Jill A. Barney

The effects of increasing plasma concentrations of dexmedetomidine in humans

Background This study determined the responses to increasing plasma concentrations of dexmedetomidine in humans. Methods Ten healthy men (20–27 yr) provided informed consent and were monitored (underwent electrocardiography, measured arterial, central venous [CVP] and pulmonary artery [PAP] pressures, cardiac output, oxygen saturation, end-tidal carbon dioxide [ETCO2], respiration, blood gas, and catecholamines). Hemodynamic measurements, blood sampling, and psychometric, cold pressor, and baroreflex tests were performed at rest and during sequential 40-min intravenous target infusions of dexmedetomidine (0.5, 0.8, 1.2, 2.0, 3.2, 5.0, and 8.0 ng/ml; baroreflex testing only at 0.5 and 0.8 ng/ml). Results The initial dose of dexmedetomidine decreased catecholamines 45–76% and eliminated the norepinephrine increase that was seen during the cold pressor test. Catecholamine suppression persisted in subsequent infusions. The first two doses of dexmedetomidine increased sedation 38 and 65%, and lowered mean arterial pressure by 13%, but did not change central venous pressure or pulmonary artery pressure. Subsequent higher doses increased sedation, all pressures, and calculated vascular resistance, and resulted in significant decreases in heart rate, cardiac output, and stroke volume. Recall and recognition decreased at a dose of more than 0.7 ng/ml. The pain rating and mean arterial pressure increase to cold pressor test progressively diminished as the dexmedetomidine dose increased. The baroreflex heart rate slowing as a result of phenylephrine challenge was potentiated at both doses of dexmedetomidine. Respiratory variables were minimally changed during infusions, whereas acid–base was unchanged. Conclusions Increasing concentrations of dexmedetomidine in humans resulted in progressive increases in sedation and analgesia, decreases in heart rate, cardiac output, and memory. A biphasic (low, then high) dose–response relation for mean arterial pressure, pulmonary arterial pressure, and vascular resistances, and an attenuation of the cold pressor response also were observed.

Sedative, amnestic, and analgesic properties of small-dose dexmedetomidine infusions.

This research determined the safety and efficacy of two small-dose infusions of dexmedetomidine by evaluating sedation, analgesia, cognition, and cardiorespiratory function. Seven healthy young volunteers provided informed consent and participated on three occasions with random assignment to drug or placebo. Heart rate, blood pressure, respiratory rate, ETCO2, O2 saturation, and processed electroencephalogram (bispectral analysis) were monitored. Baseline hemodynamic measurements were acquired, and psychometric tests were performed (visual analog scale for sedation; observer’s assessment of alertness/sedation scale; digit symbol substitution test; and memory). The pain from a 1-min cold pressor test was quantified with a visual analog scale. After a 10-min initial dose of saline or 6 &mgr;g · kg−1 · h−1 dexmedetomidine, volunteers received 50-min IV infusions of saline, or 0.2 or 0.6 &mgr;g · kg−1 · h−1 dexmedetomidine. Measurements were repeated at the end of infusion and during recovery. The two dexmedetomidine infusions resulted in similar and significant sedation (30%–60%), impairment of memory (approximately 50%), and psychomotor performance (28%–41%). Hemodynamics, oxygen saturation, ETCO2, and respiratory rate were well preserved throughout the infusion and recovery periods. Pain to the cold pressor test was reduced by 30% during dexmedetomidine infusion. Small-dose dexmedetomidine provided sedation, analgesia, and memory and cognitive impairment. These properties might prove useful in a postoperative or intensive care unit setting. Implications: The &agr;2 agonist, dexmedetomidine, has sedation and analgesic properties. This study quantified these effects, as well as cardiorespiratory, memory and psychomotor effects, in healthy volunteers. Dexmedetomidine infusions resulted in reversible sedation, mild analgesia, and memory impairment without cardiorespiratory compromise.

Impedance-Derived cardiac indices in supine and upright exercise

Impedance cardiography was used to determine the classical systolic time intervals (STIs) (i.e., pre-ejection period (PEP), left ventricular ejection time (LVET) and the quotient PEP/LVET), in young, healthy, male subjects during supine and seated exercise. With increasing exercise, there was a tendency toward decreases in PEP, LVET, and PEP/LVET. In the seated position, there was an increase in transthoracic Zo incident to the caudal migration of thoracic blood—a result of the postural change. With seated exercise, there were—in contrast to supine exercise—greater decreases in PEP/LVET and greater increases in the Heather index. Similarly, there was a tendency toward increases in dZ/dtmin and the Rapid Ejection Index. We suggest that these differences are related to increased myocardial contractility resulting from the postural augmentation of cardio-sympathetic activity, added to that of exercise per se. This study, as well as previous ones, indicates that impedance cardiography is reliable, effective, and more practicable than the arteriographic method for monitoring STIs. We also believe that certain impedance-derived indices (i.e., transthoracic Zo, dZ/dtmin and the Heather Index) have considerable potential value for physiologic and clinical investigation.

High concentrations of isoflurance do not block the sympathetic nervous system activation from desflurane

Purpose: The volatile anesthetic desflurane has been associated with neurocirculatory responses that have been relatively refractory to adjuvant treatment. We have employed desflurane to evaluate the integrity of the sympathetic nerve recording after establishment of the anesthetized state with another anesthetic agent. This retrospective evaluation of data from volunteers determined if higher concentrations of isoflurane that were sufficient to block the neurocirculatory response to laryngeal and tracheal stimulation would abolish the neurocirculatory response to desflurane.Methods: Data from eight, healthy, young volunteers met our criteria for inclusion. They had been anesthetized with propofol or thiopental and intubated after neuromuscular blockade. Each subject was monitored with radial artery blood pressure (BP), heart rate (HR)(ECG), and sympathetic microneurography. Isoflurane had been administered to achieve a steady state concentration of 1.5 MAC (minimum alveolar concentration) while oxygenation and carbon dioxide were monitored with pulse oximetry and infrared spectrometry, respectively. A deep level of anesthesia was confirmed when laryngoscopy and endotracheal tube movement failed to elicit a neurocirculatory response. A brief exposure to 11% desflurane in the inspired gas was then provided.Results: The responses to desflurane included significant increases in HR, range 32–84 b/min, and BP, range 15–72 mm Hg (P<0.05). Sympathetic nerve activity increased substantially in the three volunteers with functional nerve recordings.Conclusion: In healthy volunteers receiving 1.5 MAC isoflurane, which was sufficient to block the neurocirculatory response to laryngoscopy and tracheal stimulation, there were striking increases in sympathetic outflow, HR and BP when 11% desflurane was substituted for isoflurane.RésuméObjectif: L’anesthésique volatil desflurane a été associé à des réponses neurocirculatoires relativement réfractaires à un traitement adjuvant. Nous avons utilisé le desflurane pour évaluer l’intégrité du nerf sympathique après l’installation de l’anesthésie avec un autre anesthésique. La présente évaluation rétrospective de participants volontaires a cherché à déterminer si une concentration élevée d’isoflurane, suffisante pour bloquer la réponse neurocirculatoire à la stimulation laryngée et trachéale, pouvait abolir la réponse neurocirculatoire au desflurane.Méthode: Huit jeunes volontaires en santé ont participé à l’étude. Ils ont été anesthésiés avec du propofol ou du thiopental et intubés après blocage neuromusculaire. Chaque patient a été surveillé par le monitorage de la tension de l’artère radiale (TA) et de la fréquence cardiaque (FC) (ECG) et par la microneurographie sympathique. L’isoflurane a été administré jusqu’à une concentration stationnaire de 1,5 CAM (concentration alvéolaire minimale) et l’oxygénation et le gaz carbonique ont été vérifiés par l’oxymétrie pulsée et la spectrométrie à infrarouge, respectivement. Un niveau profond d’anesthésie a été confirmé lorsque la laryngoscopie et le mouvement du tube endotrachéal n’ont pu provoquer de réponse neurocirculatoire. Les sujets ont été soumis ensuite à une brève exposition au desflurane à 11 % dans le gaz inspiré.Résultats: Les réactions au desflurane comprennent des augmentations significatives de la FC, 32–84 b/min, et de la TA, 15–72 mmHg (P<0,05). L’activité du nerf sympathique a beaucoup augmenté chez les trois participants qui présentaient des enregistrements fonctionnels du nerf.Conclusion: Chez des volontaires sains qui reçoivent 1,5 CAM d’isoflurane, dose suffisante pour empêcher la réponse neurocirculatoire à la laryngoscopie et à la stimulation trachéale, on a noté des hausses importantes de la décharge sympathique, de la FC et de la TA lorsque du desflurane à 11 % a été substitué à l’isoflurane.

The Effectiveness of Oxygen Delivery and Reliability of Carbon Dioxide Waveforms: A Crossover Comparison of 4 Nasal Cannulae

BACKGROUND:Effective O2 delivery and accurate end-tidal CO2 (ETCO2) sampling are essential features of nasal cannulae (NCs) in patients with compromised respiratory status. We studied 4 NC designs: bifurcated nasal prongs (NPs) with O2 delivery and CO2 sensing in both NPs (Hudson), separate O2/CO2 NPs (Salter), and CO2 sensing in NPs with cloud O2 delivery outside the NPs via multi vents (Oridion) and dual vents (Medline). We hypothesized that design differences between NCs would influence O2 delivery and ETCO2 detection. METHODS:Forty-five healthy volunteers, 18 to 35 years, participated in an unrestricted, randomized block design, each subject serving as their own control in a 4-period crossover study design of 4 NCs during one session. Monitoring included electrocardiogram, posterior pharynx O2 sampling from a Hauge Airway (Sharn Anesthesia Products, Tampa, FL), and NC ETCO2. In 11 volunteers, radial artery blood was sampled from a catheter for partial pressures of O2 and carbon dioxide (PaO2 and PaCO2) determination. Per randomization, each NC was positioned, and data were collected over 2 minutes (ETCO2, pharyngeal O2, PaO2, and PaCO2) during room air and during O2 fresh gas flows (FGFs) of 2, 4, and 6 Lpm. Statistical analyses were performed with SAS Analytics Pro, Version 9.3, and JMP Statistical Software, Version 11 (SAS Institute Inc., Cary, NC), significance at P < 0.05. RESULTS:Blood gas analyses indicated PaCO2 during steady state at each experimental time period remained unchanged from physiologic baseline. PaO2 did not differ between NC devices at baseline or 2 Lpm O2. The PaO2 at 4 Lpm from the separate NPs and bifurcated NCs was significantly higher than the multi-vented NC. Pharyngeal O2 with the NC with separate NPs was significantly higher than multivented and dual-vented cloud delivery NCs at 2, 4, and 6 Lpm FGF. Pharyngeal O2 with the NC with bifurcated NPs was significantly higher than the multi-vented NC at 2 Lpm, and higher than cloud delivery NCs at 4 and 6 Lpm FGF. ETCO2 was significantly lower with the NC with bifurcated NPs compared to the other 3 NCs, consistent with errant CO2 tracings at higher FGF. CONCLUSIONS:NCs provide supplemental inspired O2 concentrations for patients with impaired pulmonary function. Accurate measures of ETCO2 are helpful in assessing respiratory rate and determining whether CO2 retention is occurring from hypoventilation. These findings suggest the NC with separate NPs was the most effective in delivering O2 and the most consistent at providing reliable CO2 waveforms at higher FGFs.

Clinical Application Of ECG R-wave Triggered, Ensemble Averaged Impedance Waveforms

A new, computerized impedance cardiograph (the CIC1000, SORBA Medical Systems, Inc., Milwaukee, WI), which employs ECG R-wave triggered, ensemble-averaging algorithms, was evaluated. The CIC-lo00 and the conventional Kubicek impedance cardiograph were compared and found to provide similar values of stroke volume. In addition, new patch electrodes were tested at various sites and compared to the traditional circumferential band electrodes. The positioning of these electrodes proved to be critical in comparative studies with circumferential band electrodes. The optimal patch electrode array was applied to cardiac patients and compared with thermodilution measurements of cardiac output. The CIC-lo00 cardiac output values were in good agreement (r=0.81) with the thermodilution cardiac output values. Thus the CIC-lo00 may have potential as a clinical monitoring instrument.

Impedance cardiography and circulatory response to stress

The authors have used impedance cardiography as a monitor in many investigations. In one study, cardiac output measurements indicated that cardiopulmonary reflexes were critical in human adjustment to the upright posture. However, a sudden increase in transthoracic Z/sub 0/ during prolonged head-up tilt was found to be an immediate prelude to fainting, suggesting that a rapid shift in blood volume triggered the fainting reaction. In other experiments, the authors developed ensemble-averaging methods which permit online monitoring of blood pressure, cardiac output and thoracic blood volume in postoperative patients. They believe impedance cardiography to be a valuable tool for clinical monitoring of circulatory events.<<ETX>>

Baroreceptor Reflex Control of Heart Rate During Isoflurane Anesthesia in Humans

The effect of isoflurane alone (Group 1) and isoflurane following thiopental (Groups 2 and 3) on baroreflex control of heart rate in humans was investigated in this study. Phenylephrine (the pressor test) and sodium nitroprusside (the depressor test) were used to induce moderate changes in arterial blood pressure and to alter the stimulation of baroreceptor sites. In addition, graded neck suction was employed to examine carotid baroreflex control of heart rate. In Group 3 subjects, phenylephrine was infused continuously during anesthesia to maintain mean arterial blood pressure near control levels. The pressor- and neck-suction-derived baroreflex slopes were decreased progressively from awake to 1.0 and 1.5 MAC isoflurane. The slopes of the depressor responses were decreased at 1.0 MAC but showed little further depression at 1.5 MAC. For each method, the depression of baroreceptor slopes from control to 1.0 MAC and 1.5 MAC was similar among the three groups. Maintenance of arterial blood pressure (Group 3) and the utilization of thiopental (Group 2) did not significantly alter the depression of baroreflex responses during increasing levels of isoflurane anesthesia. Neck suction derived slopes compared favorably with the pressor test slopes (r = 0.75, P < 0.001). This study indicates that the depression of arterial baroreflex heart rate responses under isoflurane anesthesia are less pronounced than the depression of baroreflex responses noted by other investigators for halothane or enflurane. The neck suction technique appears to be a sensitive method useful in assessing the carotid sinus reflex in awake and anesthetized humans.

Moderate, Short-Term, Local Hyperglycemia Attenuates Forearm Endothelium-Dependent Vasodilation After Transient Ischemia-Reperfusion in Human Volunteers

OBJECTIVE Acute hyperglycemia causes endothelial dysfunction in diabetic patients, abolishes ischemic pre- and postconditioning, and is an independent predictor of adverse outcome after myocardial infarction in nondiabetic patients. Its effects on endothelial-dependent vasodilation are controversial in healthy subjects. The authors studied the effect of moderate short-term local hyperglycemia on forearm endothelium-dependent vasodilation in healthy volunteers. DESIGN Randomized, crossover, blinded, 2-visit, pilot design. SETTING Veterans Affairs Medical Center. PARTICIPANTS Five male and 3 female healthy adult volunteers (23±4 years; height 171±13 cm; weight 66±9 kg; [mean±standard error of the mean]). INTERVENTIONS At each visit, volunteers received an infusion through a brachial artery catheter of either 0.9% saline or dextrose in the experimental, non-dominant arm, to establish mild forearm hyperglycemia. Hemodynamics and forearm blood flow (FBF; plethysmography) were measured at baseline, during brachial artery infusions of acetylcholine in consecutive increments (5, 10, and 15 μg/min), before ischemia (20 min, blood pressure cuff at 200 mmHg), and after 15 minutes of reperfusion. Blood glucose and insulin concentrations were determined from venous samples. The effect of duration of intra-arterial dextrose on FBF was examined. MEASUREMENTS AND MAIN RESULTS Dextrose increased steady-state blood glucose concentration in the experimental but not the control arm (dominant arm). Dextrose increased FBF compared with saline (4.5±0.5 v 2.6±0.4 mL/min/100 g of tissue, respectively). Acetylcholine caused similar increases in FBF in the absence and presence of dextrose (+239±90% v+203±75%, respectively, during 15 μg/min). The duration of dextrose did not affect this acetylcholine-induced vasodilation. Acetylcholine-stimulated increases in FBF were attenuated in dextrose-treated versus saline after reperfusion (+180±18% v+257±53%, respectively, during 10 μg/min). Interventions in the experimental arm did not affect FBF in the control arm. CONCLUSION These results indicated that moderate, short-term, local hyperglycemia induced by intra-arterial administration of dextrose attenuated forearm endothelial-dependent vasodilation after ischemia-reperfusion injury in healthy volunteers.

EFFECT OF AGE AND CORONARY HEART DISEASE ON AUTONOMIC RESPONSES TO CIRCULATORY STRESS

Publisher Summary There is a growing interest in the role of the autonomic nervous system in circulatory pathophysiology. Studies have shown that the degree of the impairment of certain circulatory reflexes is directly related to the degree of cardiac dysfunction suggesting that autonomic stress testing is clinically useful. Previous studies have indicated that age is also an important determinant of autonomic response; it becomes important, therefore, to separate the changes because of aging from those due to cardiac disease. The chapter provides an overview of autonomic alterations because of aging and coronary heart disease (CHD). There is evidence that to a significant degree, the alterations in autonomic response of stable CHD patients to preload stress are because of the effects of normal aging.