Use of Concentrated Insulin in the Management of Calcium Channel Blocker Overdose: A Case Report.

INTRODUCTION: Hyperinsulinemia-euglycemia therapy [HIE] is a first line therapy recommended in symptomatic calcium channel blocker overdose patients. HIE, particularly if administered in concentrations typically used for glycemic control, would result in a substantial amount of hypotonic fluid administration, which places patients at risk of volume overload. Therefore, it may be beneficial to utilize a concentrated insulin as a strategy to mitigate fluid overload risks. We report the case of a 73 years old, 69.9 kg female, who presented to the emergency department after an accidental ingestion of 70 mg amlodipine and was treated with HIE utilizing a uniquely concentrated insulin infusion. CASE PRESENTATION: HIE at 10 units/kg/hr. was used for approximately 17 hours. Insulin was changed from a 1 unit/mL concentration to 16 unit/mL. Dextrose 10% infusion was initiated up to a max of 650 mL/hr. and norepinephrine infusion up to a max of 10 mcg/min. DISCUSSION: Approximate fluid requirements from the 16 unit/mL concentration of insulin totaled 1 L as compared to a 1 unit/mL concentration which would have required 17 L, a total savings of 16 L. This savings potentially decreased the risk of cerebral or pulmonary edema associated with fluid overload. CONCLUSION: Use of a concentrated insulin in the setting of a calcium channel blocker or beta blocker overdose provides a unique strategy to mitigate the effects associated with fluid overload.

Terapia de insulina y glucosa para el tratamiento de intoxicación grave con bloqueantes de canales de calcio en pediatría. Reporte de un caso / Insulin/glucose therapy for the treatment of severe calcium channel blocker poisoning in pediatrics. Case report

La intoxicación por bloqueantes de los canales de calcio es un cuadro poco frecuente en la población pediátrica. Los signos y síntomas pueden progresar de forma rápida y llevar al colapso cardiovascular y muerte. El sostén hemodinámico con inotrópicos y vasopresores no suele ser efectivo. La terapia con insulina y glucosa es un complemento eficaz del tratamiento inicial, que está ampliamente estudiado, y se utiliza en diferentes patologías con compromiso hemodinámico. Se presenta el caso de una paciente pediátrica con antecedente de ingestión de dosis altas de amlodipina con fines suicidas, con descompensación hemodinámica refractaria al tratamiento de soporte inotrópico habitual. A partir del tratamiento con insulina y glucosa, se logró la estabilidad hemodinámica, con evolución favorable de la paciente.

Calcium channel blocker poisoning is a rare condition in the pediatric population. Signs and symptoms can be rapidly progressive and lead to cardiovascular collapse and death. Hemodynamic support with inotropics and vasopressors is usually not effective. The insulin/glucose therapy is an effective complement to the initial treatment, which is widely studied and used in different pathologies with hemodynamic compromise. The case of a pediatric patient with a history of high-dose ingestion of amlodipine for suicidal purposes, with hemodynamic decompensation refractory to usual inotropic support treatment, is presented. From the insulin/glucose treatment, hemodynamic stability was achieved with a favorable evolution

[Insulin/glucose therapy for the treatment of severe calcium channel blocker poisoning in pediatrics. Case report]. / Terapia de insulina y glucosa para el tratamiento de intoxicación grave con bloqueantes de canales de calcio en pediatría. Reporte de un caso.

Calcium channel blocker poisoning is a rare condition in the pediatric population. Signs and symptoms can be rapidly progressive and lead to cardiovascular collapse and death. Hemodynamic support with inotropics and vasopressors is usually not effective. The insulin/glucose therapy is an effective complement to the initial treatment, which is widely studied and used in different pathologies with hemodynamic compromise. The case of a pediatric patient with a history of highdose ingestion of amlodipine for suicidal purposes, with hemodynamic decompensation refractory to usual inotropic support treatment, is presented. From the insulin/glucose treatment, hemodynamic stability was achieved with a favorable evolution.

La intoxicación por bloqueantes de los canales de calcio es un cuadro poco frecuente en la población pediátrica. Los signos y síntomas pueden progresar de forma rápida y llevar al colapso cardiovascular y muerte. El sostén hemodinámico con inotrópicos y vasopresores no suele ser efectivo. La terapia con insulina y glucosa es un complemento eficaz del tratamiento inicial, que está ampliamente estudiado, y se utiliza en diferentes patologías con compromiso hemodinámico. Se presenta el caso de una paciente pediátrica con antecedente de ingestión de dosis altas de amlodipina con fines suicidas, con descompensación hemodinámica refractaria al tratamiento de soporte inotrópico habitual. A partir del tratamiento con insulina y glucosa, se logró la estabilidad hemodinámica, con evolución favorable de la paciente.

Extracorporeal treatment for calcium channel blocker poisoning: systematic review and recommendations from the EXTRIP workgroup.

BACKGROUND: Calcium channel blockers (CCBs) are commonly used to treat conditions such as arterial hypertension and supraventricular dysrhythmias. Poisoning from these drugs can lead to severe morbidity and mortality. We aimed to determine the utility of extracorporeal treatments (ECTRs) in the management of CCB poisoning. METHODS: We conducted systematic reviews of the literature, screened studies, extracted data, summarized findings, and formulated recommendations following published EXTRIP methods. RESULTS: A total of 83 publications (6 in vitro and 1 animal experiments, 55 case reports or case series, 19 pharmacokinetic studies, 1 cohort study and 1 systematic review) met inclusion criteria regarding the effect of ECTR. Toxicokinetic or pharmacokinetic data were available on 210 patients (including 32 for amlodipine, 20 for diltiazem, and 52 for verapamil). Regardless of the ECTR used, amlodipine, bepridil, diltiazem, felodipine, isradipine, mibefradil, nifedipine, nisoldipine, and verapamil were considered not dialyzable, with variable levels of evidence, while no dialyzability grading was possible for nicardipine and nitrendipine. Data were available for clinical analysis on 78 CCB poisoned patients (including 32 patients for amlodipine, 16 for diltiazem, and 23 for verapamil). Standard care (including high dose insulin euglycemic therapy) was not systematically administered. Clinical data did not suggest an improvement in outcomes with ECTR. Consequently, the EXTRIP workgroup recommends against using ECTR in addition to standard care for patients severely poisoned with either amlodipine, diltiazem or verapamil (strong recommendations, very low quality of the evidence (1D)). There were insufficient clinical data to draft recommendation for other CCBs, although the workgroup acknowledged the low dialyzability from, and lack of biological plausibility for, ECTR. CONCLUSIONS: Both dialyzability and clinical data do not support a clinical benefit from ECTRs for CCB poisoning. The EXTRIP workgroup recommends against using extracorporeal methods to enhance the elimination of amlodipine, diltiazem, and verapamil in patients with severe poisoning.

Angiotensin axis antagonists increase the incidence of haemodynamic instability in dihydropyridine calcium channel blocker poisoning.

CONTEXT: Amlodipine, a dihydropyridine calcium channel blocker (CCB), is the leading cause of cardiovascular drug-related overdose deaths in the USA. In contrast, angiotensin-II receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs) cause minimal toxicity in overdose. ACEIs/ARBs are often combined with dihydropyridines in hypertension treatment. Co-ingested ARBs/ACEIs may significantly contribute to the toxicity of dihydropyridine, but this has not been investigated. OBJECTIVE: To investigate the clinical outcomes from dihydropyridine overdoses with ARBs/ACEIs versus dihydropyridine overdoses alone. METHODS: This was a retrospective study of patients reported to the New South Wales Poisons Information Centre (NSW PIC) and 3 toxicology units (Jan 2016 to Jun 2019) in Australia. Patients >14 years who took an overdose of dihydropyridines (amlodipine, felodipine, lercanidipine, nifedipine) were included. Concurrent overdoses with non-dihydropyridine CCBs, alpha-blockers and beta-blockers were excluded. Patient demographics, drugs exposure details, serial vital signs, treatments and outcome were collected. RESULTS: There were 100 patients. 68 took mixed overdoses of dihydropyridines with ARBs/ACEIs and 32 took single overdoses of dihydropyridines without ARBs/ACEIs. The mixed group had lower median nadir mean arterial pressures (62 vs 75 mmHg, p < 0.001), more frequently had hypotension (OR 4.5, 95%CI: 1.7-11.9) or bradycardia (OR 8.8, 95%CI: 1.1-70). Multivariable analysis indicated the mixed overdoses had an 11.5 mmHg (95%CI: 4.9-18.1) lower minimum systolic blood pressure (SBP) compared with the single group; other factors associated with a lower minimum SBP were higher doses [2.3 mmHg (95%CI: 1.1-3.5) lower per 10 defined daily doses] and younger age [2.2 mmHg (95%CI: 0.3-4.2) higher per decade]. A larger proportion of the mixed ingestion group received intravenous fluids (OR 5.7, 95%CI: 1.8-18.6) and antidotes and/or vasopressors (OR 2.9, 95%CI: 1.004-8.6). CONCLUSION: Combined overdoses of dihydropyridines with ARBs/ACEIs caused more significant hypotension and required more haemodynamic support than overdoses of dihydropyridines alone.

Postmortem fatal and non-fatal concentrations of amlodipine.

Amlodipine is a dihydropyridine calcium channel blocker widely used in the treatment of high blood pressure and coronary heart disease. Intoxication can lead to reflex tachycardia following massive hypotension and death. The objective of this work was to study the post-mortem concentrations of amlodipine in 62 patients in order to determine whether the use of the reference concentrations from the living patients was applicable in postmortem setting, and to define more precisely the fatal and non-fatal postmortem concentrations of amlodipine. The amlodipine concentrations were measured in femoral whole blood by LC-MS/MS validated method. When sufficient information was available, the data were classified into 2 different groups, based on the conclusions of the autopsy and toxicological results: G1: non-toxic death and G2: fatal poisoning involving amlodipine alone or as part of a multidrug poisoning. The median concentration of amlodipine [1st quartile - 3rd quartile] of the whole population (n = 62) was 81 [42-134] ng/mL. Twenty-two cases were classified as G1 and thirteen as G2. The observed median [1st quartile - 3rd quartile] concentration of amlodipine was 66 [40.5-79.5] ng/mL in G1 and 240 [170-404] ng/mL in G2. The median concentrations observed in "non-toxic" deaths (66 ng/mL) were three times higher than those usually observed in living patients. Amlodipine distribution ratio between plasma and whole blood concentrations seems insufficient to explain this difference and postmortem redistribution from organs should be considered, and could suggest the same redistribution pattern for other drugs belonging to the same family.

Calcium channel blocker and beta blocker overdose, and digoxin toxicity management.

While relatively uncommon, an overdose of calcium channel blockers, beta blockers, or digoxin can result in significant morbidity and mortality, and management can be complex. An acute overdose will require different management strategies than chronic toxicity while on therapeutic dosing. Toxicity from these agents must be considered in bradycardic and hypotensive patients. This supplement provides an evidence-based overview of emergency department management of calcium channel blocker overdose, beta blocker overdose, and digoxin toxicity, and focuses on the caveats of treatment for each.

Persistent Hyperinsulinemia Following High-Dose Insulin Therapy: A Case Report.

INTRODUCTION: Overdoses of beta-adrenergic antagonists and calcium channel antagonists represent an uncommonly encountered but highly morbid clinical presentation. Potential therapies include fluids, calcium salts, vasopressors, intravenous lipid emulsion, methylene blue, and high-dose insulin. Although high-dose insulin is commonly used, the kinetics of insulin under these conditions are unknown. CASE REPORT: We present a case of a 51-year-old male who sustained a life-threatening overdose after ingesting approximately 40 tablets of a mixture of amlodipine 5 mg and metoprolol tartrate 25 mg. Due to severe bradycardia and hypotension, he was started on high-dose insulin (HDI) therapy; this was augmented with epinephrine. Despite the degree of his initial shock state, he ultimately recovered, and HDI was discontinued. Insulin was infused for a total of approximately 37 hours, most of which was dosed at 10 U/kg/hour; following discontinuation, serial serum insulin levels were drawn and remained at supraphysiologic levels for at least 24 hours and well above reference range for multiple days thereafter. CONCLUSION: The kinetics of insulin following discontinuation of high-dose insulin therapy are largely unknown, but supraphysiologic insulin levels persist for some time following therapy; this may allow for simple discontinuation rather than titration of insulin at the end of therapy. Dextrose replacement is frequently needed; although the duration is often difficult to predict, prolonged infusions may not be necessary.

Calcium Channel Blocker Toxicity Causing Acute Respiratory Distress Syndrome: A Commonly Used Drug Triggering a Life-Threatening Condition.

INTRODUCTION: Calcium channel blockers (CCBs) are commonly used but have the potential to cause substantial toxicity. One such underreported toxicity of CCB use is the development of acute respiratory distress syndrome (ARDS). CASE PRESENTATION: 44-year-old previously healthy woman presented to the emergency department (ED) having taken 60 tablets of 125 mg extended-release verapamil and 90 tablets of 0.25 mg clonazepam with the intent to commit suicide. On presentation to the ED, she was sedated and intubated for airway protection. She received aggressive medical resuscitation and was ventilated using low tidal volume mechanical ventilation. The hospital course was complicated by worsening hypoxia and a chest x-ray demonstrating bilateral patchy geographic areas of airspace opacities consistent with ARDS. On day 5 of hospitalization, the patient's clinical status improved significantly, and she was subsequently weaned off vasopressors and extubated. DISCUSSION: CCB toxicity can result in profound hypotension, shock, bradycardia, and conduction blocks, as well as hyperglycemia, acidosis and acute kidney injury, and ARDS. It is important for clinicians to understand the signs and symptoms of CCB toxicity, as well as how to treat it.

[Update - intoxications in critical care medicine]. / Update ­ Intoxikationen in der Intensivmedizin.

While monitoring and symptomatic care is sufficient for most intoxicated patients, some develop life threatening symptoms. We present recent changes in the recommendations of the treatment in patients with calcium channel blocker, beta blocker and high dose paracetamol intoxications. Additionally, new insights in the efficacy and safety of the use of physostigmine in anticholinergic patients and beta blockers in cocaine intoxication are discussed as well as the specific considerations in the resuscitation of intoxicated patients.

To call or not to call: behavioral determinants influencing the decision of intensivists to consult poison centers for calcium channel blocker poisoning.

Purpose: This study aimed to define the behavioral determinants influencing the decision of intensivists to consult a poison center (PC) when managing patients with calcium channel blocker (CCB) poisoning.Material and methods: Semi-structured interviews were conducted involving a convenience sample of 18 intensivists. Two independent reviewers analyzed the interview responses using the Theoretical Domains Framework. Based on the impact and frequency of the reported behaviors, we selected the most relevant domains likely to influence intensivists' decision to consult a PC for CCB poisoning.Results: Beliefs influencing physicians positively to consult a PC for CCB poisoning were identified in the following domains: knowledge (e.g., lower level of evidence), social or professional role and identity (e.g., high credibility attributed to the PC), reinforcement (e.g., multiple drug poisoning, infrequent or potentially lethal poisoning, medicolegal considerations), and behavioral regulation (e.g., facilitated access of PC to patient's hospital chart, direct communication with a toxicologist). Beliefs deterring physicians from consulting a PC for CCB poisoning were identified in the following domains: knowledge (e.g., better awareness of recommendations decreases tendency to call), goals (e.g., priority for patient stabilization), and memory, attention, and decision process (e.g., cognitive overload due to an unstable patient).Conclusion: This qualitative study identified potential behavioral targets that future implementation strategies should address to improve collaboration between PCs and intensivists. In light of our results, the Québec PC now asks clinicians if the poisoned patient is unstable prior to collecting any other information. When necessary, a teleconference with the toxicologist is proposed earlier than before.

Extracorporeal therapy for amlodipine poisoning.

A young male presented in refractory shock from amlodipine poisoning despite vasopressors, insulin-normoglycemia therapy, calcium gluconate and glucagon. He needed venoarterial ECMO for hemodynamic support and TPE to remove protein-bound amlodipine. The use of extracorporeal membrane oxygenation (ECMO) for cardiotoxic poisoning and Total Plasma Exchange (TPE) in removing drugs has been described in the literature. We report a rare case where both lifesaving extracorporeal therapies were used in a patient with a severe drug overdose. Stabilizing hemodynamics with ECMO combined with TPE for drug removal is a feasible strategy in unstable patients with amlodipine overdose.

Emergency management of calcium channel blocker overdose.

Calcium channel blockers (CCBs) are commonly used in South Africa (SA) in the management of hypertension and other cardiovascular disease. Their ubiquitous availability makes them a common agent in drug overdose (OD), whether through accidental ingestion or deliberate self-harm. It is essential that medical practitioners know how to recognise and manage CCB OD, as severe CCB OD is often fatal. As there is a lack of local literature in SA, we highlight the general principles of management of CCB OD, as well as complications and problems that may be encountered during treatment. This narrative review is based on existing clinical guidelines, retrospective studies and systematic reviews on the emergency management of CCB OD. High-dose insulin euglycaemic therapy has become the mainstay of treatment in severe CCB OD. The rationale, the recommended protocol for its use and its adverse effects are described.

Use of veno-venous extracorporeal membrane oxygenation to treat severe combined calcium channel blocker and angiotensin converting enzyme inhibitor overdose.

INTRODUCTION: Calcium channel blockers (CCBs) are a commonly prescribed medication that, at toxic levels, are capable of causing severe refractory hypotension, hypoxic respiratory failure and cardiotoxicity. There is little evidence currently guiding the approach to managing CCB overdose, particularly when combined with other antihypertensive agents. CASE REPORT: We describe the use of veno-venous extracorporeal membrane oxygenation (VV ECMO) in a previously healthy man following combined overdose with amlodipine and lisinopril in a suicide attempt. ECMO was used to provide oxygenation support, allowing for the amlodipine and lisinopril to be metabolized and cleared while also reducing ventilator-induced lung injury (VILI) and avoiding the complications associated with venous-arterial (VA) ECMO, such as differential hypoxemia. CONCLUSION: Limited case reports suggesting the use of ECMO in CCB overdose have employed VA ECMO due to CCB-induced cardiotoxicity. We believe that, if cardiac function has been preserved, VV ECMO should be considered a viable treatment strategy for CCB and ACE-I overdose resulting in refractory hypoxemic respiratory failure.

Outcomes following calcium channel blocker exposures reported to a poison information center.

BACKGROUND: Calcium channel blockers (CCBs) are widely used drugs that have a narrow therapeutic index. Even minor overdoses must be treated in-hospital due to the risk of severe hypotension and bradycardia. We aimed to describe trends in CCB use and overdoses in Denmark. METHODS: Data on enquiries concerning CCBs reported to the Danish Poisons Information Center (DPIC) from January 2009 to January 2015 was coupled with data on hospitalization and mortality obtained from Danish National Registers. We obtained data on the general use of CCBs in Denmark and retrieved medical charts on fatal cases. RESULTS: From a total of 126,987 enquiries to the DPIC in 2009-2014 we identified 339 CCB unique exposures (3‰ of all). Children < 5 years accounted for 20% all exposures and these were classified as 'intake during playing' (61%) and 'medication errors' (39%). Among adults 'suicidal poisonings' (58%), and 'medication errors' (34%) were most frequent. A majority (81%) of exposures led to hospital admission. Seven patients (2%) died from the CCB exposure and all were adults with 'suicidal poisoning'. Amlodipine accounted for 95% of all CCB prescriptions, was involved in 71% of enquiries and in 29% of fatalities. Verapamil accounted for 3% of prescriptions, was involved in 13% of enquiries and 57% of fatalities. CONCLUSION: Four fifths of enquiries to the DPIC result in hospitalization and one fifth concern small children. Mortality were infrequent and occurred only in adults with suicidal exposures and with and an overrepresentation of verapamil exposures.

An Overview of Hyperinsulinemic-Euglycemic Therapy in Calcium Channel Blocker and ß-blocker Overdose.

Both calcium channel blockers (CCBs) and ß blockers (BBs) are associated with fatal substance exposures within the United States. Cases of overdose with these agents have the potential to be both complex and difficult to manage. A variety of pharmacologic treatment options are available for clinicians to use to help mitigate harm from these poisonings. Hyperinsulinemic-euglycemic therapy (HIET) was once regarded as a last-ditch effort to treat patients in highly refractory cases. In recent years, this therapy has become a routine therapy in the treatment of CCB/BB overdose. This article provides a literature review regarding HIET in cases of overdose with CCB and BB agents. Relevant literature articles from 1997-2018 were identified and reviewed using the PubMed and Embase databases. The following search terms were used to identify potential articles: "hyperinsulinemic-euglycemic therapy," "overdose," "calcium channel blocker," "beta blocker," and "insulin." Articles published in the English language were included in this review. A manual search of reference lists was also conducted. Much of the literature is limited to case reports, series, retrospective chart reviews, and small prospective studies. The success rate observed in published case series ranged from 80.4-100%. Regular insulin is most commonly dosed at an initial bolus of 1 unit/kg followed by a regular insulin infusion of 0.5-1 unit/kg/hour. Euglycemia is often maintained using intravenous fluids containing dextrose. Hyperinsulinemic-euglycemic therapy exhibited a promising safety profile, provided close monitoring is conducted. More research is needed to determine optimal strategies for maintaining euglycemia, ideal monitoring parameters, and consistent efficacy goals.

Pharmacological and mechanical management of calcium channel blocker toxicity.

Cardiovascular instability associated with calcium channel blocker toxicity comprises a small percentage of overdose presentations, yet they are associated with a high mortality rate. We detail the management of a 64-year-old man who took an intentional overdose of 840 mg nimodipine. We include the treatment he received and highlight the scarcity of evidence behind the use of gastric decontamination, calcium, glucagon, intravenous lipid emulsion, high-dose insulin therapy, sodium bicarbonate, vasopressors and methylene blue in calcium channel blocker toxicity. Additionally, the article explores the use of electrical pacing and venoarterial extracorporeal membrane oxygenation (VA-ECMO). Following successful weaning of VA-ECMO, the patient was successfully extubated but remained neurologically impaired due to hypoxic-ischaemic brain injury, critical care polyneuropathy and renal failure requiring dialysis. He has cerebral performance category 3; he has mild cognitive impairment but able to perform some activities of daily living independently and communicate his thoughts and needs. He requires no respiratory or cardiovascular support.

Barriers and Facilitators of Intensivists' Adherence to Hyperinsulinemia-Euglycemia Therapy in the Treatment of Calcium Channel Blocker Poisoning.

INTRODUCTION: Adherence to poison center (PC) recommendations for the management of calcium channel blocker (CCB) poisoning is inconsistent. This study aimed to identify behaviors that determine adherence to hyperinsulinemia-euglycemia therapy (HIET) for CCB poisoning. METHODS: Semistructured interviews were conducted involving a convenience sample of 18 intensivists. Interview responses were analyzed using the theoretical domains framework (TDF) to identify relevant domains influencing physician adherence to HIET. Two independent reviewers performed qualitative content analysis of the interview transcripts to identify beliefs influencing decisions to initiate HIET. Initially, beliefs were classified and frequencies reported as being likely to facilitate, likely to decrease, or unlikely to affect adherence. Subsequently, beliefs were linked to a domain within the TDF. Based on the potential impact on physician behavior and frequency of reported behavior, we selected the most relevant domains likely to influence physician adherence to HIET for CCB poisoning. RESULTS: Positive beliefs were identified in the following domains: "behavioral regulation" (e.g., algorithm for adjustment of perfusions), "belief about capabilities" (e.g., confidence about being able to manage HIET), "belief about consequences" (e.g., fear of clinical deterioration), and "reinforcement" (e.g., clinical instability). Negative beliefs were identified in the following domains as "nature of behavior" (e.g., preference for vasopressors over HIET) and "environmental context and resources" (e.g., accessing dextrose 50% and increased nurse workload). CONCLUSION: This qualitative study identified potential behavioral targets for future implementation strategies to address to improve adherence to HIET.

Amlodipine (150 mg) Poisoning: A Case Study.

BACKGROUND: Treatments of patients with amlodipine (a calcium channel blocker, CCB) overdose/poisoning remain challenging and death is certain if not intervened timely. Furthermore, for the society, the availability and common use of this drug can drive more vulnerable groups, especially children, towards an accidental/suicidal poisoning. CASE REPORT: Herein, we describe the case of an 18 year-old-adolescent girl who took 150 mg of amlodipine with the suicidal intentions and was admitted in our hospital approximately 4-hours after the ingestion. She developed circulatory failure and tachypnea. Decontamination, calcium, glucagon, and dual vasopressors were started, however, persistent hypotension led to the initiation of hyperinsulinemiceuglycemia therapy. She recovered fully and discharged without any complications in few days. This case educates not only about the successful use of variant drugs in the management of CCB overdose/poisoning, but also calls for the attention of the society for a safe storage of often used drugs, especially away from the children/adolescents.