Toni D. Uhrich

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.

The efficacy of dexmedetomidine versus morphine for postoperative analgesia after major inpatient surgery.

Thirty-four patients scheduled for elective inpatient surgery were randomized equally to receive either dexmedetomidine (initial loading dose of 1-&mgr;g/kg over 10 min followed by 0.4 &mgr;g · kg−1 · h−1 for 4 h) or morphine sulfate (0.08 mg/kg) 30 min before the end of surgery. We determined heart rate (HR), mean arterial blood pressure (MAP), respiratory rate (RR), sedation and analgesia (visual analog scale), and use of additional morphine in the postanesthesia care unit (PACU) and up to 24 h after surgery. Groups were similar for patient demographics, ASA physical status, surgical procedure, baseline hemodynamics, and intraoperative use of drugs and fluids. Dexmedetomidine-treated patients had slower HR in the PACU (by an average of 16 bpm), whereas MAP, RR, and level of sedation were similar between groups. During Phase I recovery, dexmedetomidine-treated patients required significantly less morphine to achieve equivalent analgesia (PACU dexmedetomidine group, 4.5 ± 6.8 mg; morphine group, 9.2 ± 5.2 mg). Sixty minutes into recovery only 6 of 17 dexmedetomidine patients required morphine in contrast to 15 of 17 in the morphine group. The administration of dexmedetomidine before the completion of major inpatient surgical procedures significantly reduced, by 66%, the early postoperative need for morphine and was associated with a slower HR in the PACU.

Absence of bronchodilation during desflurane anesthesia: a comparison to sevoflurane and thiopental.

Background Bronchospasm is a potential complication in anyone undergoing general anesthesia. Because volatile anesthetics relax bronchial smooth muscle, the effects of two newer volatile anesthetics, desflurane and sevoflurane, on respiratory resistance were evaluated. The authors hypothesized that desflurane would have greater bronchodilating effects because of its ability to increase sympathetic nervous system activity. Methods Informed consent was obtained from patients undergoing elective surgery with general anesthesia. We recorded airway flow and pressure after thiopental induction and tracheal intubation (baseline) and for 10 min after beginning volatile anesthesia (∼ 1 minimum alveolar concentration inspired). Respiratory system resistance was determined using the isovolume technique. Results Fifty subjects were randomized to receive sevoflurane (n = 20), desflurane (n = 20), or thiopental infusion (n = 10, 0.25 mg · kg−1 · h−1). There were no differences between groups for age, height, weight, smoking history, and American Society of Anesthesiologists physical class. On average, sevoflurane reduced respiratory resistance 15% below baseline, whereas both desflurane (+5%) and thiopental (+10%) did not decrease respiratory resistance. The respiratory resistance changes did not differ in patients with and without a history of smoking during sevoflurane or thiopental. In contrast, administration of desflurane to smokers resulted in the greatest increase in respiratory resistance. Conclusions Sevoflurane causes moderate bronchodilation that is not observed with desflurane or sodium thiopental. The bronchoconstriction produced by desflurane was primarily noted in patients who currently smoked.

Recovery from sevoflurane anesthesia: a comparison to isoflurane and propofol anesthesia.

Backgroud Sevoflurane has a lower blood:gas partition coefficient than isoflurane, which may cause a more rapid recovery from anesthesia; it also might cause faster emergence times than for propofol‐based anesthesia. We evaluated a database that included recovery endpoints from controlled, randomized, prospective studies sponsored by Abbott Laboratories that compared sevoflurane to isoflurane or propofol when extubation was planned immediately after completion of elective surgery in adult patients. Methods Sevoflurane was compared to isoflurane in eight studies (N = 2,008) and to propofol in three studies (N = 436). Analysis of variance was applied using least squares method mean values to calculate the pooled mean difference in recovery endpoints between primary anesthetics. The effects of patient age and case duration also were determined. Results Sevoflurane resulted in statistically significant shorter times to emergence (‐3.3 min), response to command (‐3.1 min), orientation (‐4.0 min) and first analgesic (‐8.9 min) but not time to eligibility for discharge (‐1.7 min) compared to isoflurane (mean difference). Times to recovery endpoints increased with increasing case duration with isoflurane but not with sevoflurane (patients receiving isoflurane took 4‐5 min more to emerge and respond to commands and 8.6 min more to achieve orientation during cases longer than 3 hr in duration than those receiving sevoflurane). Patients older than 65 yr had longer times to orientation, but within any age group, orientation was always faster after sevoflurane. There were no differences in recovery times between sevoflurane and propofol. Conclusions Recovery from sevoflurane was 3‐4 min faster than with isoflurane in all age groups, and the difference was magnified in longer‐duration surgical cases (> 3 hr).

A review of recovery from sevoflurane anaesthesia: comparisons with isoflurane and propofol including meta-analysis.

Background: Sevoflurane has a lower blood:gas partition coefficient than isoflurane and thus should be associated with a more rapid recovery from anaesthesia.

Absence of renal and hepatic toxicity after four hours of 1.25 minimum alveolar anesthetic concentration sevoflurane anesthesia in volunteers.

Sevoflurane is degraded by CO2 absorbents to Compound A.The delivery of sevoflurane with a low fresh gas flow increases the generation of Compound A. The administration of Compound A to rats can produce injury to renal tubules that is dependent on both the dose and duration of exposure to Compound A. The present study evaluated renal and hepatic function in eight volunteers after a 1-L/min delivery of 3% (1.25 minimum alveolar anesthetic concentration) sevoflurane for 4 h. Volunteers gave their informed consent and provided 24-h urine collections before and for 3 days after sevoflurane anesthesia. Urine samples were analyzed for glucose, protein, albumin, and alpha- and pi-glutathione-S-transferase. Daily blood samples were analyzed for markers of renal and liver injury or dysfunction. Circuit Compound A and plasma fluoride concentrations were determined. During anesthesia, the average maximal inspired Compound A concentration was 39 +/- 6 (mean +/- SD). The median mean arterial pressure, esophageal temperature, and end-tidal CO2 were 62 +/- 6 mm Hg, 36.5 +/- 0.3[degree sign]C, and 30.5 +/- 0.5 mm Hg, respectively. Two hours after anesthesia, the plasma fluoride concentration was 50 +/- 9 [micro sign]mol/L. All markers of hepatic and renal function were unchanged after anesthesia (repeated-measures analysis of variance P > 0.05). Low-flow sevoflurane was not associated with renal or hepatic injury in humans based on unchanged biochemical markers of renal and liver function. Implications: Sevoflurane delivered in a 3% concentration with a fresh gas flow of 1 L/min for 4 h generated an average maximal Compound A concentration of 39 ppm but did not result in any significant increase in sensitive markers of renal function or injury, including urinary protein, albumin, glucose, and alpha- and pi-glutathione-S-transferase. (Anesth Analg 1998;86:662-7)

Desflurane-mediated Sympathetic Activation Occurs in Humans Despite Preventing Hypotension and Baroreceptor Unloading

Background Increasing concentrations of desflurane result in progressive decreases in blood pressure (BP) and, unlike other currently marketed, potent volatile anesthetics, heightened sympathetic nervous system activity. This study aimed to determine whether baroreflex mechanisms are involved in desflurane‐mediated sympathetic excitation. Methods Healthy volunteers were anesthetized with desflurane (n = 8) or isoflurane (n = 9). Heart rate (HR; measured by electrocardiograph), blood pressure (BP; measured by arterial catheter), and efferent sympathetic nerve activity (SNA; obtained from percutaneous recordings from the peroneal nerve) were monitored. Baroreflex sensitivity was evaluated at baseline while volunteers were conscious and during 0.5, 1, and 1.5 minimum alveolar concentration (MAC) anesthesia via bolus injections of nitroprusside (100 micro gram) and phenylephrine (150 micro gram) to decrease and increase BP. To prevent the BP decline with increasing depths of anesthesia, phenylephrine was infused to maintain mean BP at the 0.5 MAC level. Results The HR, BP, and SNA were similar between the groups at the conscious baseline measurement. Efferent SNA did not change during higher MAC of isoflurane, but it increased progressively as desflurane concentrations were increased beyond 0.5 MAC, despite maintaining BP at the 0.5 MAC value with phenylephrine infusions (P < 0.05). Cardiac baroslopes (based on changes in HR) were progressively and similarly decreased with increasing concentrations of isoflurane and desflurane (P < 0.05). Sympathetic baroslopes (based on SNA) decreased with increasing isoflurane concentrations but were maintained with increasing concentrations of desflurane; the response was significantly different between groups. Conclusions The increase in basal levels of SNA with increasing concentrations of desflurane persisted despite “fixing” BP and thus is probably not due to hypotension and unloading of the baroreceptors. Further, the preservation of reflex increases in SNA to nitroprusside during desflurane indicates that desflurane preserves one component of the baroreflex in humans when BP is “fixed.”

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.