Malcolm Daniel

Fentanyl, esmolol, and clonidine blunt the transient cardiovascular stimulation induced by desflurane in humans.

Background:A rapid increase In the end-tidal concentration of desflurane to greater than 1 MAC transiently increases heart rate, arterial blood pressure, and circulating epinephrine and vasopressin concentrations. We hypothesized that drugs that block sympathetic activity or decrease sympathetic outflow (an oploid, a β-adrenergic antagonist, and an α2-adrenergic agonist) would blunt these responses. Methods:After induction of anesthesia with intravenous propofol 2 mg/kg in ten healthy male volunteers age 25 ± 1 yr (mean ± standard error), anesthesia was maintained with 4% end-tidal desflurane in oxygen (0.55 MAC) via an endotracheal tube for 32 min. Controlled ventilation provided normocapnia. We then increased the end-tidal desflurane concentration within 1 min to 8% (1.1 MAC) and maintained this concentration for 10 min. On separate days, five of these volunteers were similarly anesthetized except that 5 min before the increase to 8% desflurane, we administered intravenous fentanyl 1.5 µg/kg and on another day 4.5 µg/kg (dose randomly assigned). On 2 separate days, intravenous esmolol 0.75 mg/kg was given to five volunteers 1.5 min before, or clonidine 4.3 µg/kg by mouth to four volunteers 90 min before, the increase from 4% to 8% desflurane. Results:Without pretreatment, the increase to 8% desflurane increased heart rate (from 57 ± 2 to 118 ± 6 beats/ min at peak, mean ± standard error) and mean arterial blood pressure (from 66 ± 2 to 118 ± 5 mmHg). At the time of peak hemodynamic changes (within 1-2 min of the increase in desflurane concentration), plasma epinephrine and norepinephrine concentrations increased (from 22 ± 6 to 339 ± 83 pg/ml and from 205 ± 19 to 283 ± 30 pg/ml, respectively). Fentanyl 1.5 and 4.5 µg/kg attenuated the heart rate increase by 61 ± 14% and 70 ± 7% and the mean arterial blood pressure Increase by 31 ± 16% and 46 ± 11% but did not alter the epinephrine or norepinephrine response at the time of peak cardiovascular changes. Esmolol attenuated the heart rate response but no other response. Clonidine attenuated all responses except that of norepinephrine and also caused postanesthesia sedation. Conclusions:Fentanyl, esmolol, and clonidine blunt the transient cardiovascular response to a rapid increase in desflurane concentration. Fentanyl may be the most clinically useful of these drugs because it blunts the increase in heart rate and blood pressure, has minimal cardiovascular depressant effects, and imposes little postanesthetlc sedation.

Fentanyl augments the blockade of the sympathetic response to incision (MAC-BAR) produced by desflurane and isoflurane: desflurane and isoflurane MAC-BAR without and with fentanyl.

Background Heart rate (HR) or mean arterial blood pressure (MAP) may increase in response to incision despite the absence of a motor response. The authors hypothesized that the MAC‐BAR (minimum alveolar concentration of an anesthetic that blocks adrenergic response to incision) for isoflurane would exceed that for desflurane, and that fentanyl would decrease the MAC‐BAR for each anesthetic in a dose‐dependent manner. Methods Seventy‐one patients were randomly allocated to one of six groups: desflurane or isoflurane without fentanyl or with 1.5 or 3 micro gram/kg fentanyl given intravenously 5 min before surgical incision. Anesthesia was induced with 2 mg/kg propofol given intravenously, and tracheal intubation facilitated with 0.1 mg/kg given intravenously. The first patient in each group received 1 MAC (end‐tidal) of the inhaled anesthetic in 60% nitrous oxide (0.55 MAC), balance oxygen, maintained for at least 10 min before incision. The response was considered positive if the HR or MAP increased 15% or more. If the response was positive, the end‐tidal concentration given to the next patient was 0.3 MAC greater; if the response was negative, the end‐tidal concentration was 0.3 MAC less. The MAC‐BAR level was calculated as the mean of four independent cross‐over responses in each group. Results Desflurane and isoflurane anesthesia with 60% nitrous oxide did not change HR (P > 0.05) and decreased MAP (P < 0.05) before incision. Plasma epinephrine and norepinephrine concentrations after anesthesia and before incision were normal in all groups. The MAC‐BAR level, without fentanyl, did not differ (P > 0.05) between desflurane (1.30 +/‐ 0.34 MAC [mean +/‐ SD]) and isoflurane (1.30 +/‐ 0.18 MAC). Fentanyl given at 1.5 micro gram/kg intravenously equivalently (P > 0.05) reduced the MAC‐BAR for desflurane (to 0.40 +/‐ 0.18 MAC; P <0.05) and isoflurane (to 0.55 +/‐ 0.00 MAC; P < 0.05), but a further increase in fentanyl to 3 micro gram/kg caused no greater decrease in the MAC‐BAR for desflurane (0.48 +/‐ 0.16 MAC) and isoflurane (0.40 +/‐ 0.30 MAC). Conclusions Clinically attainable doses of desflurane and isoflurane, in 60% nitrous oxide (0.55 MAC), block the cardiovascular response to surgical incision at 1.3 MAC. Fentanyl given at 1.5 micro gram/kg decreases the MAC‐BAR for each agent with no further decrease produced by 3 micro gram/kg fentanyl.

Sympathetic nervous system does not mediate reflex pupillary dilation during desflurane anesthesia

Background Pupil size is determined by an interaction between the sympathetic and parasympathetic divisions of the autonomic nervous system. Noxious stimulation dilates the pupil in both unanesthetized and anesthetized humans. In the absence of anesthesia, dilation is primarily mediated by the sympathetic nervous system. In contrast, pupillary dilation in cats given barbiturate or cloralose anesthesia is mediated solely by inhibition of the midbrain parasympathetic nucleus. The mechanism by which noxious stimuli dilate pupils during anesthesia in humans remains unknown. Accordingly, the authors tested the hypothesis that the pupillary dilation in response to noxious stimulation during desflurane anesthesia is primarily a parasympathetic reflex. Methods In six volunteers, the alpha‐1 adrenergic receptors of the iris musculature were blocked by unilateral administration of topical dapiprazole; six other volunteers were given unilateral topical tropicamide to block the muscarinic receptors in the iris. Desflurane anesthesia was subsequently induced in all volunteers. Sympathetic nervous system activation, with reflex dilation of the pupil, was produced by noxious electrical stimulation during 4% and 8% end‐tidal desflurane, and by a rapid 4%‐to‐8% step‐up in the desflurane concentration. Pupil diameter and the change in pupil size induced by a light stimulus (light reflex amplitude) were measured with infrared pupillometry. Results Dapiprazole drops produced a Horners miosis, but pupils were equally small after induction of anesthesia. Pupillary dilation after noxious stimulation and desflurane step‐up was identical in the unblocked and dapiprazole‐blocked pupils. After tropicamide administration, the pupil was dilated and the light reflex was completely inhibited. Noxious stimulation nonetheless produced a slight additional dilation. Conclusions During desflurane anesthesia, pupillary dilation in response to noxious stimulation or desflurane step‐up is not mediated by the sympathetic nervous system (as it is in unanesthetized persons). Although inhibition of the pupillo‐constrictor nucleus may be the cause of this dilation, the mechanism remains unknown.

Repetitive Rapid increases in Desflurane Concentration Blunt Transient Cardiovascular Stimulation in Humans

BackgroundRapid increases in desflurane concentrations above minimum alveolar concentration (MAC) can cause transient (2–4-min) circulatory changes, possibly from stimulation of rapidly-adapting airway receptors. We hypothesized that the initial increase in concentration would produce greater changes than subsequent increases. MethodsAnesthesia was induced with propofol in nine volunteers (25 ± 1 yr old, mean ± SE) and maintained with 4% end-tidal desflurane for 32 min. We increased the desflurane to 8% (1.1 MAC) in 1 min, maintained this concentration for 10 min, and then decreased it to 4% for 32 min. We repeated this process twice. After 1 week, 5 subjects were treated similarly except that the second increase in concentration occurred 10 min and (on a separate occasion) 75 min after the initial increase. Four subjects received the initial increase after 75 rather than 32 min of anesthesia. in four we applied the repeated sequences in a background of 60% nitrous oxide. When a minimal cardiovascular response followed an increase of anesthetic concentration, a 60-s supramaximal 100-Hz tetanic stimulus was applied to an ulnar nerve percutaneously to test for sympathetic responsiveness. ResultsThe initial increase in concentration increased heart rate (HR) from 57 ± 2 to a peak of 119 ± 7 beats/min (P < 0.05); mean arterial blood pressure (MAP) from 66 ± 3 to 119 ± 5 mmHg (P < 0.05); and plasma epinephrine by > 10-fold (P < 0.05). The second and third increases in desflurane concentration increased HR and MAP by less than 20% of the initial increases, regardless of the timing of the later concentration increases. Responses to initial concentration increases after 75 min of anesthesia did not differ from those after 32 min. increases in plasma epinephrine with the second and third increases in desflurane concentration were attenuated. Subjects who did not responded to the second or third increase in desflurane always responded to tetanic electrical stimulation with substantial increases in HR and MAP (P < 0.05). Addition of nitrous oxide did not change results except for a smaller increase in MAP (P < 0.05). Ulnar nerve stimulation increased HR and MAP but not epinephrine or norepinephrine concentrations. ConclusionsAn initial rapid increase in desflurane to 1.1 MAC produces much more stimulation than do subsequent increases, regardless of the presence of nitrous oxide. The decreased response is consistent with the hypothesis that stimulation of rapidly-adapting airway receptors produce the initial response.

Cardiovascular Stimulation Induced by Rapid Increases in Desflurane Concentration in Humans Results from Activation of Tracheopulmonary and Systemic Receptors

Background It was hypothesized that stimulation of rapidly adapting airway receptors produces the transient (2–4 min) circulatory responses to rapid increases in desflurane concentrations greater than 6%. Accordingly, it was reasoned that increasing the concentration of desflurane in one lung, without altering the concentration of desflurane in systemic blood, should cause cardiovascular stimulation, whereas once the airway receptors had adapted to the stimulation, an initial increase in the systemic concentration of desflurane should have little effect.

Fentanyl, clonidine, and repeated increases in desflurane concentration, but not nitrous oxide or esmolol, block the transient mydriasis caused by rapid increases in desflurane concentration

Initial, but not subsequent, inhalation of 8% desflurane produces transient sympathetic stimulation.We hypothesized that initial but not subsequent increases should produce pupil dilation, and that N2 O, fentanyl, and clonidine, but not esmolol, should blunt the response. In 10 volunteers, we maintained anesthesia with 4% end-tidal desflurane in oxygen for 32 min, then increased the concentration to 8% for 10 min. In nine of the volunteers, we twice repeated the increase to 8%, separating each increase by a 32-min period at 4%. On separate days, five volunteers received 4%-8% desflurane in 60% N2 O; five received fentanyl 1.5 micro gram/kg or 4.5 micro gram/kg intravenously 5 min before 4%-8% desflurane; four received clonidine 4.3 micro gram/kg, orally, 90 min before 4% to 8%; and four received esmolol 0.75 mg/kg, intravenously, 1.5 min before 4%-8%. Without other drugs present, 4%-8% desflurane transiently increased pupil diameter to 5.4 +/- 0.5 mm (mean +/- SD), with subsequent 4%-8% increases producing attenuated responses (2.9 +/- 1.5 and 3.2 +/- 1.8 mm). N2 O produced a higher peak (6.2 +/- 0.7 mm). Fentanyl 1.5 micro gram/kg and 4.5 micro gram/kg decreased peak diameter (2.3 +/- 0.9 and 1.6 +/- 0.3 mm), as did clonidine (2.3 +/- 1.7 mm) but not esmolol. We conclude that, concurrent with sympathetic stimulation, an initial rapid increase in desflurane concentration transiently increases pupil diameter, whereas repeated increases produce attenuated responses. N2 O augments, fentanyl and clonidine attenuate, and esmolol does not affect the response. (Anesth Analg 1995;81:372-8)

Propofol Fails to Attenuate the Cardiovascular Response to Rapid Increases in Desflurane Concentration

Background A rapid increase in desflurane concentration to greater than 1 MAC transiently increases heart rate, arterial blood pressure, and circulating catecholamine concentration. Because propofol decreases sympathetic outflow, it was hypothesized that propofol would blunt these responses. Methods To test this hypothesis, five healthy male volunteers were studied three times. After induction of anesthesia with 2 mg *symbol* kg sup ‐1 propofol, anesthesia was maintained with 4% end‐tidal desflurane in oxygen (0.55 MAC) via an endotracheal tube for 32 min. On separate occasions, in random order, either no propofol or 2 mg *symbol* kg sup ‐1 propofol was administered either 2 or 5 min before increasing end‐tidal desflurane concentration from 4% to 8%. Results Without propofol pretreatment, the increase to 8% desflurane transiently increased heart rate (from 63+/‐3 beats/min to 108 +/‐5 beats/min, mean+/‐SEM; P < 0.01), mean arterial pressure (from 73+/‐1 mmHg to 118+/‐6 mmHg; P < 0.01), and epinephrine concentration (from 14+/‐1 pg *symbol* ml sup ‐1 to 279+/‐51 pg *symbol* ml sup ‐1; P < 0.05). There was no significant change in norepinephrine concentration (from 198+/‐37 pg *symbol* ml sup ‐1 to 277+/‐46 pg *symbol* ml sup ‐1). The peak plasma epinephrine concentration was attenuated by each propofol pretreatment (158+/‐35 pg *symbol* ml sup ‐1, propofol given 2 min before, and 146 + 41 pg *symbol* ml sup ‐1, propofol given 5 min before; P < 0.05), but neither propofol pretreatment modified the cardiovascular or norepinephrine responses. Conclusions Although able to blunt the increase in epinephrine concentration, propofol 2 mg *symbol* kg sup ‐1 propofol does not attenuate the transient cardiovascular response to a rapid increase in desflurane concentration to greater than 1 MAC.