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Objective: High-anion gap metabolic acidosis (HAGMA) most commonly results from excess urea, lactate, ketones and exposure to toxins such as salicylate and toxic alcohols. Accumulation of pyroglutamic acid (PGA) is a rare cause of HAGMA. The exact incidence of HAGMA caused by PGA accumulation is unknown. A recent prospective study reported that high urine PGA concentrations were associated with 10% of patients with HAGMA. PGA is processed by the glutamate-glutathione cycle. The commonest cause of PGA accumulation is glutathione depletion. This causes the loss of negative feedback on gamma-glutamylcysteine (PGA precursor) production. Other causes include malnutrition, alcoholism, liver failure and sepsis. Though rare, deficiency of either glutathione synthetase causing gamma-glutamylcysteine (PGA precursor) accumulation or 5-oxoprolinase resulting in reduced PGA metabolism, also cause PGA accumulation. We describe a case of confirmed PGA accumulation after repeated supratherapeutic paracetamol use. Case report: A 32-year-old female presented with ongoing pain from shingles despite having taken 96 x 665 mg modified-release paracetamol caplets over the preceding two days. Two years prior, she suffered a gastric ulcer perforation following excessive ibuprofen use for dysmenorrhea. She subsequently ceased using NSAIDs and substituted these with regular use of four modifiedrelease paracetamol tablets every 3-4 hours. On presentation vital signs were normal except a respiratory rate of 24/min. Venous blood gas showed pH 7.04, bicarbonate 5.0mmol/L, pCO2 19 mmHg, lactate 1.4mmol/L, sodium 150mmol/L, chloride 117 mmol/L and anion gap 28, indicating a partially compensated HAGMA. Serum ketones were 2.8mmol/L, salicylate undetected and normal osmolar gap. Serum paracetamol was 312 mumol/L, 2.5 hours after the last dose. Liver function, INR and creatinine were normal. PGA accumulation from chronic paracetamol misuse and glutathione depletion was suspected. Acetylcysteine was in

Rationale: Oral appliance therapy is an increasingly prescribed non-PAP alternative for treating OSA, but its efficacy is challenging to predict in individual patients, limiting its application as a first-line therapy. In small physiological studies, we have shown that pathophysiological (endotype) traits causing OSA can predict patient response to oral appliance therapy. These traits include upper airway collapsibility, arousal threshold, and ventilatory control instability (loop gain, response to arousal). Estimating these traits require invasive measurement during sleep or complex model-fitting to full in-lab polysomnographic data. Here we apply a novel, simplified method for estimating the traits causing OSA in individual patients using the ventilation-profile of the average respiratory event. We aimed to determine if PSG-derived traits were associated with oral appliance efficacy (percent reduction in total AHI from baseline). Method(s): Forty-three subjects with total AHI >= 20 hr-1 were available for analysis. The ventilation-profile of the average respiratory event was determined using the following approach: First, all scored respiratory events (apneas, hypopneas) were identified. Second, the ventilation signal for each event was calculated (uncalibrated volume x respiratory rate, expressed as percentage of eupneic [mean] ventilation) and ensemble-averaged with event-termination set to time zero for all events (Figure 1a). Surrogate measures of the endotype traits were calculated from this average respiratory event ventilation-profile as follows: mean event depth was the reduction from eupnea of the mean ventilation during the events, and considered a surrogate of pharyngeal collapsibility; the ventilatory overshoot was the peak ventilation following events as a surrogate of the arousal threshold, and the disturbance was the area under the curve (below eupnea) during the events, which were both utilized used to calculate a surrogate of loop gain (overshoot

Rationale: Oral appliance therapy is an increasingly prescribed non-PAP alternative for treating OSA, but its efficacy is challenging to predict in individual patients, limiting its application as a first-line therapy. In small physiological studies, we have shown that pathophysiological (endotype) traits causing OSA can predict patient response to oral appliance therapy. These traits include upper airway collapsibility, arousal threshold, and ventilatory control instability (loop gain, response to arousal). Estimating these traits require invasive measurement during sleep or complex model-fitting to full in-lab polysomnographic data. Here we apply a novel, simplified method for estimating the traits causing OSA in individual patients using the ventilation-profile of the average respiratory event. We aimed to determine if PSG-derived traits were associated with oral appliance efficacy (percent reduction in total AHI from baseline). Method(s): Forty-three subjects with total AHI >= 20 hr-1 were available for analysis. The ventilation-profile of the average respiratory event was determined using the following approach: First, all scored respiratory events (apneas, hypopneas) were identified. Second, the ventilation signal for each event was calculated (uncalibrated volume x respiratory rate, expressed as percentage of eupneic [mean] ventilation) and ensemble-averaged with event-termination set to time zero for all events (Figure 1a). Surrogate measures of the endotype traits were calculated from this average respiratory event ventilation-profile as follows: mean event depth was the reduction from eupnea of the mean ventilation during the events, and considered a surrogate of pharyngeal collapsibility; the ventilatory overshoot was the peak ventilation following events as a surrogate of the arousal threshold, and the disturbance was the area under the curve (below eupnea) during the events, which were both utilized used to calculate a surrogate of loop gain (overshoot

Background: Massive acetaminophen ingestion causing mitochondrial dysfunction (hypothermia, coma, hyperglycemia, and lactic acidosis) is uncommon. The use of SLED to improve acidaemia and enhance paracetamol elimination has not been previously described in this scenario. Case summary: A 44-year-old male presented to the Emergency Department 2.5-h post-overdose of 200-g (2.5 g/kg) of immediaterelease acetaminophen. On arrival, examination revealed BP 85/60mmHg, pulse 112bpm, temperature 33.9 degreeC, and BSL 13.9mmol/L. He was unconscious (GCS =3), respiratory rate of 14/min, oxygen saturations 91% (room-air) and was intubated on arrival. Venous blood gas 5.5-h post-ingestion showed pH 6.9, pCO2 58mmHg, HCO3 13mmol/L, and lactate 14mmol/L. Fifty grams of activated-charcoal were administered via nasogastric tube. A loading-dose of acetylcysteine (200mg/kg over 4-h) was given. The second infusion dose was doubled initially (200mg/kg over 16-h). Acetaminophen concentration peaked at 637mg/L (4207 mmol/L), 6-h post-ingestion. In view of severe acidaemia and a high serum paracetamol concentration, SLED was commenced 9-h post-ingestion in ICU (18-h duration). During dialysis, acetylcysteine infusion dose was increased to 400mg/kg/16-h. Plasma pyroglutamic acid concentration was undetectable. Acidaemia improved and lactate fell to normal range during the course of SLED. Apparent paracetamol half-life during SLED and post-dialysis was 6 and 10-h, respectively. Extraction ratio was 47-52%. Plasma acetaminophen clearance was steady throughout SLED (53-58 mL/min). There was no evidence of significant hepatotoxicity with a peak ALT of 76 IU/L on day 3 and peak INR of 1.9 on day 2 post-ingestion. Acetylcysteine was ceased 3 d post-initial overdose. The patient was extubated on day 4 and made a full recovery. Discussion(s): SLED was performed primarily to improve acid-base status and clear lactate but also may have reduced apparent acetaminophen elimination half-life. Endogenous p

Objective: Varenicline is a partial agonist of alpha-4 beta-2 nicotinic receptors used to treat nicotine withdrawal. It is renally eliminated, with an elimination half-life of 24-hours (range 10-54). In overdose, vomiting, hypertension, tachycardia and tachypnoea are seen. Phentermine is a sympathomimetic amine anorectic agent. Phentermine overdose results in central and peripheral adrenergic stimulation with cardiovascular and central nervous system toxicity. To date, there are no published cases reporting serum drug concentrations in patients surviving varenicline overdose. We report a case of varenicline and phentermine overdose confirmed by high performance liquid chromatography-mass spectrometry (HPLC-MS) blood analysis. Case report: A 13-year-old female presented to the emergency department 13 hours after ingesting her mother's varenicline (15 x 1 mg) and phentermine (15 x 30 mg). She began vomiting within 30 minutes of ingestion and this continued every 15-30 minutes throughout the night. On arrival, she complained of light-headedness, palpitations, anxiety and bilateral leg weakness. Initial observations were: pulse 125 bpm, sinus tachycardia, BP 123/72 mmHg, respiratory rate 24/min, saturation 97% (room air), temperature 36.7degreeC. On examination, pupils were 4 mm, equal and reactive, and she had sweaty palms. There was no clonus or tremor. She was able to stand unaided but complained of subjective left-sided weakness. There was no focal weakness on objective neurological testing. Serum electrolytes, acid-base and renal function were normal. Symptoms resolved rapidly. She was observed for 22 hours and discharged well the next day. Serum concentrations of phentermine and varenicline were assayed by HPLC-MS at 13, 17 and 22 hours post-ingestion. Phentermine concentrations were 0.16 mg/L, 0.23 mg/L and 0.16 mg/L (therapeutic range 0.18-0.51). Varenicline concentrations were 4.2 ng/mL at 13-hours and 3.5 ng/mL 22-hours post-ingestion with calculated eliminati

BACKGROUND: Understanding of clinical deterioration of emergency department patients is rapidly evolving. The aim of this study was to investigate the frequency and nature of vital sign collection and clinical deterioration in emergency care. METHODS: A descriptive exploratory approach was used. Data were collected from the records of 200 randomly selected adults with presenting complaints of abdominal pain, shortness of breath, chest pain and febrile illness from 1 January to 31 December 2014 at a 22 bed emergency department in Melbourne, Australia. RESULTS: When controlled for length of stay, heart rate was the most frequently assessed vital sign per hour (median=0.9) whilst Glasgow Coma Score was the least frequently assessed vital sign per hour (median=0.5). Clinical deterioration (one or more vital signs fulfilling hospital medical emergency team activation criteria during emergency department care) occurred in 14.5% of patients. Of the 5466 vital sign measures, 19.6% were abnormal, 1.9% indicated clinical deterioration. CONCLUSIONS: Clinical deterioration occurred in one in seven patients, and one in five vital signs documented were outside of accepted normal ranges. Thus, emergency department physiological status has implications for patient safety and nursing practice, in particular clinical handover for patients requiring hospital admission.Copyright © 2016 College of Emergency Nursing Australasia. Published by Elsevier Ltd. All rights reserved.

Objective: We report a case of suspected metal fume fever after prolonged domestic exposure to lead vapors. Case report: A 26-year-old, unemployed, man presented to hospital complaining of headache, fever, retrosternal chest pain, generalized muscle aches, nausea, vomiting (x1) and diarrhoea (x6). Ten hours earlier, he melted and poured lead to make fishing sinkers, for 2 hours, in an unventilated shed without the use of personal protective equipment. He had performed the same task twice recently without any sequelae. On examination he had global headache, generalized myalgia, pulse 138 bpm, BP 138/80 mmHg, tachypnoea (respiratory rate 22/min), temperature 38.6degreeC and oxygen saturation 99% (room-air). Lungs were clear to auscultation and neurological examination was normal. Hemoglobin was 156 g/L, leucocytes 8.8 x 109/L (normal 4.0-11 x 109/L), electrolytes and liver function tests were unremarkable. A 12-lead electrocardiogram (ECG) showed sinus tachycardia. C-reactive protein was initially 33mg/L and 88 mg/L (normal <5) the following day. Metal fume fever was suspected, however, given the presence of headache, and concern for inhalational lead toxicity, succimer was commenced until a whole blood lead could be performed the next day. This was less than 0.10 mumol/L and succimer was ceased after 4 doses. Chest X-ray was normal. He remained febrile and tachycardic for 24 hours. Blood and urine cultures were all negative. Symptoms fully resolved after 24 hours. The patient remains well post-discharge. Conclusion(s): Metal fume fever presents as a transient, flu-like illness after prolonged exposure to metal oxide fumes. Zinc oxide fume inhalation during industrial welding is the most common cause [1]. The precise pathophysiology is unknown. Theories include delayed hypersensitivity from repeated exposure to fumes and direct pulmonary inflammatory mediator-release. Lead has been suggested as a potential cause [1,2], but currently there are no documented cases repor

BACKGROUND: Understanding of clinical deterioration of emergency department patients is rapidly evolving. The aim of this study was to investigate the frequency and nature of vital sign collection and clinical deterioration in emergency care. METHODS: A descriptive exploratory approach was used. Data were collected from the records of 200 randomly selected adults with presenting complaints of abdominal pain, shortness of breath, chest pain and febrile illness from 1 January to 31 December 2014 at a 22 bed emergency department in Melbourne, Australia. RESULTS: When controlled for length of stay, heart rate was the most frequently assessed vital sign per hour (median=0.9) whilst Glasgow Coma Score was the least frequently assessed vital sign per hour (median=0.5). Clinical deterioration (one or more vital signs fulfilling hospital medical emergency team activation criteria during emergency department care) occurred in 14.5% of patients. Of the 5466 vital sign measures, 19.6% were abnormal, 1.9% indicated clinical deterioration. CONCLUSIONS: Clinical deterioration occurred in one in seven patients, and one in five vital signs documented were outside of accepted normal ranges. Thus, emergency department physiological status has implications for patient safety and nursing practice, in particular clinical handover for patients requiring hospital admission.Copyright © 2016 College of Emergency Nursing Australasia. Published by Elsevier Ltd. All rights reserved.

Background: Massive acetaminophen ingestion causing mitochondrial dysfunction (hypothermia, coma, hyperglycemia, and lactic acidosis) is uncommon. The use of SLED to improve acidaemia and enhance paracetamol elimination has not been previously described in this scenario. Case summary: A 44-year-old male presented to the Emergency Department 2.5-h post-overdose of 200-g (2.5 g/kg) of immediaterelease acetaminophen. On arrival, examination revealed BP 85/60mmHg, pulse 112bpm, temperature 33.9 degreeC, and BSL 13.9mmol/L. He was unconscious (GCS =3), respiratory rate of 14/min, oxygen saturations 91% (room-air) and was intubated on arrival. Venous blood gas 5.5-h post-ingestion showed pH 6.9, pCO2 58mmHg, HCO3 13mmol/L, and lactate 14mmol/L. Fifty grams of activated-charcoal were administered via nasogastric tube. A loading-dose of acetylcysteine (200mg/kg over 4-h) was given. The second infusion dose was doubled initially (200mg/kg over 16-h). Acetaminophen concentration peaked at 637mg/L (4207 mmol/L), 6-h post-ingestion. In view of severe acidaemia and a high serum paracetamol concentration, SLED was commenced 9-h post-ingestion in ICU (18-h duration). During dialysis, acetylcysteine infusion dose was increased to 400mg/kg/16-h. Plasma pyroglutamic acid concentration was undetectable. Acidaemia improved and lactate fell to normal range during the course of SLED. Apparent paracetamol half-life during SLED and post-dialysis was 6 and 10-h, respectively. Extraction ratio was 47-52%. Plasma acetaminophen clearance was steady throughout SLED (53-58 mL/min). There was no evidence of significant hepatotoxicity with a peak ALT of 76 IU/L on day 3 and peak INR of 1.9 on day 2 post-ingestion. Acetylcysteine was ceased 3 d post-initial overdose. The patient was extubated on day 4 and made a full recovery. Discussion(s): SLED was performed primarily to improve acid-base status and clear lactate but also may have reduced apparent acetaminophen elimination half-life. Endogenous p

Objective: Varenicline is a partial agonist of alpha-4 beta-2 nicotinic receptors used to treat nicotine withdrawal. It is renally eliminated, with an elimination half-life of 24-hours (range 10-54). In overdose, vomiting, hypertension, tachycardia and tachypnoea are seen. Phentermine is a sympathomimetic amine anorectic agent. Phentermine overdose results in central and peripheral adrenergic stimulation with cardiovascular and central nervous system toxicity. To date, there are no published cases reporting serum drug concentrations in patients surviving varenicline overdose. We report a case of varenicline and phentermine overdose confirmed by high performance liquid chromatography-mass spectrometry (HPLC-MS) blood analysis. Case report: A 13-year-old female presented to the emergency department 13 hours after ingesting her mother's varenicline (15 x 1 mg) and phentermine (15 x 30 mg). She began vomiting within 30 minutes of ingestion and this continued every 15-30 minutes throughout the night. On arrival, she complained of light-headedness, palpitations, anxiety and bilateral leg weakness. Initial observations were: pulse 125 bpm, sinus tachycardia, BP 123/72 mmHg, respiratory rate 24/min, saturation 97% (room air), temperature 36.7degreeC. On examination, pupils were 4 mm, equal and reactive, and she had sweaty palms. There was no clonus or tremor. She was able to stand unaided but complained of subjective left-sided weakness. There was no focal weakness on objective neurological testing. Serum electrolytes, acid-base and renal function were normal. Symptoms resolved rapidly. She was observed for 22 hours and discharged well the next day. Serum concentrations of phentermine and varenicline were assayed by HPLC-MS at 13, 17 and 22 hours post-ingestion. Phentermine concentrations were 0.16 mg/L, 0.23 mg/L and 0.16 mg/L (therapeutic range 0.18-0.51). Varenicline concentrations were 4.2 ng/mL at 13-hours and 3.5 ng/mL 22-hours post-ingestion with calculated eliminati

Objective: We report a case of suspected metal fume fever after prolonged domestic exposure to lead vapors. Case report: A 26-year-old, unemployed, man presented to hospital complaining of headache, fever, retrosternal chest pain, generalized muscle aches, nausea, vomiting (x1) and diarrhoea (x6). Ten hours earlier, he melted and poured lead to make fishing sinkers, for 2 hours, in an unventilated shed without the use of personal protective equipment. He had performed the same task twice recently without any sequelae. On examination he had global headache, generalized myalgia, pulse 138 bpm, BP 138/80 mmHg, tachypnoea (respiratory rate 22/min), temperature 38.6degreeC and oxygen saturation 99% (room-air). Lungs were clear to auscultation and neurological examination was normal. Hemoglobin was 156 g/L, leucocytes 8.8 x 109/L (normal 4.0-11 x 109/L), electrolytes and liver function tests were unremarkable. A 12-lead electrocardiogram (ECG) showed sinus tachycardia. C-reactive protein was initially 33mg/L and 88 mg/L (normal <5) the following day. Metal fume fever was suspected, however, given the presence of headache, and concern for inhalational lead toxicity, succimer was commenced until a whole blood lead could be performed the next day. This was less than 0.10 mumol/L and succimer was ceased after 4 doses. Chest X-ray was normal. He remained febrile and tachycardic for 24 hours. Blood and urine cultures were all negative. Symptoms fully resolved after 24 hours. The patient remains well post-discharge. Conclusion(s): Metal fume fever presents as a transient, flu-like illness after prolonged exposure to metal oxide fumes. Zinc oxide fume inhalation during industrial welding is the most common cause [1]. The precise pathophysiology is unknown. Theories include delayed hypersensitivity from repeated exposure to fumes and direct pulmonary inflammatory mediator-release. Lead has been suggested as a potential cause [1,2], but currently there are no documented cases repor

Objective: In adults sleep-disordered breathing (SDB) has been associated with impaired baroreflex control of blood pressure (BP), which has been linked to increased cardiovascular morbidity. In children, the long-term effects of SDB on baroreflex sensitivity (BRS) and BP variability (BPV) are unknown. Method(s): Children previously diagnosed with SDB (n= 40) and 20 nonsnoring controls aged 11-16. y underwent overnight polysomnography with continuous BP measurement, four years after the original diagnosis. At follow-up, SDB was categorized as resolved (absence of snoring and obstructive apnea hypopnea index (OAHI) <= 1) or unresolved (continued to snore or had an OAHI > 1). BRS and BPV were calculated using cross-spectral analysis and power spectral analysis, respectively. Result(s): Only children with resolved obstructive sleep apnea (OSA) at follow-up demonstrated an increase in BRS from 9.7+/-3(msmmHg-1) at baseline to 11.8+/-4(msmmHg-1) at follow-up (P= 03). However, children with all severities of both resolved and unresolved SDB showed a significant decrease in BPV from baseline to follow-up (a decrease in total power BPV (P < .05) and a shift in BPV spectra away from respiratory-related frequencies (increased low-frequency/high-frequency [LF/HF] ratio, P < .01). The change in OAHI was the sole determinant of change in BRS, HF power, and LF/HF ratio. Conclusion(s): Improvement in SDB was associated with improved BP control, regardless if SDB was treated or spontaneously resolved four years after initial diagnosis. Our findings highlight the importance of monitoring children to ensure improvement of SDB and reduce the risk for cardiovascular morbidity in the future. © 2013.

Objective: In adults sleep-disordered breathing (SDB) has been associated with impaired baroreflex control of blood pressure (BP), which has been linked to increased cardiovascular morbidity. In children, the long-term effects of SDB on baroreflex sensitivity (BRS) and BP variability (BPV) are unknown. Method(s): Children previously diagnosed with SDB (n= 40) and 20 nonsnoring controls aged 11-16. y underwent overnight polysomnography with continuous BP measurement, four years after the original diagnosis. At follow-up, SDB was categorized as resolved (absence of snoring and obstructive apnea hypopnea index (OAHI) <= 1) or unresolved (continued to snore or had an OAHI > 1). BRS and BPV were calculated using cross-spectral analysis and power spectral analysis, respectively. Result(s): Only children with resolved obstructive sleep apnea (OSA) at follow-up demonstrated an increase in BRS from 9.7+/-3(msmmHg-1) at baseline to 11.8+/-4(msmmHg-1) at follow-up (P= 03). However, children with all severities of both resolved and unresolved SDB showed a significant decrease in BPV from baseline to follow-up (a decrease in total power BPV (P < .05) and a shift in BPV spectra away from respiratory-related frequencies (increased low-frequency/high-frequency [LF/HF] ratio, P < .01). The change in OAHI was the sole determinant of change in BRS, HF power, and LF/HF ratio. Conclusion(s): Improvement in SDB was associated with improved BP control, regardless if SDB was treated or spontaneously resolved four years after initial diagnosis. Our findings highlight the importance of monitoring children to ensure improvement of SDB and reduce the risk for cardiovascular morbidity in the future. © 2013.

During the first year of life there is significant maturation of the hypoxic ventilatory response (HVR) in human infants. Compared with adults, healthy term infants have an immature HVR until at least 6 months of age. There are few studies in infants on the effects of sleep state on the HVR but these suggest that at early postnatal ages there is initially no sleep-state related difference; this is followed by a developmental trend towards the adult situation in which the response is depressed in REM sleep compared with NREM. Maternal cigarette smoking is a major risk factor for SIDS and the mechanism for this may involve a depressed HVR in the exposed infant; however studies are limited and the wide variation in cigarette consumption makes interpretation of results difficult. Arousal responses to hypoxia are of vital importance and a failure to arouse has been implicated in SIDS. Sleeping infants frequently fail to arouse in response to hypoxia in QS, whereas in AS they invariably arouse; furthermore arousal latency is longer in QS compared with AS. The oxygen saturation at which infants arouse is not different between sleep states, suggesting that desaturation is more rapid in AS. In QS younger infants arouse more readily than at older ages and arousal is depressed by maternal smoking. These findings suggest that depression of the arousal response to hypoxia in AS may have life-threatening consequences. Infants at increased risk for SIDS have been shown to have both depressed ventilatory and arousal responses to hypoxia, thus they may be at even greater risk. © 2005 Elsevier B.V. All rights reserved.

During the first year of life there is significant maturation of the hypoxic ventilatory response (HVR) in human infants. Compared with adults, healthy term infants have an immature HVR until at least 6 months of age. There are few studies in infants on the effects of sleep state on the HVR but these suggest that at early postnatal ages there is initially no sleep-state related difference; this is followed by a developmental trend towards the adult situation in which the response is depressed in REM sleep compared with NREM. Maternal cigarette smoking is a major risk factor for SIDS and the mechanism for this may involve a depressed HVR in the exposed infant; however studies are limited and the wide variation in cigarette consumption makes interpretation of results difficult. Arousal responses to hypoxia are of vital importance and a failure to arouse has been implicated in SIDS. Sleeping infants frequently fail to arouse in response to hypoxia in QS, whereas in AS they invariably arouse; furthermore arousal latency is longer in QS compared with AS. The oxygen saturation at which infants arouse is not different between sleep states, suggesting that desaturation is more rapid in AS. In QS younger infants arouse more readily than at older ages and arousal is depressed by maternal smoking. These findings suggest that depression of the arousal response to hypoxia in AS may have life-threatening consequences. Infants at increased risk for SIDS have been shown to have both depressed ventilatory and arousal responses to hypoxia, thus they may be at even greater risk. © 2005 Elsevier B.V. All rights reserved.