Transient Increase In Heart Rate Research Articles

A phase I clinical trial assessing the safety, tolerability, and pharmacokinetics of inhaled ethanol in humans as a potential treatment for respiratory tract infections.

Current treatments for respiratory infections are severely limited. Ethanol's unique properties including antimicrobial, immunomodulatory, and surfactant-like activity make it a promising candidate treatment for respiratory infections if it can be delivered safely to the airway by inhalation. Here, we explore the safety, tolerability, and pharmacokinetics of inhaled ethanol in a phase I clinical trial. The study was conducted as a single-centre, open-label clinical trial in 18 healthy adult volunteers, six with no significant medical comorbidities, four with stable asthma, four with stable cystic fibrosis, and four active smokers. A dose-escalating design was used, with participants receiving three dosing cycles of 40, 60%, and then 80% ethanol v/v in water, 2 h apart, in a single visit. Ethanol was nebulised using a standard jet nebuliser, delivered through a novel closed-circuit reservoir system, and inhaled nasally for 10 min, then orally for 30 min. Safety assessments included adverse events and vital sign monitoring, blood alcohol concentrations, clinical examination, spirometry, electrocardiogram, and blood tests. No serious adverse events were recorded. The maximum blood alcohol concentration observed was 0.011% immediately following 80% ethanol dosing. Breath alcohol concentrations were high (median 0.26%) following dosing suggesting high tissue levels were achieved. Small transient increases in heart rate, blood pressure, and blood neutrophil levels were observed, with these normalising after dosing, with no other significant safety concerns. Of 18 participants, 15 completed all dosing cycles with three not completing all cycles due to tolerability. The closed-circuit reservoir system significantly reduced fugitive aerosol loss during dosing. These data support the safety of inhaled ethanol at concentrations up to 80%, supporting its further investigation as a treatment for respiratory infections.Clinical trial registration: identifier ACTRN12621000067875.

Comparative evaluation of the effectiveness of nebulized dexmedetomidine V/S intravenous dexmedetomidine in blunting hemodynamic response to intubation – A prospective and randomized study

Background: Endotracheal intubation stimulates sympathetic system causing transient increase in heart rate and blood pressure which may be detrimental in patients with cardiovascular and cerebrovascular comorbidities. Intravenous dexmedetomidine given preoperatively prevents these unfavorable changes caused by endotracheal intubation. Aims and Objectives: The aims of this study were to compare effectiveness of nebulized dexmedetomidine and intravenous dexmedetomidine given preoperatively in blunting hemodynamic response (HR) to intubation. Materials and Methods: One hundred and twenty ASA I and II patients (either gender between 18 and 60 years) undergoing elective surgeries under general anesthesia were randomized into two equal groups in this prospective and comparative study. Thirty minutes before induction, Group IV received dexmedetomidine 0.50 μg/kg (diluted with normal saline [NS] to 50 mL) as slow IV infusion and nebulization with 5 mL NS, while Group N received nebulization with dexmedetomidine 1 μg/kg mixed with NS up to 5 mL along with 50 mL NS given as slow IV infusion. HR and mean arterial pressure (MAP) were noted at different intervals until extubation. Sedation score using Ramsay Sedation Scale (post-administration of drug) and adverse effects were noted. Comparison of HR and MAP was done using unpaired “t” test (P=0.05). Results: IV dexmedetomidine and nebulized dexmedetomidine given pre-induction were comparable in reducing stress response to intubation. The sedation score in both groups was comparable post-administration of drug. The incidence of hypotension was significantly more in IV group. Conclusion: Nebulized dexmedetomidine was equally efficacious in blunting HR to intubation as IV dexmedetomidine with fewer side effects making its administration safer for maintaining hemodynamic stability.

Concomitant medications associated with ischemic, hypertensive, and arrhythmic events in MDMA users in FDA adverse event reporting system.

3,4-Methylenedioxymethamphetamine (MDMA) is currently being investigated as an adjunctive treatment to therapy for posttraumatic stress and other anxiety related disorders in clinical trials. Within the next few years MDMA-assisted therapy is projected for approval by regulatory authorities. MDMA's primary mechanism of action includes modulation of monoamine signaling by increasing release and inhibiting reuptake of serotonin, norepinephrine, and, to a lesser extent, dopamine. This pharmacology affects sympathomimetic physiology. In controlled trials, special attention has been given to cardiovascular adverse events (AEs), because transient increases in heart rate and blood pressure have been observed during the MDMA-assisted therapy sessions. Finding and quantifying the potential drivers of cardiac AEs in clinical trials is difficult since only a relatively small number of participants have been included in these studies, and a limited set of allowed concomitant drugs has been studied. In this study a more diverse set of reports from the FDA Adverse Event Reporting System was surveyed. We found 17 cases of cardiovascular AEs, in which the individuals had taken one or more substances in addition to MDMA. Interestingly, all of those concomitant medications and illicit substances, including opioids, stimulants, anticholinergics, and amphetamines, had been previously associated with cardiovascular AEs. Furthermore, in none of the reports MDMA was marked as the primary suspect.

Electrocardiographic Changes in Young Healthy Male Smokers

Background: Smoking increases the risk of CVD, however, the magnitude of this increase in risk varies substantively according to a range of factors. Smoking-related CVD risks are highest in current and recent smokers, compared to never smokers and those who have quit in the more distant past. Risk also increases with increasing duration of use and with greater intensity of smoking, as measured by the number of cigarettes smoked per day. Methods: In the present study, a total of 60 male smokers having a history of smoking of more than 2 years and smoking at least 3 cigarettes per day were included in the study, provided they met the inclusion and exclusion criteria. 60 healthy male patients were included as controls/non-smokers. Demographic details were noted. Past, present and other relevant histories were recorded. Physical examination was done. Standard 12 lead ECG was done in the resting state after 2 hours of abstinence from strenuous physical activity, smoking and/or any caffeinated beverages. Results: In the present study, it was observed that the mean age of the non-smokers was lower (27.85 ± 5.11 years) than that of smokers (30.22 ± 5.26 years); P value: 0.014. Only males were included in the present study. The BMI and heart rate were similar in the smokers and non-smokers; P value: more than 0.05. The majority of the cases had normal axis on ECG in both the groups (86.66% in non-smokers and 70% in smokers). Left axis deviation was more common than the right axis deviation in both the groups. The difference between the two groups was statistically insignificant; P value: 0.063. The width and height of the P wave were similar in both the groups; P value: more than 0.05. The R wave was significantly bigger in the smokers (12.53 ± 4.63 mm) than in the non- smokers (10.05 ± 2.93 mm); P value: 0.001. The duration of PR interval was significantly more in the smokers (140.10 ± 18.37 ms) as compared to non-smokers (129.45 ± 19.90 ms); P value: 0.003. T wave inversion was present in 10% cases of smokers while no case in the non-smoker group had T wave inversion; P value: 0.027. The ST segment was normal in most of the cases (98.33% in the non-smokers and 96.66% in the smokers’ groups); P value: more than 0.05. All the cases in both the groups had normal sinus rhythm with normal PR interval, no tall T wave, no wide QRS interval or shortened QT interval. Conclusion: The study concluded that the smokers have a mean age of 30.22 ± 5.26 years. The heart rate is similar to non-smokers. In general, normal axis on ECG is more common. Left axis deviation is more prevalent than right axis deviation. Smokers have bigger R waves, increased PR duration and inverted T waves. This may be because smoking generally causes a transient increase in heart rate and ECG changes, especially those pertaining to ST-T segment.

Randomized trial of bolus ephedrine or mephentermine for maintenance of arterial pressure and fetal outcome during spinal anesthesia for the cesarean section

Background and Aims: Spinal anesthesia remains the preferred choice for cesarean deliveries, but hypotension is one of the common complications which may have detrimental effects on both the mother and fetus. In this study, we compared the efficacy and adverse effects of bolus doses of ephedrine hydrochloride and mephentermine sulfate administered intravenously to treat spinal-induced hypotension and the fetal outcomes through Apgar scores and umbilical cord blood gas analysis in the lower segment cesarean section. Material and Methods: In this prospective, randomized, double-blind study, 60 patients undergoing the lower segment cesarean section (LSCS) under spinal anesthesia were randomized into two groups of 30 each using computer-generated random numbers which were kept in an opaque envelope. Patients were pre-loaded with Ringer's lactate solution 10 ml/kg before the spinal anesthesia. Hypotension was defined as the fall in systolic blood pressure of less than or equal to 20% of the baseline or systolic blood pressure of less than 90 mmHg. Whenever hypotension occurred, patients in group E (ephedrine) received a bolus dose of ephedrine 6 mg intravenous and patients in group M (mephentermine) received a bolus dose of mephentermine 6 mg intravenous. Intra-operative recording included maternal hemodynamic parameters and the number of bolus doses of study drugs required to treat maternal hypotension and the adverse effects of study drugs. The Apgar score and umbilical cord blood gas values were recorded. Data were analyzed by analysis of variance test, Student's t-test, and Chi-square test. A P value of < 0.05 was considered as significant. Results: There was a statistically significant (p < 0.05) increase in systolic and mean arterial blood pressure at the second min and fourth min after administration of ephedrine in group E compared to mephentermine in group M. The systolic blood pressure at the second min in the ephedrine group was 114.3 ± 12.06, whereas in the mephentermine group, it was 106.10 ± 8.41 and was statistically significant (p < 0.05). At the fourth min, the systolic blood pressure in the ephedrine group was 115.03 ± 8.87, whereas in the mephentermine group, it was 108.46 ± 8.10 and was statistically significant (p < 0.05). There was a transient increase in heart rate immediately after administration of spinal anesthesia. The mean number of bolus doses of vasopressor consumption was 2.4 (14.4 mg) in the ephedrine group and 2 (12 mg) in the mephentermine group. The umbilical cord blood gas analysis and Apgar scores were similar in both the groups. Three patients (10%) developed bradycardia in the mephentermine group compared to the ephedrine group (0%). The incidence of nausea (13.3% vs 3.3%) and vomiting (10% vs 1%) was higher in the ephedrine group compared to the mephentermne group, and it was not statistically significant (p > 0.05). No significant differences were observed in the umbilical arterial blood pH and Apgar scores. Conclusion: In conclusion, after hypotension, ephedrine and mephentermine administration as bolus doses are equally efficacious in preventing spinal-induced hypotension in patients undergoing the cesarean section and are associated with similar neonatal outcomes.

Decrase in cerebral blood flow during maximal handgrip isometric contraction – a brief report

Findings of the studies on the relationship between isometric handgrip contraction and changes in cerebral blood flow (CBF) are contradictory. The aim of the study was to evaluate CBF changes during one minute of a maximal handgrip isometric contraction. Our main hypothesis was that the maximal handgrip test will cause a decrease in CBF related to the decrease in handgrip strength. The study protocol included a transcranial Doppler ultrasound measurement of middle cerebral arterial mean flow velocity (Vmean) with the concomitant measurement of the sustained maximal handgrip strength over a period of one minute in 12 healthy subjects of both sexes. The main findings indicate that a maximal handgrip exercise causes a significant decrease in cerebral blood flow that is slightly more prominent on the contralateral side. This decrease is accompanied by a significant but transient increase in heart rate and also by an important (16%) increase in mean arterial pressure. The maximal isometric contraction may result in an considerable decrease in cerebral blood flow that in certain cases may become even clinically relevant. In the light of our findings, we suggest that maximal isometric contractions should be better avoided as a therapeutic tool and that isometric exercises of intensities up to 60% of maximal voluntary contraction are better used.

Extremity trauma impairs renal tolerance to hemorrhage

BACKGROUDHemorrhage is often accompanied and/or caused by extremity trauma (ET) in both battlefield or civilian trauma scenarios. However, the impacts of ET on tolerance to hemorrhage and resultant renal injury remain unclear. We hypothesize that ET impairs tolerance to hemorrhage and renal ischemia, resulting in increased acute kidney injury (AKI) and mortality.METHODSSprague Dawley rats (11–13 wks) underwent pressure‐controlled hemorrhage (at MAP of 70 or 55 mmHg) with or without ET. Animals were randomly divided into groups: (time) control, ET (without hemorrhage), 70mmHg, 55mmHg, ET+70mmHg, and ET+55mmHg (n ≥ 7 for each group). Rats were anesthetized (inactin), and the femoral and carotid arteries were catheterized to measure MAP and to induce hemorrhage. Renal blood flow (RBF) was measured using a perivascular ultrasonic flow probe. After baselines were recorded, ET was induced via clamping the retrofemoral tissue groups for 30 sec using an L‐shaped hemostat, followed by closed fibula fracture using a 15‐gauge needle. Hemorrhage was induced 5 minutes after ET with target MAP maintained for up to 3 hours by withdrawal or reinfusion of shed blood with a dual direction pump (0.5 ml/min). Blood and urine samples were collected from arterial and bladder catheters before, and 1, 2, and 3 hours after hemorrhage.RESULTSET alone without hemorrhage caused a transient increase in heart rate without significantly affecting other measurements. Less blood withdrawal was required to maintain the target MAP during pressure‐controlled hemorrhage in groups with ET compared to groups without ET, and infusion back of shed blood was required 1 hour after hemorrhage in the 55mmHg+ET group (Figure A). Hemorrhage to 70mmHg caused significant decreases in RBF (Figure B), urine flow, and renal oxygen delivery (RDO2), but increased filtration fraction (FF) with no effect on creatinine clearance (Ccr), potassium, lactate, or urine albumin levels. In ET+70mmHg group, decreases in RBF and RDO2 were exacerbated, and impaired Ccr and FF with significant increases in circulating creatinine, potassium, lactate, and urine albumin levels were observed. All animals in groups 70mmHg and ET+70mmHg survived. Hemorrhage to 55mmHg caused significant decreases in RBF, urine flow, and RDO2 which were greater than observed the 70mmHg group. Hemorrhage to 55mmHg also caused decreases in Ccr and FF and increases in circulating creatinine, potassium, lactate, and urine albumin levels. When ET was combined with hemorrhage to 55mmHg, no further decreases in RBF and RDO2 were observed. However, ET+55mmHg animals showed exacerbated decreases in urine flow and exacerbated increases in circulating creatinine, potassium, and lactate levels. All animals survived for 3 hours following hemorrhage to 55mmHg, but only 50% animals survived in ET+55mmHg group.CONCLUSIONSOur data suggest that ET impairs tolerance to hemorrhage, exacerbates renal hypoperfusion, and increases risks for AKI and mortality. Although underlying mechanisms are unclear, the study provides important evidence that traumatic tissue injury should be considered as a critical component if using animal models to conduct translational studies on hemorrhage.Figures A and B represent the volume loss to maintain target MAP and related renal blood flow following different levels of hemorrhage with or without ET. ET is extremity trauma, Bas is baseline, Pre is Pre‐hemorrhage (5 minutes after ET). * P&lt; 0.05 70mmHg vs ET+70mmHg, + P&lt; 0.01 55 mmHg vs ET+55mmHg, n = 7 for 70mmHg and ET+70mmHg; n = 8 for 55mmHg and ET+55mmHg.Figure 1

TLR7 agonist modulation of postasphyxial neurophysiological and cardiovascular adaptations in preterm fetal sheep.

Activation of Toll-like receptors (TLRs) after hypoxic-ischemic brain injury can exacerbate injury but also alleviate cell loss, as recently demonstrated with the TLR7 agonist Gardiquimod (GDQ). However, TLR agonists also modulate vascular function and neuronal excitability. Thus, we examined the effects of TLR7 activation with GDQ on cardiovascular function and seizures after asphyxia in preterm fetal sheep at 0.7 gestation (104 days, term ∼147 days). Fetuses received sham asphyxia or asphyxia induced by umbilical cord occlusion for 25 min or asphyxia followed by a continuous intracerebroventricular infusion of 3.34 mg of GDQ from 1 to 4 h after asphyxia. Fetuses were monitored continuously for 72 h postasphyxia. GDQ treatment was associated with sustained, moderate hypertension for 72 h (P < 0.05), with a transient increase in heart rate. Electroencephalographic (EEG) power was suppressed for the entire postasphyxial period in both groups, whereas EEG spectral edge transiently increased during the GDQ infusion compared with asphyxia alone (P < 0.05), with higher β- and lower δ-EEG frequencies (P < 0.05). This increase in EEG frequency was not related to epileptiform activity. After the GDQ infusion, there was earlier onset of high-amplitude stereotypic evolving seizures, with increased numbers of seizures and seizure burden (P < 0.05). Hemodynamic function and seizure activity are important indices of preterm wellbeing. These data highlight the importance of physiological monitoring during preclinical testing of potential neuroprotective strategies.

Low intensity, continuous wave focused ultrasound reversibly depresses heart rate in anesthetized mice

Focused ultrasound (FUS) can noninvasively and reversibly modulate brain activity. Observed motor activity or behavioral changes are commonly used to infer neuromodulatory effects. Changes in autonomic nervous system regulation such as heart and respiratory function can potentially be used for studying the effects of FUS neuromodulation that do not produce outwardly observable motor or behavioral activity. In this study, low pressure (850 kPa), long duration (120 s) continuous-wave (CW) FUS at 2 MHz was targeted such that the focus spanned the visual cortex, hippocampus, and thalamus. These parameters were shown to reversibly depress heart rate in in vivo mice anesthetized with sodium pentobarbital by an average of 8.1 ± 3.7%. Following stimulus offset, heart rate either increased or varied in trend. Higher pressure (2 MPa), short duration (0.3 s) pulses at the same frequency resulted in either small, transient increases in heart rate or no change. Thermocouple measurements show the peak temperature elevation in the dura to be approximately 2 °C. Thermal simulations predict a peak temperature increase in the brain of 2.3 °C. These results indicate that CW FUS can alter autonomic nervous system regulation through very low heating and show that cardiorespiratory responses can be altered as a result of FUS neuromodulation.

A Novel, Low-Cost, Wide-Field, Infant Retinal Camera, "Neo": Technical and Safety Report for the Use on Premature Infants.

PurposeTo report the technical aspects, systemic, and ocular safety of a novel, low-cost, wide-field, infant retinal camera for use on premature infants.MethodsThe device, the “3nethra Neo” (Neo) is a 120° portable, contact, wide-field, unibody camera, with a CMOS sensor (2040 × 2040 resolution) and a warm light-emitting diode (LED) illumination source. The Neo was used to image 140 awake, preterm infants between postmenstrual age (PMA) of 28 to 37 weeks, undergoing retinopathy of prematurity (ROP) screening. Baseline, ‘during procedure', at 5 minutes, and for 60 minutes postprocedure, readings of oxygen saturation and heart rate were recorded. The device design, optics, illumination, and software specifications were compared with the RetCam 3.ResultsStudy defined bradycardia (9 infants, 6.4%), tachycardia (3 infants, 2.1%), and hypoxia (2 infants, 1.4%) were observed but there were no clinically significant systemic changes that required intervention during or following any of the study time intervals. There was a transient increase in heart rate by 9.68 (7.53–11.83; P < 0.0001) and marginal decrease in oxygen saturation (−1.94 [−1.60 to −2.28], P < 0.0001), which started to return to baseline 5 minutes after the procedure. Transient redness was seen in two eyes (0.7%) of two infants. No other ocular adverse effects were observed.ConclusionsThe Neo is easy to use in preterm infants and being compact was readily portable. There were no significant ocular or systemic adverse effects, potentially allowing it to be a viable low-cost device for ROP screening in low resource settings.Translational RelevanceThe camera provides a safe and affordable alternative to image the retina of infants by using novel illumination and lens mechanics and has the potential of worldwide acceptance.

Determining the Effects of Combined Liraglutide and Phentermine on Metabolic Parameters, Blood Pressure, and Heart Rate in Lean and Obese Male Mice

Liraglutide, a glucagon-like peptide 1 (GLP-1) receptor agonist, and phentermine, a psychostimulant structurally related to amphetamine, are drugs approved for the treatment of obesity and hyperphagia. There is significant interest in combination use of liraglutide and phentermine for weight loss; however, both drugs have been reported to induce systemic hemodynamic changes, and as such the therapeutic window for this drug combination needs to be determined. To understand their impact on metabolic and cardiovascular physiology, we tested the effects of these drugs alone and in combination for 21 days in lean and obese male mice. The combination of liraglutide and phentermine, at 100 μg/kg/day and 10 mg/kg/day, respectively, produced the largest reduction in body weight in both lean and diet-induced obese (DIO) mice, when compared with both vehicle and monotherapy-treated mice. In lean mice, combination treatment at the aforementioned doses significantly increased heart rate and reduced blood pressure, whereas in DIO mice, combination therapy induced a transient increase in heart rate and decreased blood pressure. These studies demonstrate that in obese mice, the combination of liraglutide and phentermine may reduce body weight but only induce modest improvements in cardiovascular functions. Conversely, in lean mice, the additional weight loss from combination therapy does not improve cardiovascular parameters.

Evaluation of neuraxial anesthesia in bearded dragons (Pogona vitticeps)

ObjectiveTo assess the feasibility, success rate, onset, duration and extent of motor/sensory block following intrathecal injection of lidocaine in bearded dragons (Pogona vitticeps). Study designProspective experimental study. AnimalsA group of eight adult bearded dragons (0.333 ± 0.048 kg). MethodsThe animals were sedated with alfaxalone (15 mg kg−1) subcutaneously. Neuraxial injections were performed with 1% lidocaine (2 mg kg−1) or 0.9% sodium chloride (0.2 mL kg−1) in all animals with a 7 day interval. If the initial injection did not result in motor block of the pelvic limbs within 10 minutes, a second injection was performed at the same dose. Measurements consisted of bilateral mechanical stimulation of limbs; 25%, 50%, and 75% of the trunk’s length; and cloacal tone. Animals were monitored for any untoward side effects by monitoring heart rate (HR), respiratory rate, righting reflex and head position. ResultsSuccess rate following the first injection of lidocaine was 50% (four out of eight animals) and increased to 75% (six out of eight animals) following a second injection. Onset of motor/sensory block occurred within 5 minutes in all successful injections. Duration and extent were variable, with most bearded dragons presenting motor/sensory block of cloaca and pelvic limbs (six out of six) and 25% of the trunk (five out of six) with mean ± standard deviation (range) duration of 49 ± 28 (25–100), 48 ± 25 (25–90) and 40 ± 14 (25–50) minutes, respectively. Confirmation of intrathecal injection by aspiration of cerebrospinal fluid was not possible. Neuraxial lidocaine significantly increased depth and duration of sedation, with a transient increase in HR, compared with saline. Conclusion and clinical relevanceNeuraxial lidocaine is a feasible technique with moderate success rate and low risk of complication in bearded dragons. This technique has potential for improving the management of anesthesia in this species.

119 Toll-Like Receptor-4 Agonist Monophosphoryl Lipid A Attenuates Severity of Acute Lung Injury and Hemodynamic Changes in an Ovine Model of Cutaneous Burn and Pneumonia Sepsis

Sepsis remains the most detrimental complication of burn patients. About 47% of mortalities following severe burn can be attributed to sepsis. P. aeruginosa is the most common cause of infections in burn patients. Monophosphoryl Lipid A (MPLA), a Toll-like receptor 4 agonist is used as an adjunct vaccine to support host response. The genomic responses to MPLA in sheep are quite similar to those of humans. The aim of this study was that MPLA treatment significantly attenuates severity of multi-organ dysfunctions using well-characterized ovine model of sepsis induced by cutaneous burn and pneumonia. Twelve chronically instrumented female sheep were subjected to 20% total body surface area, 3rd° cutaneous burn under anesthesia and analgesia. 24 hrs after burn, sheep were randomly allocated into 2 groups; 1) MPLA (2.5 µg/kg IV for 50 mins), n=6, 2) Control (saline IV), n=6. After 24 hrs of MPLA/saline treatment, pneumonia was induced by instillation of P. aeruginosa (1.6–2.5 x 1010 CFUs) into the lungs by bronchoscope. Then sheep were placed on ventilator, fluid resuscitated and cardiopulmonary variables were monitored for 24 hrs in a conscious state (total duration: 72 hrs). All sheep survived the 72-hr study period. MPLA significantly improved pulmonary gas exchange (PaO2/FiO2 ratio and oxygenation index) compared to control (63–72 hrs). MPLA significantly attenuated decreases in mean arterial pressure, stroke volume index and systemic vascular resistance index changes (60–72, 54–57, and 69–72 hrs, respectively), and stabilized cardiac index (60–69 hrs) compared to control. MPLA also reduced plasma troponin-I level (72 hr), and reversed increased blood lactate to normal levels (54–66 hrs). Modified sheep SOFA scores were significantly lower in MPLA group compared to control (54 - 72 hrs). During MPLA infusion, transient increases in heart rate, body temperature and pulmonary artery pressure were observed, but these changes were returned to baseline within 2 hrs. Post burn treatment with MPLA not only attenuated severity of acute lung injury, but also stabilized hemodynamic changes and prevented onset of sepsis following pneumonia induction. This novel immuno-modulation approach should be considered as an adjunct therapy for burn patients to prevent further infections. The results are highly translational to the clinical care of burn patients.

Cardiovascular safety profile of a fixed-dose combination of glycopyrrolate and formoterol fumarate delivered via metered dose inhaler using co-suspension delivery technology

BackgroundGlycopyrrolate/formoterol fumarate (GFF) metered dose inhaler (MDI) is a fixed-dose combination of the long-acting muscarinic antagonist (LAMA), glycopyrrolate (GP), and the long-acting β2-agonist (LABA), formoterol fumarate (FF), delivered via metered dose inhaler using innovative co-suspension delivery technology. Here we report the results of two studies that examined the cardiovascular safety of GFF MDI. MethodsThe thorough QT (TQT) study was a Phase I, randomized, double-blind, single-dose, crossover study to assess GFF MDI 18/9.6 (Bevespi Aerosphere®), GFF MDI 144/38.4 and GP MDI 144 μg, compared with placebo MDI and open-label moxifloxacin 400 mg (active control) in healthy volunteers (PT003009). The cardiovascular safety study in patients with chronic obstructive pulmonary disease (COPD) was a Phase IIb, randomized, multicenter, double-blind, 14-day dosing, parallel-group study to evaluate GFF MDI 36/9.6, GP MDI 36 and FF MDI 9.6 μg compared with open-label FF dry powder inhaler (DPI; Foradil® Aerolizer®) 12 μg, in patients with moderate-to-severe COPD (PT003003 [NCT01349803]). ResultsSeventy healthy volunteers were randomized in the TQT study. GFF MDI 144/38.4, GFF MDI 18/9.6 and GP MDI 144 μg all met the confidence interval-based criteria for negative QT prolongation potential. In the study in patients with COPD, 237 subjects were randomized and treated. GFF MDI 36/9.6, GP MDI 36, and FF MDI 9.6 μg did not result in clinically meaningful changes from baseline in 24-h mean heart rate at Day 14 (primary endpoint) or in any of the other Holter monitoring endpoints at Day 14, compared with FF DPI 12 μg. ConclusionsNo clinically significant effects on cardiovascular safety occurred at therapeutic or supratherapeutic doses of GFF MDI, apart from a small and transient increase in heart rate following supratherapeutic dose of GFF MDI 144/38.4 μg. Furthermore, there were no unexpected safety findings reported in either healthy volunteers or patients with COPD.

Simultaneous Transients of Intracranial Pressure and Heart Rate in Traumatic Brain Injury: Methods of Analysis.

The detection of increasing intracranial pressure (ICP) is important in preventing secondary brain injuries. Before mean ICP increases critically, transient ICP elevations may be observed. We have observed ICP transients of less than 10 min duration ,which occurred simultaneously with transient increases in heart rate (HR). These simultaneous events in HR and ICP suggest a direct interaction or communication between the heart and the brain. This chapter describes four mathematical methods and their applicability in detecting the above heart-brain cross-talk events during long-term monitoring of ICP. Recurrence plots, cross-correlation function and wavelet analysis confirmed the relationship between ICP and HR time series. Using the peaks detection algorithm with a sliding window approach we found an average of 37 cross-talk events (± SD 39). The number of events detected varied among patients, from 1 to more than 150 events. Our analysis suggested that the peaks detection algorithm based on a sliding window approach is feasible for detecting simultaneous peaks, e.g. cross-talk events in the ICP and HR signals.

Effects of Closed Endotracheal Suctioning on Systemic and Cerebral Oxygenation and Hemodynamics in Children.

To evaluate the effects of closed endotracheal tube suctioning on systemic oxygen saturation, cerebral regional oxygen saturation, and somatic regional (renal) oxygen saturation and hemodynamic variables in children. Prospective observational. A tertiary care PICU. Children aged 0-18 years, requiring invasive mechanical ventilation and with an arterial line. Closed endotracheal suction. The study included 19 sedated and intubated children, 0-18 years old. They were enrolled in an ongoing prospective observational study. We used near-infrared spectroscopy for cerebral regional oxygen saturation and somatic regional (renal) oxygen saturation. The timing of each closed endotracheal tube suctioning event was accurately identified from video recordings. We extracted systemic oxygen saturation, cerebral regional oxygen saturation, somatic regional (renal) oxygen saturation, heart rate, and systolic blood pressure and diastolic blood pressure for 5 minutes before and 5 minutes after each event and used these data for analysis. One-minute average values of these variables were used for repeated-measures analysis. We analyzed 287 endotracheal tube suctioning episodes in 19 children. Saline was instilled into the endotracheal tube during 61 episodes. The mean heart rate (107.0 ± 18.7 vs 110.2 ± 10.4; p < 0.05), mean arterial blood pressure (81.5 ± 16.1 vs 83.0 ± 15.6 mm Hg; p < 0.05), and the mean cerebral regional oxygen saturation (64.8 ± 8.3 vs 65.8 ± 8.3; p < 0.05) were increased after suctioning. The mean systemic oxygen saturation (96.9 ± 2.7 vs 96.7 ± 2.7; p = 0.013) was decreased, whereas the mean somatic regional (renal) oxygen saturation was not significantly different after endotracheal tube suctioning. Repeated-measures analysis revealed transient increases in heart rate, respiratory rate, systolic blood pressure, and diastolic blood pressure; a sustained increase in cerebral regional oxygen saturation; and transient decreases in systemic oxygen saturation and somatic regional (renal) oxygen saturation. Saline instillation did not affect oxygenation or hemodynamic variables. Closed endotracheal tube suctioning in sedated children is associated with transient but clinically insignificant changes in heart rate, blood pressure, cerebral regional oxygen saturation, systemic oxygen saturation, and somatic regional (renal) oxygen saturation. Saline instillation during endotracheal tube suctioning had no adverse effects on systemic or cerebral oxygenation.

Nonclinical Cardiovascular Studies of Prucalopride, a Highly Selective 5-Hydroxytryptamine 4 Receptor Agonist.

Patients with chronic constipation benefit from treatment with 5-hydroxytryptamine 4 (5-HT4) receptor agonists. However, the first-generation 5-HT4 receptor agonists cisapride and tegaserod were withdrawn from the market owing to rare cardiovascular adverse events that were not 5-HT4-receptor-related but due to the lack of selectivity of these drugs. Here we report the nonclinical cardiovascular profile of the selective 5-HT4 receptor agonist prucalopride. To assess its non-5-HT4 receptor-mediated effects on cardiovascular electrophysiological parameters, in vitro studies were performed in human ether-à-go-go-related gene-transfected cells, guinea pig ventricular myocytes and papillary muscle preparations, rabbit and dog Purkinje fibers, and the Langendorff rabbit heart. In vivo experiments were performed in a rabbit model for drug-induced proarrhythmogenesis, in anesthetized guinea pigs, and anesthetized and conscious dogs. In addition, human platelet aggregation and coronary artery contraction were studied to exclude interactions that have been suggested to mediate the cardiovascular effects of tegaserod. Effects at 5-HT4 receptors were evaluated in piglet and human atrial myocardium, and in anesthetized pigs. Finally, cardiovascular endpoints were investigated in chronic, repeated-dose toxicology studies at very high prucalopride doses in rats and dogs. No relevant effects were observed in any of the cardiovascular studies at concentrations at least 50 times the therapeutic plasma level. Only in pigs were minor and transient increases in heart rate and blood pressure noted upon first exposure to prucalopride, at plasma levels at least 10 times higher than human therapeutic plasma levels. Prucalopride may thus provide therapeutic benefit without the cardiovascular risks reported for other 5-HT4 receptor agonists.

Methylxanthines induce structural and functional alterations of the cardiac system in zebrafish embryos

BackgroundZebrafish embryos are emerging as a model for pharmacological and toxicological studies. We used zebrafish embryos to study the general toxicity and cardiovascular effects of eight methylxanthines: aminophylline, caffeine, diprophylline, doxofylline, etophylline, 3-isobutyl-1-methylxanthine (IBMX), pentoxifylline and theophylline.MethodsMicroinjections of the eight methylxanthines were performed in 1-2 cell stage zebrafish embryos and the general toxicity and cardiovascular effects were analyzed at different time points. Embryotoxicity and teratogenicity were evaluated to understand the general toxicity of these compounds. Structural and functional alterations of the heart were evaluated to assess the cardiovascular effects.ResultsOur results showed different activity patterns of the methylxanthines drugs. Caffeine, IBMX, pentoxifylline and theophylline were highly embryotoxic and teratogenic; aminophylline, doxofylline and etophylline were embryotoxic and teratogenic only at higher doses, and diprophylline showed a minimal (<10%) embryotoxicity and teratogenicity. Most of these drugs induced structural alteration of the heart in 20-40% of the injected embryos with the maximum dose. This structural alteration was fatal with the embryos ultimately dying within 120 hpf. All the drugs induced a transient increase in heart rate at 48 hpf which returned to baseline within 96 hpf. This functional effect of methylxanthines showed similarity to the studies done in humans and other vertebrates.ConclusionOur results indicate the potential toxicity and teratogenicity of different methylxanthines in the embryos during embryonic development, the most sensitive period of life. Although interspecies differences need to be considered before drawing any conclusion, our study elucidated that a single exposure of methylxanthines at therapeutic range could induce cardiac dysfunction besides causing embryotoxicity and teratogenicity. Of all the drugs, diprophylline appeared to be safer, with lower degree of embryotoxicity, teratogenicity and cardiac toxicity as compared to other methylxanthines.

Cerebrovascular Responses to Trigeminal Nerve Stimulation in Humans

The mammalian diving reflex, evoked by cold water face immersion, is characterized by peripheral vasoconstriction, an increase in blood pressure (BP) and a concomitant reduction in heart rate (HR). Trigeminal nerve stimulation (TGS) partly mediates these reflex induced cardiovascular adjustments, which are thought to conserve blood flow and oxygen for delivery to the brain and heart. We aimed to characterise the cerebrovascular responses to TGS under isocapnic conditions, and those evoked by generalized sympathetic activation during thermoreceptor stimulation with ice water hand immersion (cold pressor test; CPT).In eight healthy men (23±6 years) continuous recordings of middle cerebral artery velocity (MCA Vmean; transcranial Doppler), HR (ECG), mean BP (Finometer) and the partial pressure of end‐tidal carbon dioxide (PETCO2) were obtained. Cerebral vascular conductance index (CVCi) was calculated as; MCA Vmean/MAP. Participants underwent 3 minutes of CPT, with ice water (4°C) right hand immersion, and 3 minutes of TGS evoked by ice packs placed on the forehead and cheeks. Trials were randomized and separated by a 20‐minute resting period. Supplemental CO2 was added to the inspired air in order to maintain isocapnia throughout the TGS and CPT trials.During TGS a decline in heart rate was observed, while mean BP rose progressively (p&lt;0.05). MCA Vmean did not change significantly with TGS (baseline; 56.9 ± 3.4 cm/s, minute 3; 56.2 ± 3.3 cm/s, p&gt;0.05), while CVCi was reduced (baseline; 0.79 ± 0.50 cm/s, minute 3; 0.66 ± 0.47 cm/s, p&lt;0.05). In contrast, CPT was associated with a transient increase in HR during the first minute, and a constant elevation in mean BP (p&lt;0.05). MCA Vmean was significantly increased during CPT (baseline; 57.5 ± 2.9 cm/s, minute 3; 64.6 ± 3.6 cm/s; p&lt;0.05) and CVCi decreased (baseline; 0.73 ± 0.41 cm/s, minute 2; 0.64 ± 0.38 cm/s, p&lt;0.05). PETCO2 remained unchanged from baseline in both TGS and CPT trials.These preliminary findings suggest that cerebral perfusion is elevated during generalized sympathetic activation evoked by the CPT, whereas MCA Vmean remains unchanged during TGS under isocapnic conditions.Support or Funding InformationJPF is funded by the British Heart Foundation.

Six Years in the Life of a Mother Bear - The Longest Continuous Heart Rate Recordings from a Free-Ranging Mammal

Physiological monitoring of free-ranging wild animals is providing new insights into their adaptations to a changing environment. American black bears (Ursus americanus) are highly adaptable mammals, spending up to half the year hibernating, and the remainder of the year attempting to gain weight on a landscape with foods that vary seasonally and year to year. We recorded heart rate (HR) and corresponding activity of an adult female black bear over the course of six years, using an implanted monitor. Despite yearly differences in food, and an every-other year reproductive cycle, this bear exhibited remarkable consistency in HR and activity. HR increased for 12 weeks in spring, from minimal hibernation levels (mean 20–25 beats/minute [bpm]; min 10 bpm) to summer active levels (July daytime: mean 95 bpm). Timing was delayed following one cold winter. In August the bear switched from primarily diurnal to nocturnal, coincident with the availability of baits set by legal hunters. Activity in autumn was higher when the bear was with cubs. Birthing of cubs in January was identified by a transient increase in HR and activity. Long-term physiological and behavioral monitoring is valuable for understanding adaptations of free-ranging animals to climate change, food availability, and human-related stressors.