Autonomic functioning among cocaine-exposed kindergarten-aged children: Examination of child sex and caregiving environmental risk as potential moderators.

The purpose of this study was to examine the hypothesis that child sex moderates the association between prenatal cocaine exposure (PCE) and autonomic functioning as well as to examine the role that caregiving environmental risk played in sex differences in autonomic functioning among exposed children. Measures of the parasympathetic nervous system (indexed by respiratory sinus arrhythmia [RSA]) and the sympathetic nervous system (indexed by skin conductance level [SCL]) were obtained from 146 (75 cocaine-exposed, 38 male; and 71 nonexposed, 36 male) children during baseline and a task designed to elicit negative affect (NA). We also examined the role of caregiving environmental risk as a moderator of the association between PCE and autonomic functioning separately for boys and girls. PCE boys had a significantly higher baseline RSA and lower baseline SCL than PCE girls or nonexposed children. Environmental risk also moderated the association between PCE and baseline RSA for boys, but not girls, such that boys with PCE and high environmental risk had the highest baseline RSA. These findings indicate that exposed boys had significantly lower levels of sympathetic activation while at rest. However, for autonomic reactivity, the exposed girls had a larger change in both RSA and SCL relative to nonexposed girls while exposed boys had significantly smaller increases in SCL during environmental challenge. Finally, girls with both PCE and high environmental risk had the highest levels of parasympathetic reactivity during challenge. These results underscore the importance of examining sex differences and considering comorbid environmental risk factors when examining developmental outcomes in cocaine-exposed children and highlight the complexity involved with understanding individual differences in cocaine-exposed populations.

Acute Pediatric Colchicine Toxicity is Associated with Marked Bradydysrhythmias.

BACKGROUND: Colchicine ingestion is rare but highly lethal. Patients usually die of multiorgan failure and cardiogenic shock. Colchicine is not only associated with depressed myocardial function but also with fatal heart rhythm disturbances, such as complete heart block, ventricular tachycardia, and asystole. While histologic changes of myocytes are well known, the mechanism by which colchicine affects cardiac impulse generation and conduction is not fully understood. CASE REPORT: We present a case of colchicine ingestion with sinus bradycardia, marked sinus arrhythmia, and first- and second-degree heart block. A 10-year-old previously healthy boy was brought to the emergency department for the sudden onset of dizziness, abdominal pain, and vomiting after ingesting his grandfather's colchicine and furosemide. His symptoms improved with ondansetron and intravenous normal saline. However, because of the colchicine ingestion, he was admitted to the pediatric intensive care unit for observation. He first developed PR prolongation (∼4-30 h postingestion) followed by marked sinus bradycardia and sinus arrhythmia along with second-degree heart block (∼48-60 hours postingestion). The minimum heart rate was 40 beats/min. Marked sinus arrhythmia was observed, suggesting an increase in parasympathetic activity. His heart rhythm improved initially with less sinus arrhythmia followed by resolution of heart block. He was discharged home without any sequelae. Holter monitoring 1 week after discharge showed normal heart rate variability for age. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case provides novel insights into how colchicine may affect the heart's electrophysiology. Colchicine may increase the parasympathetic tone enough to cause sinus bradycardia and different degrees of heart block.

Inhibitors of phosphodiesterases PDE2, PDE3, and PDE4 do not increase the sinoatrial tachycardia of noradrenaline and prostaglandin PGE1 in mice.

Phosphodiesterases PDE2, PDE3, and PDE4 are expressed in murine sinoatrial cells. PDE3 and/or PDE4 reduce heart rate but apparently do not influence the tachycardia mediated through sinoatrial ß1- and ß2-adrenoceptors despite the high content of sinoatrial cAMP. The function of PDE2 is, however, uncertain. Prostaglandin PGE1 elicits sinoatrial tachycardia through EP receptors, but the control by phosphodiesterases is unknown. We investigated on spontaneously beating right atria of mice the effects of the PDE2 inhibitors Bay 60-7550 and EHNA on basal beating and the tachycardia produced by noradrenaline (3 nM) and PGE1 (1 µM). Bay 60-7550 (1 µM), but not EHNA (10 µM), increased basal sinoatrial beating. EHNA also failed to produce tachycardia in the presence of the adenosine deaminase inhibitor 2'-deoxycoformycin (10 µM), remaining inconclusive whether PDE2 reduces basal sinoatrial beating. Rolipram (10 µM) and cilostamide (300 nM) caused moderate tachycardia. The tachycardia evoked by Bay 60-7550 was similar in the absence and presence of rolipram. Noradrenaline elicited stable tachycardia that was not increased by Bay 60-7550. A stable tachycardia caused by PGE1 was not increased by the inhibitors of PDE2, PDE3, and PDE4. Unlike PDE3 and PDE4 which reduce murine basal sinoatrial beating, a possible effect of PDE2 needs further research. The stable tachycardia produced by noradrenaline and PGE1, together with the lack potentiation by the inhibitors of PDE2, PDE3, and PDE4, suggests that cAMP generated at the receptor compartments is hardly hydrolyzed by these phophodiesterases. Evidence from human volunteers is consistent with this proposal.

Early plasma exchange for treating ricin toxicity in children after castor bean ingestion.

Plasma exchange (PE) for the treatment of ricin toxicity has not been previously reported. Here we describe the use of PE to treat children who experienced ricin toxicity after ingesting castor beans. Seven children (median age: 8.1 years) who consumed castor beans (median: 5 beans) were treated with PE. All had bradycardia and sinus arrhythmia, and most had experienced episodes of vomiting and/or diarrhea. PE settings were blood flow, 50-80 mL/min; PE rate, 600-800 mL/h; volume of exchange, 1440-1950 mL. Median time from ingestion to PE was 73 h. All clinical symptoms disappeared and vital signs rapidly returned to normal after PE; no severe organ dysfunction occurred. All children were discharged and recovered uneventfully. Concentrations of all serum biochemical parameters significantly decreased immediately after PE. Some, but not all, of these parameters were also significantly decreased at 48 and 72 h after PE compared with before PE. Our findings suggest that PE can be an effective early intervention in the treatment of ricin toxicity due to castor bean ingestion.

Behavior problems among cocaine exposed children: role of physiological regulation and parenting.

This study examined interrelations between prenatal cocaine exposure, child autonomic regulation, parenting behavior and child sex on parent-reported behavior problems at 36 months of age. We hypothesized that respiratory sinus arrhythmia (RSA) at 13 months of age would mediate the relation between cocaine exposure and behavior problems. We also hypothesized that child sex, maternal negative affect, and maternal sensitivity observed at 13 months of age would moderate the relation between RSA and behavior problems. Results revealed that cocaine exposure predicted low baseline RSA and low RSA withdrawal during a negative affect task. Low baseline RSA, in turn, predicted fewer behavior problems offering support for an indirect association between cocaine exposure and behavior problems. The association between baseline RSA and behavior problems was further moderated by maternal negative affect such that high baseline RSA was more strongly related to behavior problems under conditions of high compared to low maternal negative affect. Results also revealed a near significant trend for baseline RSA to be more strongly related to behavior problems among boys than girls. These findings highlight several possible pathways toward behavior problems among cocaine exposed children.

Symptomatic sinus bradycardia after a treatment course of high-dose oral prednisone.

BACKGROUND: High-dose corticosteroid therapy is used to treat several severe autoimmune diseases. Despite a common knowledge in the medical community of the adverse effects of chronic corticosteroid use, there is much less awareness of the affects that can occur after very high doses are administered in a relatively short period of time. OBJECTIVE: Our objective was to report on the outpatient-based practice of administering high-dose corticosteroids for autoimmune disease and the possible bradycardic response that can occur as a result. CASE REPORT: We present a case of a 45-year-old female with multiple sclerosis who presented to the emergency department with symptomatic sinus bradycardia secondary to a regimen of high-dose corticosteroid therapy. CONCLUSIONS: More patients with autoimmune diseases may be placed on outpatient-based treatment regimens of high-dose corticosteroids in the future. It is important for emergency physicians to be aware of bradycardia as a possible adverse effect, as many of these patients may present to the emergency department for evaluation.

Heart rate decrease during crizotinib treatment and potential correlation to clinical response.

BACKGROUND: Crizotinib is used for the treatment of advanced anaplastic lymphoma kinase (ALK)-rearranged nonsmall cell lung cancer (NSCLC). Sinus bradycardia (SB) is a side effect listed in its package insert. We investigated the frequency and timing of SB, patient characteristics associated with SB during crizotinib treatment, and potential correlation between heart rate (HR) changes and clinical response to crizotinib. METHODS: A retrospective chart review was conducted of the timing and frequency of SB, patient characteristics, and clinical response of patients to crizotinib treatment. RESULTS: Forty-twp patients who had ALK-rearranged or mesenchymal epithelial transition (MET)-amplified NSCLC and received treatment with oral crizotinib 250 mg twice daily who were enrolled in 2 crizotinib trials (PROFILE 1001 and PROFILE 1005) were analyzed. There was an average decrease of 26.1 beats per minute (bpm) from the pretreatment HR among all patients during crizotinib treatment. Twenty-nine patients (69%) experienced at least 1 episode of SB (HR, <60 bpm). The average time to the lowest HR recorded was 18.6 weeks (range, 5-72 weeks). Patients who experienced SB were significantly older (aged 55.8 years vs 47.8 years; P = .0336), had a lower pretreatment HR (mean, 77.9 bpm vs 100.6 bpm; P = .002), and were on crizotinib longer (52.9 weeks vs 24.6 weeks; P = .0050) than patients who did not experience SB. The overall response rate (P = .0195) and the maximum tumor shrinkage (P = .0205) were significantly greater in patients who experienced SB. CONCLUSIONS: HR decrease is common during crizotinib treatment. It remains to be determined whether the correlation between HR decrease and clinical response to crizotinib reflects a biomarker of drug efficacy or a time/cumulative dose-dependent phenomenon.

Symptomatic 5-fluorouracil-induced sinus bradycardia.

5-Fluorouracil (5-FU) is a commonly used anti-neoplastic agent. 5-FU has been not uncommonly associated with cardiotoxicity, although the many potentially causative mechanisms are yet to be established. Here, we present the case of a 61-year-old gemstone miner who developed symptomatic sinus bradycardia while receiving a continuous 5-FU infusion combined with radiotherapy for locally advanced rectal cancer. This dysrhythmia is an unusual type of 5-FU toxicity, our case being the second described. We review the actions of 5-FU and the various proposed mechanisms of its cardiotoxic effects.

Longitudinal evidence for unfavorable effects of antidepressants on heart rate variability.

BACKGROUND: It was previously shown that antidepressants are associated with diminished vagal control over the heart. Longitudinal studies are needed to test the causality of this association further. METHODS: Longitudinal data were obtained in the Netherlands Study of Depression and Anxiety. At baseline and at 2-year follow-up, heart rate and cardiac vagal control as indexed by respiratory sinus arrhythmia were measured in 2114 subjects (mean age = 42.0 years; 66.2% female), who either used antidepressants at one or two time points (n = 603) or did not use antidepressants at any time point (n = 1511). Linear mixed-model analyses were conducted to compare changes in respiratory sinus arrhythmia and heart rate over time across antidepressant-naive subjects, subjects who started using an antidepressant during follow-up, subjects who stopped using an antidepressant, and persistent antidepressant users. Analyses were adjusted for demographics, health, and lifestyle factors. RESULTS: Compared with continuous nonusers, subjects who started the use of a tricyclic antidepressant or a serotonergic and noradrenergic antidepressant showed a significantly greater increase in heart rate and a decrease of respiratory sinus arrhythmia at 2 years. Subjects who started the use of selective serotonin reuptake inhibitors also showed a decrease in respiratory sinus arrhythmia, but their heart rate did not increase. Discontinuing antidepressants systematically caused opposite effects; levels returned in the direction of those observed among nonusers. CONCLUSIONS: These 2-year longitudinal results indicate that all antidepressants cause a decrease in cardiac vagal control. After discontinuing antidepressants, autonomic function recovers, suggesting that the unfavorable effects are (partly) reversible.

Slow heart-slow brain: consequence of short-term occupational exposure to toluene in a young woman: what is the real mechanism?

Herein we describe a case of acute occupational exposure to toluene in a 27-year-old female patient, presented to the emergency department of our institute. On admission she had electrocardiographic signs of profound sinus bradycardia with sinus arrhythmia and low amplitude slow wave activity recorded on her electroencephalogram (EEG). The mechanisms underlying the cerebral and cardiac effects of toluene are also discussed.

Linear and nonlinear quantification of respiratory sinus arrhythmia during propofol general anesthesia.

Quantitative evaluation of respiratory sinus arrhythmia (RSA) may provide important information in clinical practice of anesthesia and postoperative care. In this paper, we apply a point process method to assess dynamic RSA during propofol general anesthesia. Specifically, an inverse Gaussian probability distribution is used to model the heartbeat interval, whereas the instantaneous mean is identified by a linear or bilinear bivariate regression on the previous R-R intervals and respiratory measures. The estimated second-order bilinear interaction allows us to evaluate the nonlinear component of the RSA. The instantaneous RSA gain and phase can be estimated with an adaptive point process filter. The algorithm's ability to track non-stationary dynamics is demonstrated using one clinical recording. Our proposed statistical indices provide a valuable quantitative assessment of instantaneous cardiorespiratory control and heart rate variability (HRV) during general anesthesia.

Opioid microinjection into raphe magnus modulates cardiorespiratory function in mice and rats.

The raphe magnus (RM) participates in opioid analgesia and contains pain-modulatory neurons with respiration-related discharge. Here, we asked whether RM contributes to respiratory depression, the most prevalent lethal effect of opioids. To investigate whether opioidergic transmission in RM produces respiratory depression, we microinjected a mu-opioid receptor agonist, DAMGO, or morphine into the RM of awake rodents. In mice, opioid microinjection produced sustained decreases in respiratory rate (170 to 120 breaths/min), as well as heart rate (520 to 400 beats/min). Respiratory sinus arrhythmia, indicative of enhanced parasympathetic activity, was prevalent in mice receiving DAMGO microinjection. We performed similar experiments in rats but observed no changes in breathing rate or heart rate. Both rats and mice experienced significantly more episodes of bradypnea, indicative of impaired respiratory drive, after opioid microinjection. During spontaneous arousals, rats showed less tachycardia after opioid microinjection than before microinjection, suggestive of an attenuated sympathetic tone. Thus, activation of opioidergic signaling within RM produces effects beyond analgesia, including the unwanted destabilization of cardiorespiratory function. These adverse effects on homeostasis consequent to opioid microinjection imply a role for RM in regulating the balance of sympathetic and parasympathetic tone.

Phosphodiesterases PDE3 and PDE4 jointly control the inotropic effects but not chronotropic effects of (-)-CGP12177 despite PDE4-evoked sinoatrial bradycardia in rat atrium.

Acting through a low-affinity site of the beta(1)-adrenoceptor (beta(1L)AR), CGP12177 causes sinoatrial tachycardia and positive inotropic effects in left atrium but not in the ventricle of the rat. However, inhibition of either PDE3 or PDE4 also uncovers positive inotropic effects of CGP12177 in ventricle, but whether these phosphodiesterases also control the atrial agonist effects of CGP12177 was unknown. We, therefore, investigated the effects of the PDE3-selective inhibitor cilostamide (300 nM) and PDE4 inhibitor rolipram (1 microM) on the (-)-CGP12177-evoked increases of sinoatrial beating rate and force of paced left atria of the rat. Rolipram (n = 8) increased basal sinoatrial rate by 27 +/- 5 bpm but cilostamide (n = 8) had no effect. The chronotropic potency of (-)-CGP12177 (-logEC(50)M = 7.5) was not changed by rolipram and cilostamide or their combination. (-)-CGP12177 increased left atrial force with intrinsic activity 0.25 compared to (-)-isoprenaline. Rolipram (n = 8) and cilostamide (n = 8) did not change basal force of left atria but concurrent rolipram + cilostamide (n = 8) increased force by 52 +/- 9% of the effect of 200 microM (-)-isoprenaline. Neither rolipram nor cilostamide affected the inotropic potency of (-)-CGP12177 (-logEC(50)M = 7.4) but concurrent rolipram + cilostamide caused potentiation (-logEC(50)M = 8.2) and converted (-)-CGP12177 into a full agonist compared to (-)-isoprenaline. Cyclic AMP appears to maintain sinoatrial rate and PDE4 elicits bradycardia through hydrolysis of cAMP in a compartment distinct from the beta(1L)AR-induced cAMP compartment through which (-)-CGP12177 causes tachycardia. In contrast to the (-)-CGP12177-evoked tachycardia, not controlled by PDE3 and PDE4, these isoenzymes jointly reduce (-)-CGP12177-evoked increases of left atrial contractility through beta(1L)AR.

Thalidomide causes sinus bradycardia in ALS.

OBJECTIVE: Neuroinflammation contributes to motor neuron degeneration in ALS. Thalidomide (THL) shows potent anti-inflammatory properties and increased the lifespan in ALS transgenic mice. Thalidomide was therefore suggested as atherapeutic intervention for the treatment of ALS.We conducted a pilot, randomized clinical trial of THL in patients with ALS to assess safety, feasibility, and preliminary estimates of treatment efficacy. METHODS: Patients were randomized to THL in combination with riluzole (n = 18) or riluzole alone (n = 19). THL was initiated at 100 mg per day for 6 weeks. Thereafter, the dose was increased every week by 50 mg until reaching the dose of 400 mg per day and planned to continue for another 12 weeks. RESULTS: Within 12 weeks of THL treatment, nine THL patients (50%) developed bradycardia defined as a heart rate below 60 beats per minute (bpm) and ranged from 46 to 59 bpm. Mean heart rate dropped by 17 bpm with THL treatment. Severe symptomatic bradycardia of 30 bpm occurred in one patient. A further patient died from sudden unexpected death. The study was terminated prematurely for safety concerns. The secondary outcome variables showed similar results for both groups. CONCLUSION: Bradycardia was the most common adverse event of THL treatment in ALS. THL-related bradycardia does not appear to be ALS-specific. It is conceivable, however, that the unexpected frequency and severity of THL-induced bradycardia may be related to subclinical involvement of the autonomic nervous system in ALS. The cardiac toxicity discourages further clinical trials and compassionate use of THL in ALS. ClinicalTrials.gov Identifier: NCT00231140.