The vitamin B12 analog cobinamide is an effective hydrogen sulfide antidote in a lethal rabbit model

Background and purpose. Hydrogen sulfide (H₂S) is a highly toxic gas for which no effective antidotes exist. It acts, at least in part, by binding to cytochrome c oxidase, causing cellular asphyxiation and anoxia. We investigated the effects of three different ligand forms of cobinamide, a vitamin B12 analog, to reverse sulfide (NaHS) toxicity. Methods. New Zealand white rabbits received a continuous intravenous (IV) infusion of NaHS (3 mg/min) until expiration or a maximum 270 mg dose. Animals received six different treatments, administered at the time when they developed signs of severe toxicity: Group 1—saline (placebo group, N = 9); Group 2—IV hydroxocobalamin (N = 7); Group 3—IV aquohydroxocobinamide (N = 6); Group 4—IV sulfitocobinamide (N = 6); Group 5—intramuscular (IM) sulfitocobinamide (N = 6); and Group 6—IM dinitrocobinamide (N = 8). Blood was sampled intermittently, and systemic blood pressure and deoxygenated and oxygenated hemoglobin were measured continuously in peripheral muscle and over the brain region; the latter were measured by diffuse optical spectroscopy (DOS) and continuous wave near infrared spectroscopy (CWNIRS). Results. Compared with the saline controls, all cobinamide derivatives significantly increased survival time and the amount of NaHS that was tolerated. Aquohydroxocobinamide was most effective (261.5 ± 2.4 mg NaHS tolerated vs. 93.8 ± 6.2 mg in controls, p < 0.0001). Dinitrocobinamide was more effective than sulfitocobinamide. Hydroxocobalamin was not significantly more effective than the saline control. Conclusions. Cobinamide is an effective agent for inhibiting lethal sulfide exposure in this rabbit model. Further studies are needed to determine the optimal dose and form of cobinamide and route of administration.     

Intramuscular dimethyl trisulfide: efficacy in a large swine model of acute severe cyanide toxicity

Background: Cyanide is a deadly compound used as a terrorist agent. Current FDA approved antidotes require intravenous administration, limiting their utility in a mass casualty scenario. Dimethyl trisulfide (DMTS), a sulfur-based molecule, binds cyanide converting it to the less toxic by-product thiocyanate. Studies evaluating efficacy in rodents have been performed, but a large, clinically relevant animal model has not been reported.

Objective: This study evaluates the efficacy of intramuscular DMTS on survival and clinical outcomes in a swine model of acute, severe cyanide toxicity.

Methods: Anesthetized swine were instrumented for continuous monitoring of hemodynamics. Prior to potassium cyanide infusion animals were acclimated and breathing spontaneously. At 5-minutes post-apnea animals were treated with DMTS or saline. Vital signs, hemodynamics, and laboratory values were evaluated at various time points.

Results: Baseline values and time to apnea were similar in both groups. Survival in the DMTS treated group was 83.3% and 0% in saline controls (p?=?.005). The DMTS group returned to breathing at a mean time of 19.3?±?10?min after antidote, control animals did not return to breathing (CI difference 8.8, 29.8). At the end of the experiment or time of death, mean lactate was 9.41?mmol/L vs. 4.35?mmol/L (CI difference –10.94,0.82) in the saline and DMTS groups, respectively and pH was 7.20 vs. 7.37 (CI difference –0.04, 0.38). No adverse effects were observed at the injection site.

Conclusion: Intramuscular administration of DMTS improves survival and clinical outcomes in our large animal swine model of acute cyanide toxicity.     

Revisiting the physiological effects of methylene blue as a treatment of cyanide intoxication

Background: Although methylene blue (MB) had long been proposed to counteract the effects of cyanide (CN) intoxication, research on its mechanisms of action and efficacy has been abandoned for decades. Recent studies on the benefits of MB in post-anoxic injuries have prompted us to reexamine the relevance of this historical observation.

Methods: Our study was performed in adult male Sprague–Dawley rats and on HEK293T epithelial cells. First, the effects and toxicity of MB (0–80?mg/kg) on circulation and metabolism were established in four urethane-anesthetized rats. Then nine rats received a lethal infusion of a solution of KCN (0.75?mg/kg/min) and were treated by either saline or MB, at 20?mg/kg, a dose that we found to be innocuous in rat and to correspond to a dose of about 4?mg/kg in humans. MB was also administered 5?min after the end of a sub-lethal exposure to CN in a separate group of 10 rats. In addition, ATP/ADP ratio, ROS production, mitochondrial membrane potential (Δψm) and cellular O₂ consumption rate (OCR) were determined in HEK293T cells exposed to toxic levels of CN (200?µM for 10?min) before and after applying a solution containing MB (1–100?µM for 10?min).

Results: Methylene blue was found to be innocuous up to 50?mg/kg. KCN infusion (0.75?mg/kg/min) killed all animals within 7–8?min. MB (20?mg/kg) administered at the same time restored blood pressure, cardiac contractility and limited O₂ deficit, allowing all the animals to survive, without any significant methemoglobinemia. When administered 5?min after a non-lethal CN intoxication, MB sped up the recovery of lactate and O₂ deficit. Finally, MB was able to decrease the production of ROS and restore the ATP/ADP ratio, Δψm as well as OCR of epithelial cells intoxicated by CN.

Conclusions: The present observations should make us consider the potential interest of MB in the treatment of CN intoxication. The mechanisms of the antidotal properties of MB cannot be accounted for by the creation of a cyanomethemoglobinemia, rather its protective effects appears to be related to the unique properties of this redox dye, which, depending on the dose, could directly oppose some of the consequences of the metabolic depression produced by CN at the cellular level.     

High-dose hydroxocobalamin administered after H2S exposure counteracts sulfide-poisoning-induced cardiac depression in sheep

Abstract

Context. Severe H₂S poisoning leads to death by rapid respiratory and cardiac arrest, the latter can occur within seconds or minutes in severe forms of intoxication. Objectives. To determine the time course and the nature of H₂S-induced cardiac arrest and the effects of high-dose hydroxocobalamin administered after the end of sulfide exposure. Materials and methods. NaHS was infused in 16 sedated mechanically ventilated sheep to reach concentrations of H₂S in the blood, which was previously found to lead to cardiac arrest within minutes following the cessation of H₂S exposure. High-dose hydroxocobalamin (5 g) or saline solution was administered intravenously, 1 min after the cessation of NaHS infusion. Results. All animals were still alive at the cessation of H₂S exposure. Three animals (18%) presented a cardiac arrest within 90 s and were unable to receive any antidote or vehicle. In the animals that survived long enough to receive either hydroxocobalamin or saline, 71% (5/7) died in the control group by cardiac arrest within 10 min. In all instances, cardiac arrest was the result of a pulseless electrical activity (PEA). In the group that received the antidote, intravenous injection of 5 g of hydroxocobalamin provoked an abrupt increase in blood pressure and blood flow; PEA was prevented in all instances. However, we could not find any evidence for a recovery in oxidative metabolism in the group receiving hydroxocobalamin, as blood lactate remained elevated and even continued to rise after 1 h, despite restored hemodynamics. This, along with an unaltered recovery of H₂S kinetics, suggests that hydroxocobalamin did not act through a mechanism of H₂S trapping. Conclusion. In this sheep model, there was a high risk for cardiac arrest, by PEA, persisting up to 10 min after H₂S exposure. Very high dose of hydroxocobalamin (5 g), injected very early after the cessation of H₂S exposure, improved cardiac contractility and prevented PEA.     

Do Adenosine Receptors Play a Role in Amitriptyline‐Induced Cardiovascular Toxicity in Rats?

Objective: The aim of the our study was to investigate the role of adenosine receptors on cardiovascular toxicity induced by amitriptyline, a tricyclic antidepressant agent. Therefore, the hypothesis of this study was that adenosine receptor antagonists would improve and/or prevent amitriptyline‐induced hypotension and conduction abnormalities in an anesthetized rat model of amitriptyline intoxication. Methods: Two separate experimental protocols were performed. Amitriptyline intoxication was induced by the infusion of amitriptyline 0.94 mg/kg/min until 40–45% reduction of mean arterial pressure (MAP). Sodium cromoglycate (10 mg/kg) was injected i.v. to inhibit the A₃ receptor‐mediated activation of mast cells. In protocol 1, after amitriptyline infusion, while control animals (n = 8) were given dextrose solution, treatment groups received a selective adenosine A₁ antagonist DPCPX (8‐cyclopentyl‐1,3‐Dipropylxanthine, 20 µg/kg/min, n = 8) or a selective A_2a antagonist CSC (8‐(3‐chlorostyryl) caffeine, 24 µg/kg/min, n = 8) for 60 minutes. In protocol 2, after the sodium cromoglycate, while control group of rats (n = 8) recevied a dextrose solution, treatment groups of rats were administered DPCPX (20 µg/kg/min, n = 8) or CSC (24 µg/kg/min, n = 8) infusion to block adenosine A₁ and A_2a receptors for 20 minutes before amitriptyline infusion. After pretreatment with adenosine antagonists, all rats were given a dose of 0.94 mg/kg/min of amitriptyline infusion during 60 minutes. Outcome measures were mean arterial pressure (MAP), heart rate (HR), QRS duration and survival rate. Results: In protocol 1, amitriptyline infusion significantly reduced MAP and prolonged QRS within 15 minutes. HR was not changed significantly during the experiments. While dextrose did not improve MAP and QRS prolongation, DPCPX or CSC administration developed a significant improvement in MAP compared to the dextrose group within 10 min (88.5 ± 2.8%, 75.6 ± 4.7% and 50.1 ± 14.7%, p < 0.01, p < 0.05, respectively). Both DPCPX and CSC decreased QRS prolongation (p < 0.05) and increased median survival time significantly (log‐rank test, p < 0.00001). In protocol 2, pretreatment with DPCPX or CSC prevented the reduction in MAP due to amitriptyline toxicity compared to rats administered dextrose infusion (99.5 ± 2.6%, 102.4 ± 2.6%, 81.8 ± 5.4, p < 0.01 at 30 min; 98.0 ± 2.9%, 93.5 ± 6.0%, 64.9 ± 4.7, p < 0.001, p < 0.01 at 40 min, respectively). Pretreatment with DPCPX or CSC also prevented the QRS prolongation (p < 0.05) and increased median survival time significantly (log‐rank test, p < 0.0001). Conclusion: Adenosine antagonists were found to be effective in improving hypotension, QRS prolongation and survival time in our rat model of amitriptyline toxicity. Additionally, amitriptyline‐induced cardiotoxicity was abolished by pretreatment with adenosine receptor antagonists. These results suggest that adenosine receptors may have a role in the pathophysiology of amitriptyline‐induced cardiovascular toxicity. Adenosine A₁ and A_2a receptor antagonists may be promising agents for reversing amitriptyline‐induced cardiovascular toxicity.     

Methyprylon Overdose: Interpretation of Serum Drug Concentrations

Abstract

The effect of two forms of Prussian blue, soluble K₃ Fe[Fe(CN)₆] and insoluble Fe₄[Fe(CN)₆]₃, and of ammonium iron hexacyanoferrate (II) (NH₄Fe[Fe(CN)₆] on intestinal radiocesium absorption was investigated in rats, pigs, and humans. In rats 5?mg of antidote administered 2 min before ¹³⁴Cs tracer reduced radiocesium absorption to 2.4 - 6.3% of the oral dose. In pigs fed with Chernobyl-contaminated whey under normal feeding conditions for a 27 day period, radiocesium activity concentration was reduced from 360 Bq/kg in control animals to 10 - 30 Bq/kg by 5?g antidote/d. In man 1?g of oral Prussian blue diminished the cesium absorption from a ¹³⁴Cs-labelled test meal to 5.6 -6.4% of the controls. The inhibitory effects of colloidally soluble K₃ Fe[Fe(CN₆) and of (NH₄Fe[Fe(CN)₆] were similar with slightly less inhibition by the insoluble Fe₄[Fe(CN)₆]₃.     

Dopamine and Isoproterenol in Imipramine Intoxication in the Dog

Abstract

Artificially ventilated anesthetized dogs were given imipramine 7.5?mg/kg/hr i.v. In the first group (n=6) mechanical cardiac activity was no longer detectable after a cumulative dose of 20.0 + 6.6?mg/kg (mean ± sd). When aortic flow had decreased to 75% of its initial value, in a second group (n=5) of experiments dopamine 10 μg/kg/min and in a third group (n=5) isoproterenol 1 μg/kg/min were administered i.v. The doses of dopamine and isoproterenol were doubled when aortic flow had again decreased to 75% and 100%, respectively, of the original values. Cardiac mechanical activity was not detectable after a cumulative dose of 43.8 ± 13.3 in the dopamine and 42.5 ± 8.0?mg imipramine/kg in the isoproterenol group. These values differed significantly from that in the reference group (both 0.01 > p > 0.001). In the first group plasma imipramine concentrations at the end of the experiments were 3.06 ± 0.66, in the second 3.36 ± 0.66 and in the third 3.32 ± 1.10?mg/1. Desipramine concentrations were 0.078 ± 0.06, 0.162 ± 0.076 and 0.383 ± 0.09?mg/1 respectively. Dopamine induced a hemodynamic profile of low output and high pressure and isoproterenol one of low pressure and high output. It is concluded that dopamine combined with isoproterenol might be effective in counteracting the cardiodepressant action of imipramine.     

Effects of a thromboxane antagonist (BM 13·177) during endotoxin-induced pulmonary vasoconstriction in sheep

Summary. We investigated the effect of a thromboxane antagonist, BM 13·177, during endotoxin-induced pulmonary vasoconstriction in sheep. In control animals intravenous E-coli endotoxin (1 μg/kg) caused a transient increase of pulmonary artery and airway pressure paralleled by large concentration increases of TXB₂: in comparison peak plasma concentrations of 6-keto-PGFlα (a prostacyclin metabolite) were small and delayed in time. Pre-treatment with BM 13·177 (bolus 5 mg/kg), followed by 0·75 mg/kg/min intravenously) abolished the rise of pulmonary artery and airway pressure. Plasma concentrations of TXB₂ and 6-keto-PFGla were similar to controls. These and previous investigations imply that BM 13·177 specifically antagonizes TXA₂ on the putative receptor in pulmonary vascular and airway smooth muscle.     

Is naloxone the best antidote to reverse tramadol-induced neuro-respiratory toxicity in overdose? An experimental investigation in the rat

Context: Since the banning of dextropropoxyphene from the market, overdoses, and fatalities attributed to tramadol, a WHO step-2 opioid analgesic, have increased markedly. Tramadol overdose results not only in central nervous system (CNS) depression attributed to its opioid properties but also in seizures, possibly related to non-opioidergic pathways, thus questioning the efficiency of naloxone to reverse tramadol-induced CNS toxicity.

Objective: To investigate the most efficient antidote to reverse tramadol-induced seizures and respiratory depression in overdose.

Materials and methods: Sprague–Dawley rats overdosed with 75?mg/kg intraperitoneal (IP) tramadol were randomized into four groups to receive solvent (control group), diazepam (1.77?mg/kg IP), naloxone (2?mg/kg intravenous bolus followed by 4?mg/kg/h infusion), and diazepam/naloxone combination. Sedation depth, temperature, number of seizures, and intensity, whole-body plethysmography parameters and electroencephalography activity were measured.

Results: Naloxone reversed tramadol-induced respiratory depression (p?p?p?p?Conclusions: Diazepam/naloxone combination is the most efficient antidote to reverse tramadol-induced CNS toxicity in the rat.     

Efficiency of acidemia correction on intermittent versus continuous hemodialysis in acute methanol poisoning

Context: Acidemia is a marker of prognosis in methanol poisoning, as well as compounding formate-induced cytotoxicity. Prompt correction of acidemia is a key treatment of methanol toxicity and methods to optimize this are poorly defined.

Objective: We studied the efficiency of acidemia correction by intermittent hemodialysis (IHD) and continuous renal replacement therapy (CRRT) in a mass outbreak of methanol poisoning.

Methods: The study was designed as observational cohort study. The mean time for an increase of 1?mmol/L HCO₃^–, 0.01 unit arterial blood pH, and the total time for correction of HCO₃^– were determined in IHD- and CRRT-treated patients.

Results: Data were obtained from 18 patients treated with IHD and 13 patients treated with CRRT. At baseline, CRRT group was more acidemic than IHD group (mean arterial pH 6.79?±?0.10 versus 7.05?±?0.10; p?=?0.001). No association was found between the rate of acidemia correction and age, weight, serum methanol, lactate, formate, and glucose on admission. The time to HCO₃^– correction correlated with arterial blood pH (r=??0.511; p?=?0.003) and creatinine (r?=?0.415; p?=?0.020). There was association between the time to HCO₃^– correction and dialysate/effluent and blood flow rates (r=??0.738; p?r=??0.602; p?The mean time for HCO₃^– to increase by 1?mmol/L was 12?±?2?min for IHD versus 34?±?8?min for CRRT (p?p?=?0.024). The mean increase in HCO₃^– was 5.67?±?0.90?mmol/L/h for IHD versus 2.17?±?0.74?mmol/L/h for CRRT (p?Conclusions: Our study supports the superiority of IHD over CRRT in terms of the rate of acidemia correction.     

Essential Oil Poisoning

Abstract

Alpha-ketoglutaric acid and sodium thiosulfate antagonize the toxic effects of cyanide. The present study was performed to test whether a synergistic effect may occur. The alpha-ketoglutaric acid/sodium thiosulfate solutions were injected intraperitoneally into mice prior to exposure to hydrogen cyanide (HCN) in a dynamic inhalation chamber or preceding an intraperitoneal injection of sodium cyanide (NaCN). All lethal concentration (LCT) and lethal dose (LD) values were determined after a period of 24?h. Alpha-ketoglutaric acid alone provided no protection at 250?mg/kg when challenged with HCN. Sodium thiosulfate 500?mg/kg provided a 5% protection. However, when these doses of alpha-ketoglutaric acid and sodium thiosulfate were combined, protection was increased by 18%. Alpha-ketoglutaric acid (250?mg/kg) and sodium thiosulfate (1000?mg/kg) provided an additional 48% protection against a LCT₈₈ of HCN. A single dose of alpha-ketoglutaric acid (500?mg/kg) and sodium thiosulfate (1000?mg/kg) solutions afforded a 70% increase in survivability of the exposed animals. When mice were injected ip with 100?mg/kg of alpha-ketoglutaric acid 15 min prior to the injection of 5.5?mg/kg (LD₅₀) of NaCN, the lethality was reduced to an LD₃₀. Two hundred?mg/kg alpha-ketoglutaric acid, challenged with the same dose of NaCN, reduced the lethality to 23%. When mice were challenged with 6.0?mg/kg of NaCN (LD₇₀) pretreated with 100?mg/kg of alpha-ketoglutaric acid or 200?mg/kg of sodium thiosulfate, the LD was not altered in the former but reduced to an LD_1S in the latter. At higher doses of sodium thiosulfate (500?mg/kg), an LD₆₀ occurred at 13.6?mg/kg NaCN (2.5 x LD₅₀). Combinations of alpha-ketoglutaric acid and sodium thiosulfate proved to be very effective. Injections in which alpha-ketoglutaric acid and sodium thiosulfate (200 and 500?mg/kg, respectively) were given 15 min prior to NaCN challenges of 26.5?mg/kg (4.8 x LD₅₀) produced an average lethality of 78%. Greater doses of alpha-ketoglutaric acid and sodium thiosulfate were required to provide protection against the lethal effects of inhaled HCN than those of parenteral NaCN. Also, alpha-ketoglutaric acid and sodium thiosulfate are synergistic in their antidotal effects against both HCN and NaCN.     

Effects of hydrogen sulfide on hemodynamics, inflammatory response and oxidative stress during resuscitated hemorrhagic shock in rats

Introduction

Hydrogen sulfide (H₂S) has been shown to improve survival in rodent models of lethal hemorrhage. Conversely, other authors have reported that inhibition of endogenous H₂S production improves hemodynamics and reduces organ injury after hemorrhagic shock. Since all of these data originate from unresuscitated models and/or the use of a pre-treatment design, we therefore tested the hypothesis that the H₂S donor, sodium hydrosulfide (NaHS), may improve hemodynamics in resuscitated hemorrhagic shock and attenuate oxidative and nitrosative stresses.

Methods

Thirty-two rats were mechanically ventilated and instrumented to measure mean arterial pressure (MAP) and carotid blood flow (CBF). Animals were bled during 60 minutes in order to maintain MAP at 40 ± 2 mm Hg. Ten minutes prior to retransfusion of shed blood, rats randomly received either an intravenous bolus of NaHS (0.2 mg/kg) or vehicle (0.9% NaCl). At the end of the experiment (T = 300 minutes), blood, aorta and heart were harvested for Western blot (inductible Nitric Oxyde Synthase (iNOS), Nuclear factor-κB (NF-κB), phosphorylated Inhibitor κB (P-IκB), Inter-Cellular Adhesion Molecule (I-CAM), Heme oxygenase 1(HO-1), Heme oxygenase 2(HO-2), as well as nuclear respiratory factor 2 (Nrf2)). Nitric oxide (NO) and superoxide anion (O₂ ^-) were also measured by electron paramagnetic resonance.

Results

At the end of the experiment, control rats exhibited a decrease in MAP which was attenuated by NaHS (65 ± 32 versus 101 ± 17 mmHg, P < 0.05). CBF was better maintained in NaHS-treated rats (1.9 ± 1.6 versus 4.4 ± 1.9 ml/minute P < 0.05). NaHS significantly limited shock-induced metabolic acidosis. NaHS also prevented iNOS expression and NO production in the heart and aorta while significantly reducing NF-kB, P-IκB and I-CAM in the aorta. Compared to the control group, NaHS significantly increased Nrf2, HO-1 and HO-2 and limited O₂ ^- release in both aorta and heart (P < 0.05).

Conclusions

NaHS is protective against the effects of ischemia reperfusion induced by controlled hemorrhage in rats. NaHS also improves hemodynamics in the early resuscitation phase after hemorrhagic shock, most likely as a result of attenuated oxidative stress. The use of NaHS hence appears promising in limiting the consequences of ischemia reperfusion (IR).     

Mitigation of endotoxin-induced acute lung injury in ventilated rabbits by surfactant and inhaled nitric oxide

Objective: To evaluate the efficacy of surfactant and inhaled nitric oxide (iNO) in endotoxin-induced acute lung injury (ALI).¶Design: Prospective, randomised, controlled experimental study.¶Setting: A medical university hospital research laboratory.¶Intervention: Twenty-nine adult rabbits (2.4–3.4 kg) were given two doses of intravenous endotoxin (Escherichia coli) (0.01 mg/kg and, 12 h later, 0.1 mg/kg), and then subjected to mechanical ventilation. After 8 h these animals were allocated to four treatment groups: (1) control, (2) iNO at 20 ppm (NO), (3) surfactant at 100 mg/kg (Surf) and (4) both surfactant and iNO as in groups 2 and 3 (SNO), and ventilated for a further 6 h followed by broncho-alveolar lavage (BAL), analysis of surfactant contents in BAL fluid and histological examination of the lungs.¶Measurements and results: All the animals had developed ALI with respiratory failure 8 h after the second dose of endotoxin as evidenced by a decrease of PaO₂/FIO₂ from 520 ± 30 to 395 ± 19 mmHg and dynamic compliance (Cdyn) from 1.20 ± 0.11 to 0.73 ± 0.05 ml/cmH₂O × kg, and an increase of intrapulmonary shunting (Qs/Qt) from 7.5 ± 0.8 % to 12.9 ± 1.0 % (all measurements p < 0.01 versus baseline). In the SNO group, values for PaO₂/FIO₂, Cdyn and Qs/Qt after 6 h were 301 ± 15 mmHg, 0.67 ± 0.05 ml/cmH₂O × kg and 16.5 ± 0.8 %, compared to 224 ± 26 mmHg, 0.53 ± 0.04 ml/cmH₂O × kg and 24.1 ± 2.0 %, respectively, in the control group (all measurements p < 0.01). Both Surf and NO groups showed intermediate levels of these parameters. In both Surf and SNO groups, the minimum surface tension of BAL fluid was lower, and the content of disaturated phosphatidylcholine/total protein higher, than in the control and NO groups (p < 0.01). Histological features of lung injury were less prominent and wet/dry lung weight ratio lower in the NO, Surf and SNO groups. Decreased surfactant protein A (SP-A) and its mRNA expression were found in all endotoxin-exposed groups, but the SP-A content of the SNO group was moderately improved in comparison to the control group. Surfactant aggregate size was not affected.¶Conclusion: Early application of surfactant and iNO moderately mitigated ALI as reflected by improvement of lung mechanics, pulmonary perfusion and morphology.     

Renal effects of urodilatin in healthy subjects are independent of blockade of the cyclooxygenase and angiotensin II receptor

Objective. Little is known about the role of the renin–angiotensin–aldosterone system and the renal prostaglandins in modulating the renal vasoconstrictive and natriuretic effects of synthetic urodilatin (URO) in healthy humans. Material and methods. Twelve volunteers were pretreated in a randomized, single‐blind, crossover study with losartan 50?mg a day or placebo for 5 days. Another 12 healthy subjects received indomethacin 25?mg three times a day or placebo for 4 days and a single dose on day 5. All subjects received a URO infusion (15?ng kg^?1?min^?1) on day 5. Radioactive tracers and the lithium clearance technique were used. Results. The effective renal plasma flow (ERPF) decreased significantly during URO infusion: losartan pretreatment 573±63 to 461±76?mL/min versus placebo 540±89 to 432±90?mL/min. The urinary sodium excretion rate (UNa) increased significantly during URO infusion: losartan 335±115 to 502±134?umol/min (micromol/min) (UNa) versus placebo 386±142 to 476±137?umol/min (micromol/min) (UNa). In the indomethacin pretreated subjects, ERPF decreased significantly from 530±109 to 446±55?mL/min versus 533±89 to 449±69?mL/min in the placebo group. UNa increased significantly from 395±142 to 768±254?umol/min (micromol/min) (UNa) in the indomethacin group versus 282±117 to 552±242?umol/min (micromol/min) (UNa) in placebo. Conclusion. The renal vasoconstrictive and natriuretic effects of synthetic URO are not modified by sustained inhibition of the angiotensin II receptor or the cyclooxygenase in man in a sodium replete state.     

The use of sustained low efficiency dialysis (SLED) in massive paracetamol overdose

Context: Massive paracetamol ingestion causing mitochondrial dysfunction is uncommon. Use of sustained low-efficiency dialysis (SLED) to improve acidaemia and enhance paracetamol elimination has not been previously described.

Case details: A 44-year-old male presented to the emergency department 2.5?hours post overdose of 200?g (2.5?g/kg) of paracetamol. Examination revealed a BP 85/60?mmHg, pulse 112 bpm, temperature 33.9?°C and blood glucose of 13.9?mmol/l. Venous blood gas 5.5-hours post-ingestion showed a pH 6.9, pCO₂ 58?mmHg, HCO₃ 13?mmol/l and lactate 14?mmol/l. Fifty-grams of nasogastric activated charcoal and double-strength intravenous acetylcysteine were administered. Paracetamol concentration peaked at 4207 µmol/l six hours post-ingestion. SLED was commenced nine-hours post ingestion and acetylcysteine dose was doubled again during dialysis. Paracetamol extraction ratio was 47–52%. Plasma paracetamol clearance was steady throughout SLED (53–58?ml/min). Hepatotoxicity did not develop and the patient recovered.

Discussions: Intermittent hemodialysis (IHD) is more efficient than SLED or continuous renal replacement therapy for enhancing paracetamol elimination and clearance. IHD plasma clearance is reported to range from 36 to 215?ml/min compared with endogenous clearance of 224?ml/70?kg/min.

Conclusions: SLED improved acidaemia with only moderate overall increase in paracetamol plasma clearance. Lack of development of hepatotoxicity was likely the result of early administration of acetylcysteine rather than any effect of SLED on paracetamol elimination.     

Aminoglycoside pharmacokinetics in African-Americans with normal renal function

Objective: To compare aminoglycoside pharmaco?kinetics in African-Americans with normal renal function with published adult population values. Design: An Institutional Review Board approved concurrent study. Setting: The study was conducted at Howard University Hospital, Washington DC. Subjects: All subjects had serum creatinine levels of 1·5 mg/dl or less and were receiving aminoglycoside for suspected or documented Gram-negative infection, had no obvious underlying disease condition that could influence aminoglycoside pharmaco?kinetics and were aged 18 years or older. Main outcome measures: Volume of distribution (V_d), half-life ( t_1/2), elimination rate constant (K_e) and total body clearance ( Cl) were calculated using a one-compartment, open, linear pharmacokinetic model. Using an unpaired Student's t-test, the pharmaco?kinetic values of our patients were compared with general population values. Interventions: Patients receiving aminoglysides were identified by the pharmacist through the hospital's standard antibiotic order sheet. Twenty-five patients were enrolled after they met the inclusion criteria. Pharmacists made recommendations for dose change as part of standard of care when inappropriate doses were ordered. In collaboration with medical and nursing staff, the amount and time of dose administration, and steady-state peak and trough serum drug levels were stringently measured, documented on a data collection form and used to calculate pharmacokinetic values for our patients. The form was also used to document demographic information. Results: The following values were obtained: V_d 0·27±0·15 litres/kg, t_1/2 1·93±1·38 h, K_e 0·31±0·134/h (gentamicin), K_e 0·22±0·10/h (tobramycin), Cl 103·95±62·98 ml/kg/h (gentamicin) and Cl 118·96±84·83 ml/kg/h (tobramycin). These values are not significantly different from general population values. Following a mean tobramycin or gentamicin dose of 1·32±0·32 mg/kg ideal body weight (IBW)/dose or 1·11±0·33 mg/kg actual body weight (ABW)/dose every 8 h, patients achieved a mean peak and trough serum drug levels of 6·6±3·86 mg/litre and 1·03±0·68 mg/litre, respectively. Wide interpatient pharmacokinetic variability was also observed. Conclusions: We conclude that aminoglycoside pharmacokinetics in African-Americans seem to be consistent with the published general population values. Thus, initiating aminoglycoside regimens using population dosing guidelines appears to be appropriate. However, due to the observed wide interpatient pharmacokinetic variability, in?dividualized dosing is required with very close monitoring, to avoid or minimize toxicity.     

The effects of intravenous lipid emulsion on prolongation of survival in a rat model of calcium channel blocker toxicity

Abstract

Context. Intravenous lipid emulsion (ILE) has been shown to ameliorate the toxicity of lipid-soluble agents in animal studies and clinical cases. Objectives. To investigate the therapeutic effects of ILE in a rat model of toxicity from calcium channel blockers (CCBs), including diltiazem and nicardipine. Methods. Two sets of experiments of CCB poisoning were conducted. In the first set, 14 male Sprague-Dawley rats were sedated and treated with ILE or normal saline (NS), followed by continuous intravenous infusion of diltiazem (20 mg/kg/h). In the second experiment, the study protocol was the same except the infusion of nicardipine (20 mg/kg/h). The total dose of infused drug and the duration of survival were measured. In addition, mean arterial pressure and heart rate were monitored. Results. Survival was prolonged in the ILE group (48.4 ± 11.3 vs. 25.0 ± 3.7 min; p = 0.002). Furthermore, the cumulative mean lethal dose of diltiazem was higher in the ILE group (16.1 ± 3.8 mg/kg) than in the NS group (8.3 ± 1.1 mg/kg) (p = 0.002). With nicardipine poisoning, survival was also prolonged in the ILE group (71.0 ± 8.3 min vs. 30.6 ± 6.1 min; p = 0.002). The cumulative mean lethal dose was higher in the ILE group than in the NS group (23.7 ± 2.8 mg/kg vs. 10.2 ± 2.0 mg/kg; p = 0.002). Conclusions. ILE pretreatment prolonged survival and increased the lethal dose in a rat model of CCB poisoning using diltiazem and nicardipine.     

C OMBINATION P HARMACOTHERAPY WITH D ELAYED C OUNTERSHOCK VS S TANDARD A DVANCED C ARDIAC L IFE S UPPORT A FTER P ROLONGED V ENTRICULAR F IBRILLATION

Objective. To test the hypothesis that combination pharmacotherapy with delayed countershock would produce higher rates of return of spontaneous circulation (ROSC) and one-hour survival when compared with standard Advanced Cardiac Life Support (ACLS) therapy. Methods. A prospective, block-randomized, blinded, laboratory experiment was conducted in an established swine model of prolonged ventricular fibrillation (VF). Fifty-six female domestic swine were anesthetized, instrumented, and shocked into VF with a bipolar pacing catheter. The VF was untreated for 8 minutes, then basic CPR was done mechanically for 1 minute. At 9 minutes of VF, the animals were randomized to treatment with one of seven therapies: group 1, combination pharmacotherapy with epinephrine (0.20?mg/kg), lidocaine (1.0?mg/kg), bretylium (5.0?mg/kg), propranolol (1.0?mg), and U-74389G (3.0?mg/ kg); group 2, epinephrine (0.20?mg/kg); group 3, lidocaine (1.0?mg/kg) and bretylium (5.0?mg/kg); group 4, propranolol (1.0?mg); group 5, U-74389G (3.0?mg/kg); group 6, normal saline solution (volume equal to that for group 1); and group 7, standard ACLS (first countershock at 9 minutes of VF). Initial countershocks for groups 1–6 were given after 11 minutes of VF. Data were analyzed with two-tailed Fisher's exact test, with alpha set at 0.05. Results. Return of spontaneous circulation occurred in group 1 = 8/8 (100%); group 2 = 7/8 (88%); group 3 = 3/8 (38%); group 4 = 3/8 (38%); group 5 = 5/8 (63%); group 6 = 4/8 (50%); and group 7 = 3/8 (38%). One-hour survival occurred in group 1 = 8/8 (100%); group 2 = 5/8 (63%); group 3 = 2/8 (25%); group 4 = 2/8 (25%); group 5 = 3/8 (38%); group 6 = 2/8 (25%); and group 7 = 1/8 (13%). Conclusions. Combination pharmacotherapy with delayed countershock (group 1) produced significantly higher rates of ROSC (p = 0.03) and one-hour survival (p = 0.001) when compared with standard ACLS in this porcine model of prolonged VF.     

Zero-order metoprolol pharmacokinetics after therapeutic doses: severe toxicity and cardiogenic shock

Objective: Acute beta-blocker overdose can cause severe cardiac dysfunction. Chronic toxicity is rare but potentially severe. We report therapeutic dosing of metoprolol resulting in unusual pharmacokinetics and toxicity, given high-dose insulin therapy for treatment.

Case details: A 90-year-old female presented with hypotension, tachycardia and severe cardiac dysfunction after commencing a rapidly increasing metoprolol dose of 250?mg split daily. She was admitted to intensive care and given high-dose insulin therapy (10?U/kg/h), noradrenaline, adrenaline and dobutamine for severe cardiac dysfunction (cardiac index, 0.76?L/min/m²). She developed acute renal failure, ischaemic hepatitis and disseminated intravascular coagulopathy. Inotropes and high-dose insulin were weaned over four days with complete recovery. Metoprolol was quantified with liquid chromatography-tandem mass spectrometry and concentration-time data were analysed using MONOLIX^® vs 4.3 (www.lixoft.com). Admission metoprolol concentration was 2.39?μg/mL (therapeutic reference range: 0.035–0.5?μg/mL). Data best fitted a one compartmental model with Michaelis–Menten kinetics and zero order elimination at high concentrations. Final parameter estimates were V, 63.4?L, maximum rate [V_m], 9.57?mg?h^?1, Michaelis constant [K_m], 1.97?mg L^?1. Predicted elimination half-life decreased from 20?h over time until there was first order elimination with a half-life 9?h.

Conclusion: The time course of cardiac dysfunction was longer than acute overdose but consistent with prolonged zero order elimination of metoprolol, suggesting the patient was a poor CYP2D6 metaboliser. High-dose insulin euglycaemia appeared to be effective in combination with vasoconstrictors/inotropes.