Acute Oral Potassium Overdose: The Role of Hemodialysis

Introduction

Hyperkalemia is a common condition, particularly in the setting of renal dysfunction. Hyperkalemia due to intentional oral potassium overdose is not commonly reported.

Case Report

We present a case of acute intentional potassium overdose in a patient with normal renal function resulting in significant hyperkalemia, with a maximum serum potassium concentration of 11 mEq/L. Despite an initial course complicated by various unstable cardiac rhythms, including ventricular tachycardia, ventricular fibrillation, and pulseless electrical activity, the patient was discharged from the hospital neurologically intact. Treatment for hyperkalemia included hemodialysis.

Discussion

The role of dialysis in potassium overdose is poorly defined.

Conclusion

Based on this case and a review of the medical literature, we recommend hemodialysis for cases of potassium overdose with hemodynamic instability and significantly elevated serum potassium concentrations that do not respond promptly to medical therapy. Hemodialysis should also be considered in cases with underlying renal dysfunction.     

Tretinoin overdose: A first case report

Introduction

Tretinoin (Vesanoid) is an all-trans-retinoic acid, and is related to retinol (Vitamin A). To date, there have been several case reports on overdose with its isomer isotretinoin, but none involving overdose of tretinoin. We report the first known case of a patient who ingested a massive overdose of tretinoin.

Case Report

A 31-year-old man ingested 1000 mg of tretinoin (100 pills of Vesanoid 10 mg) in a suicide attempt. He developed nonbloody diarrhea, but otherwise had no complaints. Clinical examination was normal. The patient was treated with activated charcoal and was hydrated. The patient’s blood results did not show any deterioration on the third consecutive day. He was discharged well on the third day, but was subsequently lost to follow-up.

Discussion

Although there has been no reported experience with acute tretinoin overdose in humans, our patient took a dose approximately 3 times the recommended maximum tolerated daily dose in patients with myelodysplastic syndrome or solid tumors (195 mg/m² per day). Overdose with other retinoids such as isotretinoin have been associated with only minor symptoms that resolved quickly. Our patient had diarrhea, which also resolved quickly with symptomatic treatment and hydration.

Conclusion

We believe this to be the first case report of an acute oral overdose of tretinoin. The patient developed diarrhea, but was otherwise asymptomatic.     

A fatal case of venlafaxine overdose

Introduction

Based on its primary action of serotonin reuptake inhibition, venlafaxine overdose would be expected to result in serotonergic effects.

Case Report

A 40 year old male ingested venlafaxine without co-ingestants in a suicide attempt. The patient developed refractory ventricular fibrillation and expired approximately 9 hours post-ingestion. ECG monitoring revealed significant QRS and QT_C interval prolongation prior to his demise.

Discussion

A literature review of venlafaxine overdose cases and investigation into its mechanism of action was conducted. The potential for sodium channel blockade and implications for therapy are discussed.     

Pharmacologic evidence to support clinical decision making for peripartum methadone treatment

Rationale

Limited pharmacological data are available to guide methadone treatment during pregnancy and postpartum.

Objectives

Study goals were to (1) characterize changes in methadone dose across childbearing, (2) determine enantiomer-specific methadone withdrawal kinetics from steady state during late pregnancy, (3) assess enantiomer-specific changes in methadone level/dose (L/D) ratios across childbearing, and (4) explore relationships between CYP2B6, CYP2C19, and CYP3A4 single-nucleotide polymorphisms and maternal dose, plasma concentration, and L/D.

Methods

Methadone dose changes and timed plasma samples were obtained for women on methadone (n?=?25) followed prospectively from third trimester of pregnancy to 3 months postpartum.

Results

Participants were primarily white, Medicaid insured, and multiparous. All women increased their dose from first to end of second trimester (mean peak increase?=?23 mg/day); 71 % of women increased from second trimester to delivery (mean peak increase?=?19 mg/day). Half took a higher dose 3 months postpartum than at delivery despite significantly larger clearance during late pregnancy. Third trimester enantiomer-specific methadone half-lives (range R-methadone 14.7–24.9 h; S-methadone, 8.02–18.9 h) were about half of those reported in non-pregnant populations. In three women with weekly 24-h methadone levels after delivery, L/D increased within 1–2 weeks after delivery. Women with the CYP2B6 Q172 variant GT genotype have consistently higher L/D values for S-methadone across both pregnancy and postpartum.

Conclusions

Most women require increases in methadone dose across pregnancy. Given the shorter half-life and larger clearances during pregnancy, many pregnant women may benefit from split methadone dosing. L/D increases quickly after delivery and doses should be lowered rapidly after delivery.     

Prolonged Use of Intravenous Lipid Emulsion in a Severe Tricyclic Antidepressant Overdose

Introduction

Intravenous lipid emulsion (ILE) resuscitation is now frequently being used for severe overdoses due to lipophilic drugs. However, the optimal dose, duration, and safety are still unclear.

Case Report

A patient with refractory cardiovascular collapse following an amitriptyline overdose was treated with ILE with initial improvement. Instability recurred after ILE discontinuation and lipid therapy was restarted, but high-dose treatment was complicated by severe lipemia. A low-dose infusion was instead used, and the patient did not experience further toxicity despite amitriptyline levels in the toxic range for 21 days. He survived to discharge without long-term sequelae.

Discussion

A low-dose infusion of ILE was well tolerated and may have successfully prevented recurrent toxicity in a case of severe tricyclic antidepressant overdose.     

Cannabis and benzodiazepines as determinants of methadone trough plasma concentration variability in maintenance treatment: a transnational study

Purpose

To assess tobacco, alcohol, cannabis and benzodiazepine use in methadone maintenance treatment (MMT) as potential sources of variability in methadone pharmacokinetics.

Methods

Trough plasma (R)- and (S)-methadone concentrations were measured on 77 Australian and 74 Swiss MMT patients with no additional medications other than benzodiazepines. Simple and multiple regression analyses were performed for the primary metric, plasma methadone concentration/dose.

Results

Cannabis and methadone dose were significantly associated with lower 24-h plasma (R)- and (S)-methadone concentrations/dose. The models containing these variables explained 14–16% and 17–25% of the variation in (R)- and (S)-methadone concentration/dose, respectively. Analysis of 61 patients using only CYP3A4 metabolised benzodiazepines showed this class to be associated with higher (R)-concentration/dose, which is consistent with a potential competitive inhibition of CYP3A4.

Conclusion

Cannabis use and higher methadone doses in MMT could in part be a response to—or a cause of—more rapid methadone clearance. The effects of cannabis and benzodiazepines should be controlled for in future studies on methadone pharmacokinetics in MMT.     

Clinical pharmacokinetics of penicillins in the neonate: a review of the literature

Background

Sepsis is common in neonates and a major cause of morbidity and mortality. Sixty percent of preterm neonates receive at least one antibiotic during the first week of life, with penicillins being the most frequently administered antibiotics. The clearance (Cl), serum half-life (t_½) and volume of distribution (Vd) of penicillins are different in the neonate than in the adult. As such, the pharmacokinetics of penicillins need be studied in neonates in order to optimise therapy in this age class with these drugs.

Objectives

The aim of this study was to review the published data on the pharmacokinetics of penicillins in the neonate in order to provide a critical analysis of the literature and, consequently, a useful tool in the hands of the physician.

Methods

The bibliographic search was performed electronically using the PubMed and EMBASE databases as search engines. An initial search was performed with the keywords “pharmacokinetics”, “penicillins” and “neonates”. Secondly, other searches were performed using the keywords “pharmacokinetics” and “neonates”, followed by the name of a single antibiotic. The search included articles up to 2007.

Results

There have been few pharmacokinetic studies on the use of penicillins in neonates. The results from those few studies that have been carried out suggest that the Cl is reduced and t_½ prolonged in the neonate as compared with the more mature infant. There is little variation in Vd during the first week of life. In the premature neonate, Cl is reduced compared to the full-term infant. As postnatal age proceeds, the Cl of penicillins increases.

Conclusions

More pharmacokinetic studies are required to provide a sound scientific basis for planning a dosage regimen with penicillins in the neonate.

     

The effects of acute and chronic steady state methadone on memory retrieval in rats

Rationale

Although widely prescribed to treat opioid addiction, little is known about the possible side effects of methadone on memory functions.

Objectives

The aim of this study is to compare the effects of acute and chronic methadone on memory retrieval in rats and to explore the selectivity of possible deficits.

Methods

Administration of acute (0, 1.25, 2.5, and 5?mg/kg SC) and chronic steady state methadone (0, 10, 30, and 55?mg/kg/day SC by osmotic mini-pump) was tested on recall of three different types of information: stimulus?Creward (10-arm parallel maze), stimulus?Cresponse (8-arm radial maze), and stimulus?Cstimulus (Barnes maze). Acute and steady state methadone doses were also compared on tests of locomotor activity and reactivity to aversive stimuli (i.e., swimming and acoustic startle).

Results

In the stimulus?Creward task, acute methadone impaired performance as a result of severe depression of locomotion. This motor deficit, however, was modulated by the motivational valence of environmental stimulation. In fact, acute methadone did not eliminate forced swimming behavior. In the stimulus?Cresponse and stimulus?Cstimulus tasks, accuracy was impaired independently of direct motor deficits, but rats were hyper-reactive to aversive stimulation and, in fact, 5?mg/kg enhanced acoustic startle. Importantly, chronic steady state methadone did not affect accuracy of memory retrieval, did not depress motor or swimming activity, and did not change startle reactivity.

Conclusion

Only acute methadone impaired accuracy and/or performance on three tests of memory retrieval. These findings in rats suggest that memory deficits reported in methadone-maintained individuals may not be directly attributable to methadone.     

Population pharmacokinetics and pharmacogenetics of once daily prolonged-release formulation of tacrolimus in pediatric and adolescent kidney transplant recipients

Background and Objectives

Tacrolimus^PR is a new prolonged-release once-daily formulation of the calcineurin inhibitor tacrolimus, currently used in adult transplant patients. As there are no pharmacokinetic data available in pediatric kidney transplant recipients, the aims of this study were to develop a population pharmacokinetic model of tacrolimus^PR in pediatric and adolescent kidney transplant recipients and to identify covariates that have a significant impacts on tacrolimus^PR pharmacokinetics, including CYP3A5 polymorphism.

Methods

Pharmacokinetic samples were collected from 22 pediatric kidney transplant patients. Population pharmacokinetic analysis was performed using NONMEM. Pharmacogenetic analysis was performed on the CYP3A5 gene.

Results

The pharmacokinetic data were best described by a one-compartment model with first order absorption and lag-time. The weight normalized oral clearance CL/F [CL/F/ (weight/70)^0.75] was lower in patients with CYP3A5*3/*3 as compared to patients with the CYP3A5*1/*3 (32.2?±?10.1 vs. 53.5?±?20.2 L/h, p?=?0.01).

Conclusions

The population pharmacokinetic model of tacrolimus^PR was developed and validated in pediatric and adolescent kidney transplant patients. Body weight and CYP3A5 polymorphism were identified as significant factors influencing pharmacokinetics. The developed model could be useful to optimize individual pediatric tacrolimus ^PR dosing regimen in routine clinical practice.     

Seizures in a pediatric patient with a tiagabine overdose

Introduction

Tiagabine (TGB) is a novel antiepileptic that decreases GABA uptake. The literature contains one report of an adult with epilepsy who ingested up to 1 gram of TGB and developed status epilepticus. We reported on a pediatric patient who ingested significantly less TGB but still developed tonic-clonic seizures.

Case report

A previously healthy, 13 kg, two-year-old girl developed generalized tonic-clonic seizure activity at home approximately 1 hour after ingesting 90 mg of her grandmother’s TGB (forty five 2 mg tablets). At the hospital she had two 5 minute seizures at 1.5 and 3.5 hours post ingestion. Her serum TGB levels were 530 and 130 ng/ml approximately 5 and 11 hours post-ingestion (5–70 ng/ml trough levels with most probable range for seizure control). She was discharged 27 hours post ingestion, and she was in good condition.

Conclusion

An overdose of TGB, a novel anti-epileptic, can cause convulsive seizures.     

Four-year experience with methotrexate exposures

Introduction

Unintentional methotrexate (MTX) acute oral overdose is rarely reported.

Methods

We conducted a retrospective chart review of all human exposure calls (> 150,000 charts) for MTX ingestions reported to our Poison Center during 2000–2003.

Results

Thirteen patients met the criteria. The average amount of MTX ingested was 13.03 mg (data from 7 cases), and the average patient age was 43 years (20 months to 80 years). No significant toxicities occurred.

Discussion

Although intravenous MTX toxicity can be severe, this does not appear to be a phenomenon associated with either acute unintentional or suicidal oral ingestion.     

l-Carnitine for the Treatment of a Calcium Channel Blocker and Metformin Poisoning

Introduction

The object of the current communication is to discuss the theory and the evidence for the use of l-carnitine in calcium channel blocker and metformin poisonings.

Case Report

A 68-year-old male known for hypertension and type II diabetes was admitted to the critical care unit of a community hospital following an overdose of amlodipine and metformin. The patient was intubated, ventilated, and hemodynamically supported with vasopressors. Despite calcium, glucagon, high-dose insulin (HDI), and lipid emulsion for calcium channel blocker and bicarbonate for metabolic acidosis, the patient remained hemodynamically unstable. The patient was considered too unstable to initiate continuous renal replacement therapy; and without access to extracorporeal life support, the administration of l-carnitine was administered as a last resort. One hour after l-carnitine, the norepinephrine requirements started to decrease, the patient began to improve and was subsequently extubated successfully without apparent sequelae in less than 4 days.

Discussion

l-Carnitine combined with HDI may have helped with the calcium channel blocker (CCB) poisoning by decreasing insulin resistance, promoting intracellular glucose transport, facilitating the metabolism of free fatty acids, and increasing calcium channel sensitivity. It may have also stimulated oxidative utilization of glucose instead of converting pyruvate into lactate and contributed to decrease lactate production with metformin poisoning.     

Simultaneous Pharmacokinetic Modeling of Gentamicin,Tobramycin and Vancomycin Clearance from Neonates to Adults: Towards a Semi-physiological Function for Maturation in Glomerular Filtration

Purpose

Since glomerular filtration rate (GFR) is responsible for the elimination of a large number of water-soluble drugs, the aim of this study was to develop a semi-physiological function for GFR maturation from neonates to adults.

Methods

In the pharmacokinetic analysis (NONMEM VI) based on data of gentamicin, tobramycin and vancomycin collected in 1,760 patients (age 1 day–18 years, bodyweight 415 g–85 kg), a distinction was made between drug-specific and system-specific information. Since the maturational model for clearance is considered to contain system-specific information on the developmental changes in GFR, one GFR maturational function was derived for all three drugs.

Results

Simultaneous analysis of these three drugs showed that maturation of GFR mediated clearance from preterm neonates to adults was best described by a bodyweight-dependent exponent (BDE) function with an exponent varying from 1.4 in neonates to 1.0 in adults (Cl_GFR?=?Cl_drug*(BW/4 kg)^BDE with BDE?=?2.23*BW^?0.065). Population clearance values (Cl_drug) for gentamicin, tobramycin and vancomycin were 0.21, 0.28 and 0.39 L/h for a full term neonate of 4 kg, respectively.

Discussion

Based on an integrated analysis of gentamicin, tobramycin and vancomycin, a semi-physiological function for GFR mediated clearance was derived that can potentially be used to establish evidence based dosing regimens of renally excreted drugs in children.     

Population pharmacokinetics of peginterferon alfa-2b in pediatric patients with chronic hepatitis C

Purpose

The aim of this study was to characterize the population pharmacokinetics of peginterferon (PEG-IFN) alfa-2b in pediatric patients with chronic hepatitis C and to identify covariates influencing PEG-IFN alfa-2b disposition.

Methods

Pharmacokinetic data from a multicenter open-label study of subcutaneously administered peginterferon alfa-2b (60 μg/m²/wk) plus oral ribavirin (15 mg/kg/day) in patients with chronic hepatitis C aged 3–17 years old was used to develop a population pharmacokinetic nonlinear mixed-effects model.

Results

The final population pharmacokinetic analysis was conducted with the pooled data from 107 pediatric patients. A one-compartment model with first-order absorption, first-order elimination, exponential inter-individual variability on clearance, and a combination additive and proportional residual error model adequately described the PEG-IFN alfa-2b pharmacokinetic profile. Age (apparent clearance and apparent volume of distribution) and sex (apparent clearance) were significant covariates. The mean body surface area normalized apparent clearance of PEG-IFN alfa-2b was 0.56 L/h/m², and was similar when evaluated across the pediatric age groups.

Conclusion

The final population model suggests age-dependent increases in clearance and volume of distribution of PEG-IFN alfa-2b in pediatric patients with chronic hepatitis C. The apparent clearance normalized to body surface area was similar across pediatric age groups, supporting the use of body size–adjusted dosing in pediatric subjects.     

Serum concentrations of opioids when comparing two switching strategies to methadone for cancer pain

Purpose

Our aim was to compare pharmacological aspects of two switching strategies from morphine/oxycodone to methadone; the stop and go (SAG) strategy in which methadone is started directly after the initial opioid has been stopped, and the 3-days switch (3DS), in which morphine/oxycodone is gradually changed to methadone by cross-tapering over 3 days.

Methods

Forty-two cancer patients with pain and/or opioid side effects were assessed in this randomised trial. Trough serum concentrations of methadone, morphine, morphine-6-glucuronide (M6G), and oxycodone were measured on days 1, 2, 3, 4, 7, and 14. Primary outcome was number of patients with methadone concentrations in apparent C_SS on day 4. Secondary outcomes were exposure to opioids during the first 3 days, interindividual variation of opioid concentrations, and correlation between methadone concentrations and pain intensity (PI) day 3.

Results

Thirty-five patients received methadone (16 in the SAG group, 19 in the 3DS group). The median preswitch morphine equivalent doses were 620 (range 350–2000) mg/day in the SAG group and 800 (range 90–3600) mg/day in the 3DS group (p?=?0.43);42% reached C_SS for methadone in the SAG group on day 4 compared with 22% in the 3DS group (p?=?0.42). The SAG group was significantly less exposed to morphine/M6G/oxycodone and significantly more exposed to methadone in the first 3 days. Methadone showed a low correlation with PI. More patients dropped out after intervention in the SAG group than in the 3DS group (38% vs. 5%; p?=?0.032). One SAG patient suffered from respiratory depression on day 5.

Conclusion

The SAG group was initially more exposed to methadone and less to the replaced opioids but without observed clinical benefit and with a higher dropout rate. Patients switched to methadone should be followed closely for the first 5 days, regardless of switching strategy.     

Haemodynamics of intravenous paracetamol in neonates

Introduction

Reports on the haemodynamics of intravenous (iv) paracetamol in adult intensive care were recently published. We therefore wanted to explore the haemodynamics of iv paracetamol in neonates.

Methods

Retrospective, pooled analysis of heart rate (bpm) and blood pressure (mean, systolic, diastolic) observations collected during iv paracetamol pharmacokinetic studies in neonates. Heart rate and blood pressure were recorded just before and 30, 60, 120, 180, 240, 300 and 360 min after iv paracetamol (paired, ANOVA). Clinical characteristics in hypotensive (mean mmHg < gestational age, weeks) cases were compared with controls (Mann–Whitney U test).

Results

Based on observations in 72 neonates, heart rate decreased from 145 (SD 20) to 138 (21), 141 (20), 137 (20), 137 (22), 140 (20), 139 (20) and 140 (21) bpm (paired p?<?0.05, ANOVA p?=?0.36). There were no changes in systolic and diastolic pressure, but mean arterial pressure decreased from 46 (7) to 43 (8) mmHg at 60 min (paired p?<?0.05, ANOVA p?=?0.75). Eight neonates developed hypotension. These patients had lower pre-administration arterial pressure (38 vs 47 mmHg, p?<?0.05).

Conclusions

In a setting of open label administration to alleviate (procedural) pain, haemodynamic effects of iv paracetamol in neonates remained modest. We suggest considering impaired haemodynamics to be a relative contra-indication for iv paracetamol in neonates.     

A qualitative study exploring the reason for low dosage of methadone prescribed in the MMT clinics in China

Objectives

Dosage of methadone maintenance therapy (MMT) is an important factor influencing retention in methadone treatment. MMT clients in China received lower dosages of methadone compared with those provided in other countries. The objective of this study is to elucidate the reason for the low methadone dosage prescribed in MMT clinics in China.

Methods

Twenty-eight service providers were recruited from the MMT clinics in Zhejiang and Jiangxi Provinces, China. Qualitative in-depth interviews were conducted to ascertain the procedure for prescribing methadone in the MMT clinics.

Results

The average dosage prescribed in the 28 clinics was 35 mg/person/day. Four major themes resulting in low dosage of methadone were identified: (1) the service providers fear the liability resulting from large doses of methadone in combination with other substances which might result in overdose fatalities, (2) lack of understanding of harm reduction which resulted in low acceptance of the long term maintenance treatment approach, (3) break-down in communication between clients and service providers about dosage adjustment, and (4) dosage reduction is perceived by most service providers as an effective way to treat the side-effects associated with MMT.

Conclusions

The findings of the study highlighted the necessity to formulate clear guidelines concerning individualized dosage management and to improve training among service providers’ in MMT clinics in China.     

Late-onset seizures associated with quetiapine poisoning

Introduction

Quetiapine, a second-generation antipsychotic, acts at multiple brain neurotransmitter receptors and has the potential for serious complications. Although seizures have been described in the literature, delayed seizure onset has not been reported. We report the first case of delayed seizures after a significant quetiapine overdose.

Case Report

A 27-year-old female presented to the emergency department following an overdose of approximately 30 g of quetiapine. Twenty-four hours after arrival, the patient had 2 seizures. The patient was then intubated and remained in the ICU for four days. EEG was negative for epileptiform activity. The serum quetiapine levels (MedTox, St. Paul, MN) were 8.67 mg/L on hospital day one and 3.28 mg/L on hospital day three.

Discussion

Quetiapine poisoning, with serum levels, associated with seizures has been reported in one prior case. Our case report represents late-onset seizures with serum levels above therapeutic range (> 1 mg/L). The serum concentrations of quetiapine in this case were consistent with those in postmortem case reports.     

Transdermal fentanyl: Pharmacology and toxicology

Objective

To evaluate the underlying pharmacology safety, and misuse/abuse of transdermal fentanyl, one of the cornerstone pharmacotherapies for patients with chronic pain.

Methods

Literature was identified through searches of Medline (Pubmed) and several textbooks in the areas of pharmacology, toxicology, and pain management. A bibliographical review of articles identified by these searches was also performed. Search terms included combinations of the following: fentanyl, transdermal, patch, pharmacology, kinetics, toxicity, and poisoning. All pertinent clinical trials, retrospective studies, and case reports relevant to fentanyl pharmacology and transdermal fentanyl administered by any route and published in English were identified. Each was reviewed for data regarding the clinical pharmacology, abuse misuse, and safety of transdermal fentanyl. Data from these studies and information from review articles and pharmaceutical prescribing information were included in this review.

Results

Fentanyl is a high-potency opioid that has many uses in the treatment of both acute and chronic pain. Intentional or unintentional misuse, as well as abuse, may lead to significant clinical consequences, including death. Both the US Food and Drug Administration (FDA) and Health Canada have warned of potential pitfalls associated with transdermal fentanyl, although these have not been completely effective in preventing life-threatening adverse events and fatalities related to its inappropriate use.

Conclusions

Clinical consequential adverse effects may occur unexpectedly with normal use of transdermal fentanyl, or if misused or abused. Misuse and therapeutic error may be largely preventable through better education at all levels for both the prescriber and patient. The prevention of intentional misuse or abuse may require regulatory intervention.