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Objectives: Neonatal resuscitation guidelines recommend 0.5-1 mL saline flush following 0.01-0.03 mg/kg of epinephrine via low umbilical venous catheter for persistent bradycardia despite effective positive pressure ventilation (PPV) and chest compressions (CC). We evaluated the effects of 1 mL vs 3 mL/kg flush volumes and 0.01 vs 0.03 mg/kg doses on return of spontaneous circulation (ROSC) and epinephrine pharmacokinetics in lambs with cardiac arrest., Design: Forty term lambs in cardiac arrest were randomised to receive 0.01 or 0.03 mg/kg epinephrine followed by 1 mL or 3 mL/kg flush after effective PPV and CC. Epinephrine (with 1 mL flush) was repeated every 3 min until ROSC or until 20 min. Haemodynamics, blood gases and plasma epinephrine concentrations were monitored., Results: Ten lambs had ROSC before epinephrine administration and 2 died during instrumentation. Among 28 lambs that received epinephrine, 2/6 in 0.01 mg/kg-1 mL flush, 3/6 in 0.01 mg/kg-3 mL/kg flush, 5/7 in 0.03 mg/kg-1 mL flush and 9/9 in 0.03 mg/kg-3 mL/kg flush achieved ROSC (p=0.02). ROSC was five times faster with 0.03 mg/kg epinephrine compared with 0.01 mg/kg (adjusted HR (95% CI) 5.08 (1.7 to 15.25)) and three times faster with 3 mL/kg flush compared with 1 mL flush (3.5 (1.27 to 9.71)). Plasma epinephrine concentrations were higher with 0.01 mg/kg-3 mL/kg flush (adjusted geometric mean ratio 6.0 (1.4 to 25.7)), 0.03 mg/kg-1 mL flush (11.3 (2.1 to 60.3)) and 0.03 mg/kg-3 mL/kg flush (11.0 (2.2 to 55.3)) compared with 0.01 mg/kg-1 mL flush., Conclusions: 0.03 mg/kg epinephrine dose with 3 mL/kg flush volume is associated with the highest ROSC rate, increases peak plasma epinephrine concentrations and hastens time to ROSC. Clinical trials evaluating optimal epinephrine dose and flush volume are warranted., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Here, we report the participation of N-methyl-D-aspartate (NMDA) glutamate receptor in the mediation of cardiovascular and circulating vasopressin responses evoked by a hemorrhagic stimulus. In addition, once NMDA receptor activation is a prominent mechanism involved in nitric oxide (NO) synthesis in the brain, we investigated whether control of hemorrhagic shock by NMDA glutamate receptor was followed by changes in NO synthesis in brain supramedullary structures involved in cardiovascular and neuroendocrine control. Thus, we observed that intraperitoneal administration of the selective NMDA glutamate receptor antagonist dizocilpine maleate (MK801, 0.3 mg/kg) delayed and reduced the magnitude of hemorrhage-induced hypotension. Besides, hemorrhage induced a tachycardia response in the posthemorrhage period (i.e., recovery period) in control animals, and systemic treatment with MK801 caused a bradycardia response during hemorrhagic shock. Hemorrhagic stimulus increased plasma vasopressin levels during the recovery period and NMDA receptor antagonism increased concentration of this hormone during both the hemorrhage and postbleeding periods in relation to control animals. Moreover, hemorrhagic shock caused a decrease in NOx levels in the paraventricular nucleus of the hypothalamus (PVN), amygdala, bed nucleus of the stria terminalis (BNST), and ventral periaqueductal gray matter (vPAG). Nevertheless, treatment with MK801 did not affect these effects. Taken together, these results indicate that the NMDA glutamate receptor is involved in the hemorrhagic shock by inhibiting circulating vasopressin release. Our data also suggest a role of the NMDA receptor in tachycardia, but not in the decreased NO synthesis in the brain evoked by hemorrhage., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this article., (Copyright © 2021 Cristiane Busnardo et al.)

Clinical doctors rarely associate hyperparathyroidism with significant bradyarrhythmia. We report a rare case of a patient initially misdiagnosed with primary sick sinus syndrome, which was eventually shown to be secondary to primary hyperparathyroidism.

Fentanyl is an extremely potent synthetic opioid that has been increasingly used to adulterate heroin, cocaine, and counterfeit prescription pills, leading to an increase in opioid-induced fatal overdoses in the United States, Canada, and Europe. A vaccine targeting fentanyl could offer protection against the toxic effects of fentanyl in both recreational drug users and others in professions at risk of accidental exposure. This study focuses on the development of a vaccine consisting of a fentanyl-based hapten (F) conjugated to keyhole limpet hemocyanin (KLH) carrier protein or to GMP-grade subunit KLH (sKLH). Immunization with F-KLH in mice and rats reduced fentanyl-induced hotplate antinociception, and in rats reduced fentanyl distribution to the brain compared with controls. F-KLH did not reduce the antinociceptive effects of equianalgesic doses of heroin or oxycodone in rats. To assess the vaccine effect on fentanyl toxicity, rats immunized with F-sKLH or unconjugated sKLH were exposed to increasing subcutaneous doses of fentanyl. Vaccination with F-sKLH shifted the dose-response curves to the right for both fentanyl-induced antinociception and respiratory depression. Naloxone reversed fentanyl effects in both groups, showing that its ability to reverse respiratory depression was preserved. These data demonstrate preclinical selectivity and efficacy of a fentanyl vaccine and suggest that vaccines may offer a therapeutic option in reducing fentanyl-induced side effects., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)

In cetaceans, diving behavior immediately induces a change in blood circulation to favor flow to the brain and heart; this is achieved by intense vasoconstriction of the blood vessels that serve other organs. This blood circulation response is allied to a decrease in heart rate in order to optimize oxygen usage during diving. Vasoconstrictors are present in all mammals and stimulate the contraction of the smooth muscle in the walls of blood vessels. The most important of these vasoconstrictors are the hormones adrenaline (A), noradrenaline (NA), and angiotensin II (ANG II). At present, the contribution of these hormones to vasoconstriction during diving in cetaceans is unclear. To elucidate their possible roles, changes in serum levels of A, NA and ANG II were monitored together with heart rate in the Indo-Pacific bottlenose dolphin Tursiops aduncus during 90 and 180s dives. Both brief diving periods induced an increase in serum NA concentration and a decrease in heart rate; however, no changes were detected in serum levels of A or ANG II. These data indicate that NA may play a role in diving-induced vasoconstriction., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Metformin is a first-line oral antidiabetic therapy for patients with type 2 diabetes mellitus. Metformin-associated lactate acidosis (MALA) is a well-known, life-threatening, but rare side effect of metformin therapy. Chronic kidney disease (CKD) patients have a much greater risk of MALA. We report the case of a severe refractory MALA despite hemodialysis (HD) treatment, associated with hypoglycemia, hypothermia, and bradycardia in a neglected and thus untimely-recognized CKD patient with type 2 diabetes mellitus. Despite the recent rehabilitation of metformin as a treatment of choice for type 2 diabetes mellitus, the drug should be prescribed with caution as it can be associated with life-threatening refractory acidosis, particularly in CKD patients. Moreover, HD treatment could occasionally be ineffective, resulting in a fatal outcome.
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Objective: Several trace elements are essential for immunity and wound healing, particularly after major burns. Continuous renal replacement therapy (CRRT), which is used to treat renal failure, causes significant trace elements losses. The aim of the present review is to update the current literature and draw attention to this type of complication, as copper deficiency is rarely suspected and diagnosed in clinical conditions and may occur in chronic critically ill patients., Methods: This is an emblematic case report and review of literature., Results: Major copper and selenium deficiencies were documented in a patient with major burns complicated by renal failure. The main cause was effluent loss during prolonged CRRT. The copper deficit resulted in life-threatening bradycardia and the alteration of lipid metabolism with severe hypertriglyceridemia. The published data are scarce, but trace element losses with effluent have been previously documented, as has the affect of copper deficiency on cardiac rhythm., Conclusion: The literature regarding the specific requirements for chronically critically ill patients is limited. During prolonged CRRT, copper and selenium levels decrease and probably should be monitored during prolonged therapy. Research in this area is required., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Context: We hypothesized that in chronic digoxin toxicity, anti-digoxin antibodies (Fab) would be efficacious in binding digoxin, but this may not translate into improved clinical outcomes., Objective: This study aims to investigate changes in free digoxin concentrations and clinical effects on heart rate and potassium concentrations in chronic digoxin poisoning when anti-digoxin Fab are given., Materials and Methods: This is a prospective observational study. Patients were recruited if they have been treated with anti-digoxin Fab for chronic digoxin poisoning. Data was entered into a standardised prospective form, supplemented with medical records. Their serum or plasma was collected, analysed for free and bound digoxin and free anti-digoxin Fab concentrations., Results: From September 2013 to February 2015, 36 patients (median age, 78 years; 22 females) were recruited from 18 hospitals. Median heart rate (HR) was 49 beats/min. Initial median digoxin and potassium concentrations were 4.7 nmol/L (3.6 μg/L) (range: 2.3-11.2 nmol/L) and 5.3 mmol/L (range: 2.9-9.2 mmol/L) respectively. Beta-blockers (n = 18), calcium antagonists (n = 6), spironolactone and/or angiotensin blocking agents (n = 24) were also used concomitantly. Renal impairment and gastrointestinal symptoms were present in 31 (86%) and 22 (63%) patients respectively. Five patients died from conditions unrelated to digoxin toxicity. Median change in HR was 8 beats/min post-Fab with no effect on blood pressure; they were 4, 10 and 17 beats/min for the 1, 2 and ≥3 vials of anti-digoxin Fab groups respectively. Concomitant treatments with potassium lowering agents (12/36) and inotropic drugs (7/36) were used. Gastrointestinal effects resolved in all 22 patients. The median decrease for potassium was 0.3 mmol/L. Digoxin concentration reduced from 3.8 to 0 nmol/L post-Fab. There was a rebound observed in the free digoxin concentration in 25 patients but none had associated clinical deterioration., Conclusions: One to two vials of anti-digoxin Fab initially bound all free digoxin confirming Fab efficacy. However, this was associated with only a moderate improvement in HR and potassium, suggesting bradyarrhythmia and hyperkalaemia may be from other co-morbidities.

Hyperoxia exposure in mice leads to cardiac hypertrophy and voltage-gated potassium (Kv) channel remodeling. Because redox balance of pyridine nucleotides affects Kv function and hyperoxia alters cellular redox potential, we hypothesized that hyperoxia exposure leads to cardiac ion channel disturbances and redox changes resulting in arrhythmias. In the present study, we investigated the electrical changes and redox abnormalities caused by 72h hyperoxia treatment in mice. Cardiac repolarization changes were assessed by acquiring electrocardiogram (ECG) and cardiac action potentials (AP). Biochemical assays were employed to identify the pyridine nucleotide changes, Kv1.5 expression and myocardial injury. Hyperoxia treatment caused marked bradycardia, arrhythmia and significantly prolonged (ms) the, RR (186.2 ± 10.7 vs. 146.4 ± 6.2), PR (46.8 ± 3.1 vs. 39.3 ± 1.6), QRS (10.8 ± 0.6 vs. 8.5 ± 0.2), QTc (57.1 ± 3.5 vs. 40 ± 1.4) and JT (13.4 ± 2.1 vs. 7.0 ± 0.5) intervals, when compared with normoxia group. Hyperoxia treatment also induced significant increase in cardiac action potential duration (APD) (ex-APD90; 73.8 ± 9.5 vs. 50.9 ± 3.1 ms) and elevated levels of serum markers of myocardial injury; cardiac troponin I (TnI) and lactate dehydrogenase (LDH). Hyperoxia exposure altered cardiac levels of mRNA/protein expression of; Kv1.5, Kvβ subunits and SiRT1, and increased ratios of reduced pyridine nucleotides (NADH/NAD & NADPH/NADP). Inhibition of SiRT1 in H9C2 cells using Splitomicin resulted in decreased SiRT1 and Kv1.5 expression, suggesting that SiRT1 may mediate Kv1.5 downregulation. In conclusion, the cardiotoxic effects of hyperoxia exposure involve ion channel disturbances and redox changes resulting in arrhythmias., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Ivabradine is a drug used for the treatment of angina and chronic heart failure in cases of intolerance or insufficiency of response to beta-blocker treatment. A 47-year-old man was admitted to the emergency department of the hospital for a voluntary intoxication with 280 mg of ivabradine: he presented drowsiness and a mild sinusal bradycardia (50 bpm) associated with a well-tolerated low blood pressure at 100/50 mmHg. No complication was noted and he was discharged from the hospital on Day 3. A method for ivabradine assay in serum was obtained using liquid chromatography coupled with a mass spectrometry detection method. After a deproteinization step using QuECHERS salts and acetonitrile, a chromatographic separation was performed using a 5-µm 50 × 2.1 mm Xterra® column (Waters, France). Detection was performed using an LTQ linear ion-trap mass spectrometer equipped with an electrospray ionization source used in a positive ionization mode (ThermoFisher Scientific, San Jose CA, USA) and a detection in full MS(2) scan. The limit of quantification of ivabradine was 10 µg/L, and the method was linear up to 1000 µg/L. The ivabradine concentration in the patient's serum was 375 µg/L. This concentration value was >30 times those measured after therapeutic doses intakes. Nevertheless, the bradycardia was no more severe than the one observed with therapeutic dosage. In conclusion, this case tends to show an absence of correlation between blood concentration and severity of the troubles in cases of overdosage.

The cardiac diving response, 12-lead electrocardiogram (ECG) and the prevalence, time of onset, and possible associations of cardiac arrhythmias were examined during deep breath-hold (BH) dives. Nine elite BH divers (33.2 +/- 3.6 years; mean +/- SD) performed one constant-weight dive of at least 75% of their best personal performance (70 +/- 7 meters for 141 +/- 22 seconds) wearing a 12-lead ECG Holter monitor. Diving parameters (depth and time), oxygen saturation (SaO2), blood lactate concentration and ventilatory parameters were also recorded. Bradycardia during these dives was pronounced (52.2 +/- 12.2%), with heart rates dropping to 46 +/- 10 beats/minute. The diving reflex was strong, overriding the stimulus of muscular exercise during the ascent phase of the dive for all divers. Classical arrhythmias occurred, mainly after surfacing, and some conduction alterations were detected at the bottom of the dives. The BH divers did not show any right shift of the QRS electrical axis during their dives.

Background: Several anti-malarial drugs are associated with adverse cardiovascular effects. These effects may be exacerbated when different anti-malarials are used in combination. There has been no report yet on the potential cardiac effects of the combination artesunate-amodiaquine., Methods: Electrocardiographic (ECG) intervals in Ghanaian children with uncomplicated malaria treated with artesunate-amodiaquine (n=47), were compared with that of children treated with artemether-lumefantrine (n=30). The ECG measurements were repeated one, two, three, seven and 28 days after treatment. The ECG intervals of artesunate-amodiaquine treated subjects were correlated with plasma concentrations of desethylamodiaquine (DEAQ), the main metabolite of amodiaquine., Results: The mean ECG intervals were similar in both groups before treatment. After treatment (day 3), ECG intervals changed significantly from baseline in all subjects, but there were no differences between the two treatment groups. A significantly higher proportion of children treated with artesunate-amodiaquine developed sinus bradycardia compared with artemether-lumefantrine treated subjects (7/47 vs 0/30; χ² p=0.03). Subjects who developed bradycardia were significantly older, and had higher DEAQ concentrations than those who did not develop bradycardia. The proportion of subjects with QTc interval prolongations did not differ significantly between the groups, and no relationship between prolonged QTc intervals and DEAQ levels were observed. No clinically significant rhythm disturbances were observed in any of the subjects., Conclusion: Artesunate-amodiaquine treatment resulted in a higher incidence of sinus bradycardia than artemether-lumefantrine treatment in children with uncomplicated malaria, but no clinically significant rhythm disturbances were induced by combining artesunate with amodiaquine. These findings, although reassuring, may imply that non-amodiaquine based artemisinin combination therapy may be preferable for malaria treatment in patients who are otherwise at risk of cardiac effects.

Differences in the pools of 10 cytokine were found in blood samples from the caudal vein of mice with normal and abnormal heart rhythm. Both groups were albino mice bred by us and differing from mdx albino mice by the absence of mutation in muscular dystrophin gene. Mice with normal heart rhythm had low IL-17 content and elevated concentrations of proinflammatory cytokines IL-6 and IL-1α in comparison with the normal (according to published data). In mice with bradyarrhythmias, increased blood levels of IL-10, IL-6, IL-5, IL-2, IL-1α, IL-17, IL-4, TNF-α, and granulocyte-macrophage colony-stimulating factor were detected. The relative content of IL-4 and IL-17 in the total cytokine pool increased. The lifespan of mice with bradyarrhythmias and cytokine hyperexpression was shorter by 2-3 months in comparison with mice without heart rhythm disturbances and moderate changes in the cytokine pool.

Aim: Carotid artery stenting (CAS) may cause bradycardia and hypotension due to barostimulation. The impact of periprocedural hypotension on CAS outcome remains controversial. The role of carotid plaque volume and catecholamine hormone release during CAS on hemodynamic changes has not been investigated so far. The aim of this prospective study was to evaluate if carotid artery plaque characteristics are predictive for stress hormone release or for postprocedural hemodynamic instability., Methods: In 26 patients undergoing CAS, carotid plaque volume and morphology were assessed by two- and three-dimensional (3D)-Duplex sonography prior to the procedure. Arterial plasma adrenaline, noradrenaline and renin concentrations were measured at the time of sheath insertion and 5 minutes after stent placement. ECG, heart rate, and invasive blood pressure were monitored throughout the procedure., Results: CAS caused no significant changes in hormone release, but increasing plaque volume was related to the degree of bradycardia following stent deployment (r=0.57; P=0.01). Plaque size was not associated with postprocedural hypotension. Plaque echogenicity (echolucent, heterogeneous or echogenic) did not correlate with changes in systolic blood pressure, heart rate or catecholamine hormone release., Conclusion: CAS caused bradycardia in relation to plaque size, but did not cause catecholamine release which may indicate that the endovascular procedure is not associated with a relevant stress reaction.

The pronounced activation of sympathetic nervous system is a necessary prerequisite for the development of neurogenic pulmonary edema (NPE) in rats with balloon compression of spinal cord. In this study we examined whether this is a consequence of rapid activation of spinal pathways leading to sympathetic venoconstriction, blood pressure rise, and reflex bradycardia. We found that NPE development can be prevented by epidural upper thoracic anesthesia or by transection of the upper spinal cord. This indicates an important role of spinal pathways activation. NPE development can also be prevented by moderate blood loss, supporting the role of blood redistribution to pulmonary circulation. In rats developing NPE the catecholamine surge following spinal cord compression involved not only a dramatic increase of circulating norepinephrine but also of epinephrine levels. The pretreatment of rats with α-1 adrenoceptor blocker prazosin, α-2 adrenoceptor blocker yohimbine, or calcium channel blocker nifedipine prevented NPE development, whereas the effect of β-adrenoceptor blockade with propranolol was less convincing. In conclusion, considerable activation of thoracic spinal pathways, followed by marked catecholamine secretion, play a major role in the development of NPE in spinal cord-injured rats. Enhanced α-adrenergic nifedipine-sensitive vasoconstriction is responsible for observed blood pressure changes, subsequent baroreflex bradycardia, and blood volume redistribution, which represent major pathogenetic mechanisms of NPE development.

Introduction: Transvenous insertion of endocardial leads for permanent pacing is often accompanied by minor myocardial damage, detected thanks to the high sensitivity of cardiac troponins. It is unknown whether higher troponin levels, commensurate with more severe myocardial damage, can be encountered after implantation procedures., Methods: Over a 3-year period, 283 patients underwent an implantation of a full antibradycardia pacemaker system (pulse generator plus leads). Patients were required to have normal levels of cardiac troponin I (CTNI) on a venous blood sample taken immediately prior to elective pacemaker insertion. Post implantation CTNI levels were measured in all patients 6 hours after the procedure. Repeated samples were taken if high CTNI levels were found at 6 hours., Results: Elevated CTN-I levels were found in 167 patients (59%, 95% CI: 0.53-0.64), but only 5 of them (1.8%, 95% CI=0.8 to 4.1%) had peak CTN-I levels far exceeding the range of minimal myocardial damage (i.e. CTN-I >1.5 ng/ml). Implantation of the devices was successful in all patients and we did not observe any complications. None had clinical evidence of an acute coronary event before or during the pacemaker implantation procedure and coronary angiography revealed no significant lesions in the coronary arteries., Conclusions: CTN-I elevations after pacemaker implantation may far exceed levels corresponding to minimal myocardial damage. This should be a matter of concern, especially if an early discharge is planned after pacemaker implantation.

Objectives: To quantify cardiac troponin-I (cTnI) concentration in dogs with symptomatic bradyarrhythmias before and after artificial pacing and to correlate cTnI concentration with diagnosis, echocardiographic parameters, serology, and outcome., Animals, Materials and Methods: Medical records from the University of Pennsylvania from 2006 to 2009 were reviewed, and 14 dogs with cTnI assay results before and after pacemaker were identified. The ECG diagnosis included complete atrioventricular block (AVB), sick sinus syndrome, 2nd degree AVB, and atrial standstill. Serology, presence of premature beats, echocardiographic measurements, and pacing modality were recorded., Results: Mean cTnI concentration was elevated both pre- and post-pacing, and was significantly higher pre-pacing vs. post-pacing. Post-pacing cTnI concentration in 9 of 14 dogs (64%) remained above the reference range. Four dogs yielded high serum titers for Bartonella spp. Four dogs with markedly increased cTnI concentration had progressive left ventricular enlargement and myocardial failure as compared to pre-pacing examination., Conclusions: Elevated cTnI concentration suggests that cardiac injury persists after artificial pacing in dogs with bradyarrhythmias. Myocarditis secondary to Bartonella spp. or other causes may be an important cause of AVB in dogs. Prospective studies investigating the correlation of cTnI to potential etiology and development of post-pacing LV dysfunction and outcome are needed., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Objectives: English springer spaniels (ESS) are one of the most frequently presented breeds for pacemaker implantation in the UK and may do so at an early age. In comparison to dogs of other breeds (non-ESS) presenting for pacemaker implantation, cardiac troponin I (cTnI), the outcome and survival of ESS were investigated., Methods: Case records of dogs receiving pacemaker implantation were retrospectively reviewed., Results: Between September 2004 and October 2008, 58 dogs were presented to the Small Animal Teaching Hospital, University of Liverpool for pacemaker implantation. ESS (n=10) was the second most commonly presented breed. ESS were significantly younger than non-ESS (P=0.022). cTnI values were elevated on presentation and a significant reduction was present after pacemaker implantation (P=0.008) in all dogs. No significant difference in initial cTnI was identified comparing ESS and non-ESS (P=0.45) and median survival times were similar (P=0.37)., Clinical Significance: ESS may be predisposed to bradyarrhythmias requiring pacemaker implantation. They present at a significantly younger age than non-ESS. Survival times between ESS and non-ESS were similar, despite ESS being paced at a younger age. However, pacemaker implantation is recommended in ESS, as median survival times of 30 months with a good quality of life were achieved.

Prematurity apnea remains a major clinical problem that requires treatment choices which are sometimes difficult. Prematurity apnea occurs in most infants of gestational age at birth less than 33 weeks. It is a developmental disorder which usually reflects a "physiological" immaturity of respiratory control. However, neonatal diseases may be associated and play an additive role, resulting in an increased incidence of apnea. Careful screening should therefore be performed in order to make sure that no other factor than immaturity is involved in the occurrence of apnea. Short apnea (less than 10s, without hypoxemia and bradycardia), due to immaturity, are not clinically relevant. More prolonged apnea, that last for more than 15 or 20s, and / or apnea associated with bradycardia or oxygen desaturation, results in short-term disturbances of cerebral haemodynamics and oxygenation, which may negatively impact on neurodevelopmental outcome. Evaluating the immediate severity of apnea and the risks that apnea may affect long-term outcome remains a challenge. The choice of treatments is based on a few evidences. Caffeine citrate, which reduces the incidence of apnea, has been used for decades. However, a thorough evaluation of risks and benefits of this medication has been performed only recently. Caffeine citrate was found to be safe and resulted in unexpected benefits. In treated infants, compared with controls, indeed, a decreased incidence of the following complications was recorded: bronchopulmonary dysplasia at 36 weeks of conceptional age, patent ductus arteriosus, cerebral palsy at 18 months of age. Nasal CPAP can be used in association with caffeine citrate, when the latter is not effective enough., (Copyright 2009. Published by Elsevier SAS.)

We report a double lethal coconut crab Birgus latro L. poisoning in New Caledonia. Both patients died after showing gastro-intestinal symptoms, major bradycardia with marked low blood pressure, and finally asystolia. Both had significative hyperkaliemia, suggesting a digitaline-like substance intoxication. Traditional knowledge in the Loyalty Islands relates coconut crab toxicity to the consumption of the Cerbera manghas fruit by the crustacean. Elsewhere previous descriptions of human poisoning with the kernel of fruits of trees belonging to the genus Cerbera, known to contain cardiotoxic cardenolides, appear to be very similar to our cases. Cardenolides assays were performed on patient's serum samples, fruit kernel and on the crustacean guts, which lead us to suppose these two fatal cases were the result of a neriifolin intoxication, this toxin having been transmitted through the coconut crab.

A bedridden 85-year-old woman had hyperpotassemia (7.7 mEq/L) and bradycardia (30/min). Endocrinologic findings revealed a decrease in the renin-aldosterone system and normal adrenoglucocorticoid function. The results were consistent with the abnormalities seen in selective hypoaldosteronism with low renin activity. In addition, 9 of 11 patients, selected randomly from 72 bedridden elderly patients with normal serum sodium and potassium levels in our hospital, had diminished plasma renin activity (PRA) and plasma aldosterone concentration (PAC). The present patient was prescribed nonsteroidal anti-inflammatory drug (NSAID). NSAID reduces renal potassium excretion through the inhibition of renal prostaglandin synthesis. Therefore, the use of NSAID in bedridden elderly patients might intensify the underlying asymptomatic hypoaldosteronism and cause life-threatening hyperpotassemia.

Objective: To estimate whether fetal bradycardia-to-delivery interval or decision-to-delivery interval was related to cord arterial pH according to different causes of fetal distress., Methods: Women who delivered singleton neonates by urgent cesarean delivery because of intrapartum fetal bradycardia were retrospectively categorized into three groups according to the cause of fetal bradycardia: 1) Irreversible; 2) Potentially Reversible; and 3) Unknown (no identifiable cause). Comparisons were made between groups in regard to pH, bradycardia-to-delivery interval, and decision-to-delivery interval. Correlation analyses between pH and both intervals were then performed for different groups., Results: Of 235 cases, 39, 22, and 174 were respectively categorized into the Irreversible group, Potentially Reversible group, and Unknown group. The median pH was lower in the Irreversible group (7.094; interquartile range [IQR] 6.991-7.216) than in Potentially Reversible group (7.162; IQR 7.064-7.251) or Unknown group (7.210; IQR 7.161-7.255) (P<.001). The Irreversible group's median bradycardia-to-delivery interval was 5 minutes shorter than those of the other two groups (11 compared with 16.5 and 16 minutes, respectively; P<.001), whereas its median decision-to-delivery interval was 1 minute shorter (10 compared with 11.5 and 11 minutes, respectively; P=.001). In the Irreversible group, pH decreased with the bradycardia-to-delivery interval (Spearman's rho=-0.354; P=.027) at a rate of 0.011 per minute. Cord arterial pH did not correlate with the bradycardia-to-delivery interval in the Potentially Reversible and Unknown groups. In neither group did pH correlate with decision-to-delivery interval., Conclusion: Cord arterial pH deteriorates with bradycardia-to-delivery interval when the underlying cause of fetal distress is irreversible, but not so otherwise., Level of Evidence: II.

Objective: Debates about adverse effects of ventricular- vs. atrial-based pacing have never ended, especially regarding cardiovascular outcomes in common pacemaker populations., Methods: To investigate the contribution of right ventricular apical pacing to the left ventricular negative remodeling, we measured the inter- and intraventricular mechanical dyssynchrony by echocardiography as well as plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) level in 116 consecutive patients of symptomatic bradyarrhythmias including sinus node dysfunction (SND) in 80 and atrioventricular block in 36. Dual-chamber rate-modulated pacing (DDDR) pacemakers were implanted in 76 patients (SND, 40), and single-chamber ventricular rate-modulated pacing (AAIR) pacemakers in 40 (all SND). Clinical manifestations were retrospectively correlated., Results: After 3.5 years of pacing, DDDR pacemaker patients demonstrated higher plasma NT-proBNP concentration (503 +/- 111 pg/ml) than AAIR patients (194 +/- 42 pg/ml, p = 0.002) despite similar cardiovascular function at baseline. Multivariate regression analysis revealed that the only predictor of the highest quartile of plasma NT-proBNP, i.e. >or=386 pg/ml, was the interventricular contraction time difference (p = 0.01). Reprogramming to minimize ventricular pacing percentage in 8 patients of SND caused parallel reduction of plasma NT-proBNP., Conclusion: Interventricular mechanical dyssynchrony, imposed mostly by right ventricular apical pacing, could lead to abnormal heightening of plasma NT-proBNP concentration after chronic DDDR pacing in common pacemaker patients with normal baseline left ventricular function., ((c) 2007 S. Karger AG, Basel.)

The aim of this study was to investigate the effects of short repeated apneas on breathing pattern and circulatory response in trained (underwater hockey players: UHP) and untrained (controls: CTL) subjects. The subjects performed five apneas (A1-A5) while cycling with the face immersed in thermoneutral water. Respiratory parameters were recorded 1 minute before and after each apnea and venous blood samples were collected before each apnea and at 0, 2, 5 and 10 minutes after the last apnea. Arterial saturation (SaO2) and heart rate were continuously recorded during the experiment. Before the repeated apneas, UHP had lower ventilation, higher P(ET)CO2 (p < 0.05) and lower P(ET)O2 than CTL (p < 0.001). After the apneas, the P(ET)O2 values were always lower in UHP (p < 0.001) than CTL but with no difference for averaged P(ET)CO2 (p = 0.32). The apnea response, i.e., bradycardia and increased mean arterial blood pressure, was observed and it remained unchanged throughout the series in the two groups. The SaO, decreased in both groups during each apnea but the post-exercise SaO2 values were higher in UHP after A2 to A5 than in CTL (p < 0.01). The post-apnea lactate concentrations were lower in UHP than in CTL. These results indicate that more pronounced bradycardia could lead to less oxygen desaturation during repeated apneas in UHP. The UHP show a specific hypoventilatory pattern after repeated apneas, as well as a more pronounced cardiovascular response than CTL. They indeed showed no detraining of the diving response.

Objectives: To explore the stability of the one-point Infant Car Seat Challenge and risk factors that may be associated with oxygen desaturation events., Design, Setting, and Participants: This descriptive, nonexperimental, observational study examined the responses of 49 premature infants during two 90-minute Infant Car Seat Challenges at a tertiary health care institution., Main Outcome Measures: Three Infant Car Seat Challenge outcomes were explored: (a) pass/fail rates following two Infant Car Seat Challenge observation periods, (b) oxygen saturation and desaturation patterns during two Infant Car Seat Challenges, and (c) the association between oxygen desaturation events and infants' chronological, gestational, and corrected gestational ages., Results: The findings indicated that 86% of premature infants had stable results, 8% passed Infant Car Seat Challenge 1 but not Infant Car Seat Challenge 2, and 6% failed Infant Car Seat Challenge 1 and passed Infant Car Seat Challenge 2. In addition, the odds for oxygen desaturation events increased for infants born at less than or equal to 34 weeks gestation and hospitalized longer than 7 days., Conclusions: The Infant Car Seat Challenge success rate for identifying infants at risk for oxygen desaturation events was equal to or better than that of other screening tests for newborn medical conditions. The findings of this study will assist neonatal health care providers in making appropriate recommendations for infants' safe travel at discharge.

Experiments were conducted to test the hypothesis that branchial gas transfer is enhanced in rainbow trout during hypoxia or hypercarbia by bradycardia and systemic vasoconstriction. Gas transfer was indirectly assessed by continuous monitoring of arterial blood gases, PaO2 and PaCO2. Cardiac frequency was maximally decreased by 34.9+/-4.3 and 8.6+/-3.2 bpm in hypoxic and hypercarbic fish, respectively. Pre-treating fish with atropine (1micromol kg(-1)) attenuated or abolished the bradycardia during hypoxia and hypercarbia, respectively. However, there were no significant differences in the arterial blood gases between the control and atropinized fish. Dorsal aortic blood pressure was increased maximally by 11.3+/-2.8 and 17.7+/-2.0mm Hg in the hypoxic and hypercarbic fish. Pre-treatment of fish with prazosin (2.4micromol kg(-1)) prevented these increases in blood pressure. Blood gases were unaltered by prazosin treatment in the hypercarbic fish. However, in the hypoxic fish, gas transfer appeared to be impaired by prazosin on the basis of lowered PaO2 (by approximately 35 mm Hg compared to control fish) and increased PaCO2 (by approximately 0.3mm Hg). Because the normal hyperventilatory response to hypoxia was prevented by prazosin, it is possible that the impairment of gas transfer was related to inadequate ventilation rather than to any differences in the pressor response. The present results provide no evidence that gas transfer in rainbow trout is enhanced by bradycardia nor do they reveal any obvious benefit associated with the increases in blood pressure that accompany hypoxia and hypercarbia.

Background: Bepridil hydrochloride (Bpd) has attracted attention as an effective drug for atrial fibrillation (AF) and atrial flutter (AFL). However, serious adverse effects, including torsade de pointes (Tdp), have been reported., Methods and Results: Adverse effects of Bpd requiring discontinuation of treatment were evaluated. Bpd was administered to 459 patients (361 males, 63+/-12 years old) comprising 378 AF and 81 AFL cases. Mean left ventricular ejection fraction and atrial dimension (LAD) were 66+/-11% and 40+/-6 mm, respectively. Adverse effects were observed in 19 patients (4%) during an average follow-up of 20 months. There was marked QT prolongation greater than 0.55 s in 13 patients, bradycardia less than 40 beats/min in 6 patients, dizziness and general fatigue in 1 patient each. In 4 of 13 patients with QT prolongation, Tdp occurred. The major triggering factors of Tdp were hypokalemia and sudden decrease in heart rate. There were no differences in the clinical backgrounds of the patients with and without Tdp other than LAD and age, which were larger and older in the patients with Tdp., Conclusion: Careful observation of serum potassium concentration and the ECG should always be done during Bpd administration, particularly in elderly patients.

Background: Hyperkalemia is frequently seen during the first days of life in premature infants with a gestational age at birth less than 28 weeks. Normally, these high concentrations of potassium are well tolerated of the premature infants. In a few cases hyperkalemia leads to life-threatening cardiac arrhythmias., Case Report: We report about a 800 grams weighing preterm infant born after 26 + 4 gestational weeks. 24 hours after birth the infant developed 2 : 1 atrioventricular block due to hyperkalemia with a heart rate about 75 bpm. The bradycardia continued about 45 minutes in spite of immediate therapy concomitant by circulatory failure that resulted in an intraventricular hemorrhage of grade III with periventricular intraparenchymal lesions., Conclusions: The case report demonstrates the variations of the electrocardiogram that can be found in preterm infants with hyperkalemia and their potential risks. Therapy of symptomatic hyperkalemia is not able to interrupt early a life-threatening circulatory failure in any case.

Objectives: We tested the hypothesis that transvenous permanent pacemaker lead implantation causes clinically detectable myocardial damage., Background: Histological evidence of myocardial damage has been reported after antibradycardia pacemaker lead implantation., Methods: We studied 30 patients undergoing implantation of a full antibradycardia pacemaker system (pulse generator plus leads) and 10 patients in whom only a generator was implanted. Blood samples for cardiac troponin-I (CTNI), CK-MB mass, and myoglobin measurement were drawn at baseline, at the end of the procedure, and at 2, 6, 12, 24, 48, and 72 hours thereafter., Results: Abnormal CTNI levels were noted only in 24 of the 30 patients undergoing a full system implantation. CTNI levels were already abnormal at the end of the procedure in 16 and became so in all 24 during the next 6 hours. Peak levels were reached within 6 hours in 21 patients and were compatible with "minimal" necrosis (CTNI < 1.5 pg/mL) in 20. Maximum ventricular lead diameter and number of implanted leads were independent predictors of peak CTNI levels. CK-MB mass also increased after the procedure, but exceeded the normal range in only 10 patients. Myoglobin levels increased significantly both in patients undergoing a complete system implantation and in those where only a pulse generator was implanted., Conclusions: Transvenous insertion of endocardial leads for permanent pacing is accompanied in most patients by "minimal" myocardial damage. In this setting CTNI level kinetics are fast, characterized by early elevation and peak.

A twelve and a half year old girl of foreign nationality was been found in her domestic environment in unwakeable condition. The emergency was alarmed, and she was transferred to the children's hospital. Her condition at this time: she was unconscious and suffering from cold sweat but her circulation was stable and her respiration sufficient. Because of language barriers it was difficult to find out the antecedence of her state, but an empty box of pills (Amitryptilin) lying next to the patient may serve as a first hint to a intoxication. The father denied that his daughter might have consumed drugs or alcohol and meant that any abuse of medicine was out of the question. First urinary measurements to check if any drugs might be involved remain inconspicuous; in a control measurement of the blood 12 hours later only an elevation of the CPK is noticed as an unusual detail. The CPK-MB remains being according to normal. The native CT of the skull remains inconspicuous as well as the control with contrastation after 12 hours and a MRT-examination after 36 hours. The liquor punction does not give hints to any pathological facts. The EEG shows a high degree of continuous irregular slowe waves over both hemispheres in the delta and theta activity range. This gives reason to assume an encephalitis. The result of an electrocardiogram reveals a sinus bradycardia. The therapy was symptomatically, virustatically with aciclovir, antibiotically with cefotaxim and prophylactically against edema of brain with dexamethason. After 24 hours the patient abruptly awakes from coma and after 36 hours the reason for the coma can be stated: The toxicological examinations of the blood lead to the result: Intoxication with Baclofen. Explantation for the origin of the tablets: The family lives together with an aunt, who, after a cerebrovascular accident, was treated with Baclofen, Amitryptilin and ASA.

Acute hypercapnia was studied to assess its potential as a noninvasive and simple test for evoking neuroendocrine, cardiovascular and psychological responses to stress in man. A single breath of four concentrations of carbon dioxide (CO(2)), 5%, 25%, 35% and 50%, was administered to nine healthy volunteers in a randomized, single-blind fashion. Although no adverse effects occurred, most subjects were unable to take a full inspired vital capacity breath of 50% CO(2). In response to the remaining exposures, subjective and somatic symptoms of anxiety increased in a dose-dependent manner. Unlike 5% and 25% CO(2), 35% CO(2) stimulated significant adrenocorticotropic hormone and noradrenaline release at 2 min and cortisol and prolactin release at 15 min following inhalation. This same dose also provoked a significant bradycardia that was followed by an acute pressor response. No significant habituation of psychological, hypothalamic-pituitary-adrenal (HPA) or cardiovascular responses following 35% CO(2) was seen when this dose was repeated after 1 week. A single breath of 35% CO(2) safely and reliably produced sympathetic and HPA axis activation and should prove a useful addition to currently available laboratory tests of the human stress response.

Objectives: Fetal pulse oximetry was performed during labor in high-risk cases for fetal distress to determine the diagnostic value of this method., Methods: The fetal SpO2 values were blinded from the obstetrician so that these values did not influence clinical decisions. Mean and lowest SpO2 measurements for the last 30 min prior to either fetal scalp blood sampling or delivery were correlated with scalp pH or pH from the umbilical artery., Results: No significant correlation was found between pH and mean fetal oxygen saturation (correlation coefficient -0.02, p = 0.9). There was no significant correlation between pH and lowest fetal oxygen saturation (correlation coefficient 0.04, p = 0.84). Concerning the feasibility of the method, we found that only 23 of 65 included patients were suitable for analysis; in 20% of cases, we were not able to perform a SpO2 measurement., Conclusions: None of three cases with pH below 7.05 would have been detected using mean SpO2 over the last 30 min prior to fetal scalp blood sampling or delivery. Only one case would have been detected using the lowest SpO2 measurement over this period. We conclude that fetal SpO2 measurements during labor are of poor diagnostic value, with a disappointing feasibility and therefore are not ready for implementing into daily clinical practice.

The pharmacokinetics of lerisetron, a novel 5HT(3) antagonist, are studied together with its efficacy in inhibiting the serotonin (5-HT)-evoked transient bradycardia reflex (von Bezold-Jarisch reflex) in Sprague Dawley rats. [(14)C]Lerisetron (50, 100, and 200 microg/kg) was given to rats by intravenous (iv) injection and plasma levels of unchanged (UL) and total (unchanged + changed, TL) drug were measured by liquid chromatography with radioactivity monitoring and scintillation counting, respectively. Linearity of UL and TL pharmacokinetics over the dose range was established by noncompartmental analysis. Protein binding of lerisetron was measured in vitro by ultrafiltration. The unbound fraction was 14.4 +/- 1.4%. A nonlinear mixed effects ("population") bicompartmental pharmacokinetic analysis showed that volume of distribution and clearance (CL) were high for both forms of the drug, but CL was significantly smaller for TL [(mean +/- SEM) 0.014 +/- 0.03 L/min for UL versus 0.006 +/- 0.03 L/min for TL, p < 0.05)]. Large interindividual variabilities were observed for both forms. The response to lerisetron administration (inhibition of bradycardia) was evaluated at different doses (2, 3, 5, 6, and 10 microg/kg, iv) at times 2-180 min after dose administration and related to simulated concentrations. Inhibition was 100% 5 min after the 10-microg/kg dose and, 3 h later, it was still > 10%. Response to lerisetron was dose related in the range studied. Pharmacodynamic parameters were estimated by a sigmoid E(max) naive-pooled model. The parameters were also different between the two forms: EC(50) was 0.44 ng/mL (CV = 5.9%) for UL and 0.88 ng/mL (CV = 4.9%) for TL. We conclude that UL and TL pharmacokinetics were linear and that the differences in the kinetics and dynamics between the two forms suggest the presence of at least one metabolite., (Copyright 2002 Wiley-Liss, Inc.)

A 74-year-old man developed fever, somnolence, hyponatremia, and life-threatening sinus bradycardia for three weeks. He showed a slight elevation of lymphocyte count and protein level in the cerebrospinal fluid. A brain CT scan revealed a diffuse low density area around the hypothalamus which was identified as a high intensity signal by flair MR imaging. Marked sinus bradycardia developed with no abnormality in the echocardiograph or cardiac enzymes. Over the next 6 weeks he became alert and normal sinus rhythm resumed. The results of endocrine tests were compatible with hypothalamic insufficiency with partial hypopituitarism and the syndrome of inappropriate secretion of ADH.

We investigated the effects of an L-type and N-type Ca(2+) channel blocker, cilnidipine, on neurally mediated chronotropic responses to clarify the anti-autonomic profile of cilnidipine in anesthetized dogs. Pretreatment with cilnidipine (0.3, 1.0 and 3.0 microg/kg, i.v.), which decreased mean blood pressure by 5 to 31 mm Hg, inhibited the changes in heart rate and plasma norepinephrine concentration induced by bilateral carotid artery occlusion, whereas it had no effect on vagal nerve stimulation-induced bradycardia. These results suggest that antihypertensive and antisympathetic doses of cilnidipine fail to influence chronotropic responses mediated by parasympathetic nerve activation in the in vivo canine heart.

Objective: This study analyzed the cases of 55 children with cerebral palsy to evaluate methods for determination of the time before birth at which antenatal hypoxemia-ischemia damaged the brain., Study Design: In primate fetuses persistent fetal bradycardia develops close to the time that hypoxemia-ischemia damages basal ganglia structures in the brain. The same proved true in children in this study, so this time was thereafter used as a baseline to test the values of other proposed timers of hypoxemicischemic brain damage., Results: Basal ganglia lesions predominated when bradycardia lasted <30 minutes before birth. As the bradycardia duration lengthened, white matter and eventually watershed brain lesions predominated. Lymphocytosis appeared 25 minutes after the bradycardia began, and thrombocytopenia appeared at 20 to 28 hours. The lymphocytosis disappeared 14 to 18 hours after it first appeared., Conclusions: Counting back from the time that lymphocytosis ended and thrombocytopenia began can sometimes identify the time when hypoxemia-ischemia damaged the fetal brain.

Background: Heart-rate (HR) variability is an important predictor of mortality in patients with heart disease. We examined the effects of cilostazol, a quinolinone derivative, on HR and HR variability in patients with chronic atrial fibrillation associated with bradycardia episodes., Patients and Methods: Thirteen patients with chronic atrial fibrillation associated with bradycardia episodes (minimal HR <40/min and/or pauses, ie, episodes with an RR interval > 2.5 sec) received cilostazol (100 or 200 mg/day) orally for at least 2 months and 24-hour Holter electrocardiography was performed before and after the start of cilostazol administration., Results: Minimal HR was significantly increased, by an average of 14 beats/min (bpm), at 3.3 +/- 0.8 weeks (mean +/- SD) after the start of cilostazol treatment. The number of pauses was significantly decreased. As a consequence, mean HR was increased by an average of 18 bpm. Maximal HR was also increased by an average of 19 bpm. The circadian variation of the HR, determined by cosine fitting, was not changed by cilostazol treatment. The time-domain HR variabilities, ie, the SD of the mean RR interval and the SD of the 5-minute mean RR intervals, were also unchanged. New York Heart Association functional class was significantly improved and the plasma atrial natriuretic polypeptide level was significantly decreased after the initiation of cilostazol treatment., Conclusion: Cilostazol improves the slow HR episodes associated with chronic atrial fibrillation and maintains the HR circadian variation and time-domain variability, indicating that cilostazol has therapeutic utility for the treatment of the slow HR associated with chronic atrial fibrillation.

Background: Obesity, apneic hypoxemia, and rapid eye movement (REM) sleep are supposed to be the major causes for bradyarrhythmia in patients with obstructive sleep apnea. The aims of this study were to compare clinical findings and diagnoses in patients with obstructive sleep apnea with and without nocturnal bradyarrhythmia and to analyze the relations among hypoxemia, sleep stage, and bradyarrhythmia., Methods: During a 17-month period 239 patients were found to have sleep apnea in an ambulatory study. Patients with nocturnal bradyarrhythmia were hospitalized for 3 days and polysomnographies were performed over 2 successive nights. A Holter electrocardiogram was recorded for 48 hours., Results: Nocturnal episodes of bradyarrhythmia were identified in 17 (7%) of 239 patients. Body mass index (39 +/- 7 vs 31 +/- 5 kg/m(2)) and respiratory disturbance index (90 +/- 36 per hour vs 24 +/- 24 per hour) were significantly different (P <.01) between patients with (n = 17) and without bradyarrhythmia (n = 222). Bradyarrhythmia occurred significantly more often during REM than non-REM sleep (P <.01). There was a significant difference in end-apneic oxygen saturation in apnea/hypopnea episodes with and without bradyarrhythmia (71% +/- 9% vs 75% +/- 10%; P <.01). A linear relation between end-apneic oxygen saturation and number of sinus arrests and heart blocks could not be found., Conclusions: Patients with apnea-associated bradyarrhythmia are more overweight than patients without bradyarrhythmia. The higher respiratory disturbance index measurements found in these patients may be caused by this difference. Bradyarrhythmia occurs predominantly during REM sleep and occurred independently from decrease in oxygen saturation; a threshold value as an upper limit could not be found.