokinetics in therapeutic dosing. Three previous cases reported insulin half-lives of between 2.2 hours and 18.7 hours. The current cases add to the existing data that insulin has a variable but prolonged half-life following high-dose insulin therapy. Conclusions These findings suggest that patients are at prolonged risk of hypoglycemia following cessation of high-dose insulin infusions.

Invited Commentary

Introduction: Deliberate polypharmacy overdose is associated with an increasing proportion of admissions to the intensive care unit. Overdose on hemodynamic active substances such as calcium channel blockers can be fatal as it is associated with severe distributive shock. Methylene blue has drawn attention in critical care medicine for its use in the management of distributive shock, particularly in cases of anaphylaxis, septic shock, and shock following cardiac bypass surgery. We describe the use of methylene blue in the management of refractory shock due to calcium channel blocker (CCB) overdose. Case Report: We present a case of benzothiazepine type CCB overdose which leads to admission to the intensive care unit for the management of severe distributive shock. Conventional treatments including vasopressors and high dose insulin therapy were instituted, but despite these treatments the patient remained hypotensive. The decision was made to administer methylene blue following which the patient achieved hemodynamic stability and was successfully weaned off all vasopressors. Conclusion: This case report specifically focuses on the use of methylene blue in distributive shock secondary to CCB overdose. Currently there are no randomized control trials to support its use, and evidence is limited to observational studies including single case reports. In this case report we describe the mechanism of action of methylene blue and why we believe it makes for the perfect adjunct therapy in calcium channel blocker overdose.

Introduction. High-dose insulin therapy, along with glucose supplementation, has emerged as an effective treatment for severe beta-blocker and calcium channel-blocker poisoning. We review the experimental data and clinical experience that suggests high-dose insulin is superior to conventional therapies for these poisonings.Presentation and general management. Hypotension, bradycardia, decreased systemic vascular resistance (SVR), and cardiogenic shock are characteristic features of beta-blocker and calcium-channel blocker poisoning. Initial treatment is primarily supportive and includes saline fluid resuscitation which is essential to correct vasodilation and low cardiac filling pressures. Conventional therapies such as atropine, glucagon and calcium often fail to improve hemodynamic status in severely poisoned patients. Catecholamines can increase blood pressure and heart rate, but they also increase SVR which may result in decreases in cardiac output and perfusion of vascular beds. The increased myocardial oxygen demand that results from catecholamines and vasopressors may be deleterious in the setting of hypotension and decreased coronary perfusion.Methods. The Medline, Embase, Toxnet, and Google Scholar databases were searched for the years 1975–2010 using the terms: high-dose insulin, hyperinsulinemia–euglycemia, beta-blocker, calcium-channel blocker, toxicology, poisoning, antidote, toxin-induced cardiovascular shock, and overdose. In addition, a manual search of the s of the North American Congress of Clinical Toxicology and the Congress of the European Association of Poisons Centres and Clinical Toxicologists published in Clinical Toxicology for the years 1996–2010 was undertaken. These searches identified 485 articles of which 72 were considered relevant.Mechanisms of high-dose insulin benefit. There are three main mechanisms of benefit: increased inotropy, increased intracellular glucose transport, and vascular dilatation.Efficacy of high-dose insulin. Animal models have shown high-dose insulin to be superior to calcium salts, glucagon, epinephrine, and vasopressin in terms of survival. Currently, there are no published controlled clinical trials in humans, but a review of case reports and case series supports the use of high-dose insulin as an initial therapy.High-dose insulin treatment protocols. When first introduced, insulin doses were cautiously initiated at 0.5 U/kg bolus followed by a 0.5–1 U/kg/h continuous infusion due to concern for hypoglycemia and electrolyte imbalances. With increasing clinical experience and the publication of animal studies, high-dose insulin dosing recommendations have been increased to 1 U/kg insulin bolus followed by a 1–10 U/kg/h continuous infusion. Although the optimal regimen is still to be determined, bolus doses up to 10 U/kg and continuous infusions as high as 22 U/kg/h have been administered with good outcomes and minimal adverse events.Adverse effects of high-dose insulin. The major anticipated adverse events associated with high-dose insulin are hypoglycemia and hypokalemia. Glucose concentrations must be monitored regularly and supplementation of glucose will likely be required throughout therapy and for up to 24 h after discontinuation of high-dose insulin. The change in serum potassium concentrations reflects a shifting of potassium from the extracellular to intracellular space rather than a decrease in total body stores.Conclusions. While more clinical data are needed, animal studies and human case reports demonstrate that high-dose insulin (1–10 U/kg/hour) is a superior treatment in terms of safety and survival in both beta-blocker and calcium-channel blocker poisoning. High-dose insulin should be considered initial therapy in these poisonings.

Introduction: Brain death is a major stress on the body that is associated with a massive inflammatory response. Severe inflammation can lead to increased graft immunogenicity and increased risk of graft dysfunction. In addition, to the maintenance of normoglycaemia Insulin therapy has expressed anti-inflammatory effects in clinical and experimental studies. The objective is determining if high dose insulin therapy can suppress inflammation and maintain normoglycaemia in brain dead donors. Methods: Pilot study with an open-label prospective-controlled design. Fifteen brain dead organ donors were recruited including 6 study donors and 9 control donors. Insulin therapy was delivered to the study donors using the hyperinsulinemic normoglycaemic clamp (HNC) and was maintained for a minimum of 6 hours and continued till organ retrieval. The anti-inflammatory effect was measured by the change in the cytokine levels in the plasma of these donors. Categorical and continuous variables were expressed as summary statistics (n, median, mean, range, standard deviation) for all donors in both groups. Fisher's exact and Wilcoxon test were performed to assess differences between the groups and a p-value < 0.1 was considered significant. Results: There was no significant difference in donor characteristics between the 2 groups. CVA was the most common cause of brain death (60%). The study group had normal glucose levels (median 4.8 mmol/L) compared to the control group (median 9.0 mmol/L) (p< 0.001). There were no periods of severe hypoglycemia (glucose < 2.5 mmol/l). The levels of several pro-inflammatory mediators including; IL-6, TGF-α and MCP-1 were significantly decreased after 6 hours of treatment compared to their baseline values in the study group (p=0.03), (p=0.03) and (p=0.09), respectively. We observed an opposite trend in circulating levels of the anti-inflammatory factor IL-10 in the study group. The levels of inflammatory markers did not demonstrate a significant change after 6 hours compared to their baseline values in the control group. Conclusion: High dose insulin therapy in the form of HNC was successful in the maintenance of normoglycaemia in brain dead organ donors, without severe hypoglycaemia. Furthermore, the therapy had anti-inflammatory effects on donors, as expressed by decreased the levels of several pro-inflammatory cytokines in the study group.Table: [General demographics and characteristics of donors]Table: [change of cytokine levels at ST1 (after 6hrs)]

This case report describes the first reported overdose of the dihydropyridine calcium channel blocker (CCB) lercanidipine. A 49 yr old male presented to the Emergency Department 3 hrs after the ingestion of 560 mg of lercanidipine. In the department he had a witnessed seizure within 15 minutes of arrival attributed to the overdose. Following immediate recovery of consciousness after the seizure, he had refractory hypotension and bradycardia which failed to respond to fluid resuscitation, glucagon therapy, and intravenous calcium. He went on to require vasopressor support with noradrenaline and was treated with high dose insulin therapy which was successful in achieving cardiovascular stability. Vasopressor therapy was no longer required within one half life of lercanidipine, and the total stay on intensive care was one day before transfer to a ward.Calcium channel blocker overdose is an uncommon but life-threatening overdose. Treatment for severe toxicity is similar to b-blocker overdose. Hypotension is treated with intravenous fluid therapy, intravenous calcium and possibly glucagon with vasopressor or inotropic support as required. Atropine is used to attempt reversal of bradycardia. High doses of intravenous insulin with intravenous dextrose as required (hyperinsulinaemic euglycaemia or HIET), has also been successfully reported. Experimental animal data suggests that HIET is of benefit and potentially superior to fluid therapy, calcium, glucagon and potentially vasopressor therapy. HIET effectively and sustainably reverses hypotension, bradycardia and improves myocardial contractility and metabolism. Current advice in calcium channel blocker overdose is to begin therapy early in toxicity, starting with a 1.0 IU/kg insulin bolus followed by an infusion of 0.5 IU/kg/hr of insulin and dextrose as required titrated to clinical response.

HIGH DOSE INSULIN AND VA ECMO FOR POISON-INDUCED CARDIOGENIC SHOCK

FAILURE OF HYPERINSULINEMIC-EUGLYCEMIA IN CALCIUM CHANNEL BLOCKER OVERDOSE

Poison-induced cardiogenic shock (PICS) as a result of beta-blocker (β-blocker) or calcium channel blocker (CCB) overdose is a common and potentially life-threatening condition. Conventional therapies, including fluid resuscitation, atropine, cardiac pacing, calcium, glucagon, and vasopressors often fail to improve hemodynamic status. High-dose insulin (HDI) is an emerging therapeutic modality for PICS. In this article, we discuss the existing literature and highlight the therapeutic success and potential of HDI. Based on the current literature, which is limited primarily to case series and animal models, the authors conclude that HDI can be effective in restoring hemodynamic stability, and recommend considering its use in patients with PICS that is not responsive to traditional therapies. Future studies should be undertaken to determine the optimal dose and duration of therapy for HDI in PICS.

Pharmaceutical agents are the most common causes of poisoning in Korea. Calcium channel blockers (CCBs) are commonly used in Korea for the management of hypertension and other cardiovascular diseases, but are associated with a risk of mortality due to overdose. Due to the frequent fatalities associated with CCB overdose, it is essential that the emergency physician is capable of identifying CCB intoxication, and has the knowledge to manage CCB overdose. This article reviews the existing clinical guidelines, retrospective studies, and systematic reviews on the emergency management of CCB overdose. The following are the varied treatments of CCB overdose currently administered. 1) For asymptomatic patients: observation with enough time and decontamination, if indicated. 2) For symptomatic patients: infusion of calcium salt, high dose insulin therapy, and vasopressor (norepinephrine) or atropine for bradycardia. 3) For patients refractory to the first line therapy or with refractory shock or impending arrest: lipid emulsion therapy and extracorporeal membrane oxygenation. 4) As adjunct therapy: phosphodiesterase inhibitors, glucagon, methylene blue, pacemaker for AV block. Small CCB ingestion is known to be fatal for pediatric patients. Hence, close observation for sufficient time is required.

Calcium channel blocker poisoning is one of the most common poisonings encountered which presents with life-threatening complications. However, there is no unified approach for treating these patients in the existing literature. This study aimed to assess the effects of different treatment modalities used in calcium channel blocker poisoning, as reported by previous studies. The primary outcomes studied were mortality and hemodynamic parameters after treatment. The secondary outcomes were the length of hospital stay, length of intensive care unit stay, duration of vasopressor use, functional outcomes, and serum calcium channel blocker concentrations.A thorough literature search was performed through Ovid, PubMed, Cochrane Library, and Google Scholar from January 2014 to December 31, 2022, to identify all studies analyzing the effects of the treatment of calcium channel blocker poisoning on the desired outcomes. Two reviewers reviewed 607 published articles from January 2014 to December 2022 to identify studies analyzing the effects of the treatment of calcium channel blocker poisoning on desired outcomes.In this review, 18 case reports, one case series, and one cohort study were included. Most patients were treated with an injection of calcium gluconate or calcium chloride. The use of calcium along with dopamine and norepinephrine was found to have lower mortality rates. A few patients were also treated with injection atropine for bradycardia. High-dose insulin therapy was used in 14 patients, of whom two did not survive. In the cohort study, 66 calcium channel blocker toxicity patients were included. These patients were treated with high-dose insulin therapy. A total of 11 patients with calcium channel blocker toxicity succumbed. Although it was found to be associated with improved hemodynamic parameters and lower mortality, side effects such as hypokalemia and hypoglycemia were noted. Intravenous lipid emulsion therapy (administered to eight patients), extracorporeal life support (used in three patients with refractory shock or cardiac arrest), injection glucagon, methylene blue, albumin infusion, and terlipressin were associated with a lower mortality rate as well as improvement in hemodynamic parameters. None of the case reports provided any information on end-organ damage on long-term follow-up.

Context. Cardiovascular medication overdoses can be difficult to treat. Various treatment modalities are currently recommended. Objective. To describe patient outcomes and adverse events of high-dose insulin therapy in consecutive overdose patients in cardiogenic shock after implementation of a high-dose insulin protocol (1–10 U/kg/h, while avoiding or tapering off vasopressors). Methods. This is an observational consecutive case series of patients identified from a registry. Data were collected by retrospective chart review of patients treated by our toxicology service with this protocol from February 2007 until March 2010. Results. Twelve patients were treated with high-dose insulin. The mean age was 36.5 years (SD 11.7). Seven patients had pre-existing vasopressor therapy, and all were tapered off vasopressors while on insulin. Two patients experienced pulseless electrical activity cardiac arrest prior to high-dose insulin therapy. Intravenous fat emulsion was given to two patients. The mean maximum insulin infusion rate was 8.35 U/kg/h (mean = 8.35, SD 6.34). The mean duration of insulin infusion was 23.5 h (SD 19.7). The mean duration of glucose infusion post-insulin was 25.2 h (SD 17.7). The primary toxins were β-blocker in five, calcium channel blocker in two, combined β-blocker/calcium channel blocker in two, tricyclic antidepressant in one, and polydrug in 2. Clinical outcomes. Eleven of 12 patients survived. One patient expired 9 h into insulin therapy from cardiac arrest shortly after the insulin was stopped and a vasopressor re-initiated (protocol deviation). Adverse events. Six patients experienced a total of 19 hypoglycemic events. Hypokalemia (defined as < 3.0 mEq/L) developed in eight patients. Adverse sequelae. Necrotic digits occurred in one patient with known clotting disorder after receiving high-dose norepinephrine and INR reversal with fresh frozen plasma prior to insulin therapy. One patient was discharged with mild anoxic injury thought due to pulseless electrical activity arrest prior to insulin therapy. Three of these 12 patients have been previously described in published case reports. Conclusion. High-dose insulin therapy based on a 1–10 U/kg/h dosing guideline and recommending avoidance of vasopressors appears to be effective in the treatment of toxin-induced cardiogenic shock. Hypoglycemia was the most frequent adverse event, followed by hypokalemia. Adverse events did not lead to adverse sequelae.