Charles A. Richardson

Postoperative pharmacokinetics and sympatholytic effects of dexmedetomidine.

Dexmedetomidine is a selective alpha2-adrenoceptor agonist with centrally mediated sympatholytic, sedative, and analgesic effects. This study evaluated: 1) pharmacokinetics of dexmedetomidine in plasma and cerebrospinal fluid (CSF) in surgical patients; 2) precision of a computer-controlled infusion protocol (CCIP) for dexmedetomidine during the immediate postoperative period; and 3) dexmedetomidines sympatholytic effects during that period. Dexmedetomidine was infused postoperatively by CCIP for 60 min to eight women, targeting a plasma concentration (Cp) of 600 pg/mL. Before, during, and after infusion, blood was sampled to determine plasma concentrations of norepinephrine, epinephrine, and dexmedetomidine, and CSF was sampled to determine dexmedetomidine concentrations (CCSF). Heart rate and arterial blood pressure were measured continuously from 5 min before until 3 h after the end of infusion. During the infusion, Cp values generally exceeded the target value: median percent error averaged 21% and ranged from -2% to 74%; median absolute percent error averaged 23% and ranged from 4% to 74%. After infusion, CCSF was 4% +/- 1% of Cp. Because CCSF barely exceeded the assays limit of quantitation, CSF pharmacokinetics were not determined. During the infusion, norepinephrine decreased from 2.1 +/- 0.8 to 0.7 +/- 0.3 nmol/L; epinephrine decreased from 0.7 +/- 0.5 to 0.2 +/- 0.2 nmol/L; heart rate decreased from 76 +/- 15 to 64 +/- 11 bpm; and systolic blood pressure decreased from 158 +/- 23 to 140 +/- 23 mm Hg. We conclude that infusion of dexmedetomidine by CCIP using published pharmacokinetic parameters overshoots target dexmedetomidine concentrations during the early postoperative period. Hemodynamic and catecholamine results suggest that dexmedetomidine attenuates sympathetic activity during the immediate postoperative period. Implications: We studied the pharmacokinetic and sympatholytic effects of dexmedetomidine during the immediate post-operative period and found that during this period, the published pharmacokinetic data slightly overshoot target plasma dexmedetomidine concentrations. We also found that heart rate, blood pressure, and plasma catecholamine concentrations decrease during dexmedetomidine infusion. (Anesth Analg 1997;85:1136-42)

Dexmedetomidine Does Not Alter the Sweating Threshold, But Comparably and Linearly Decreases the Vasoconstriction and Shivering Thresholds

Background: Clonidine decreases the vasoconstriction and shivering thresholds. It thus seems likely that the alpha2 agonist dexmedetomidine will also impair control of body temperature. Accordingly, the authors evaluated the dose‐dependent effects of dexmedetomidine on the sweating, vasoconstriction, and shivering thresholds. They also measured the effects of dexmedetomidine on heart rate, blood pressures, and plasma catecholamine concentrations. Methods: Nine male volunteers participated in this randomized, double‐blind, cross‐over protocol. The study drug was administered by computer‐controlled infusion, targeting plasma dexmedetomidine concentrations of 0.0, 0.3, and 0.6 ng/ml. Each day, skin and core temperatures were increased to provoke sweating and then subsequently reduced to elicit vasoconstriction and shivering. Core‐temperature thresholds were computed using established linear cutaneous contributions to control of sweating, vasoconstriction, and shivering. The dose‐dependent effects of dexmedetomidine on thermoregulatory response thresholds were then determined using linear regression. Heart rate, arterial blood pressures, and plasma catecholamine concentrations were determined at baseline and at each threshold. Results: Neither dexmedetomidine concentration increased the sweating threshold from control values. In contrast, dexmedetomidine administration reduced the vasoconstriction threshold by 1.61 +/‐ 0.80 [degree sign] Celsius [center dot] ng sup ‐1 [center dot] ml (mean +/‐ SD) and the shivering threshold by 2.40 +/‐ 0.90 [degree sign] Celsius [center dot] ng sup ‐1 [center dot] ml. Hemodynamic responses and catecholamine concentrations were reduced from baseline values, but they did not differ at the two tested dexmedetomidine doses. Conclusions: Dexmedetomidine markedly increased the range of temperatures not triggering thermoregulatory defenses. The drug is thus likely to promote hypothermia in a typical hospital environment; it is also likely to prove an effective treatment for shivering.

Power spectral analysis of inspiratory nerve activity in the decerebrate cat

To investigate the high frequency oscillations observed in the inspiratory activity of respiratory motor nerves of decerebrate cats, we applied a signal processing technique, power spectral analysis, to the electrical activity of the phrenic and recurrent laryngeal nerves. We found two peaks in the phrenic nerve power spectral densities, one at 88.1 +/- 6.4 Hz (mean +/- S.D.) and the other at 37.1 +/- 9.7 Hz, and two peaks for the recurrent laryngeal nerve, at 87.4 +/- 10.1 Hz and at 55.4 +/- 5.1 Hz. We identified 3 factors affecting the peaks. Anesthetics reduced or eliminated the 88 Hz peak and produced new low frequency peaks in the phrenic and recurrent laryngeal nerves. Increasing end-tidal CO2 decreased the bandwidth of the 88 Hz peak and increased its amplitude relative to that of the low frequency peak. Decreasing body temperature from 38 to 30 degrees C reduced the frequency of the 88 Hz peak by 5.0 Hz/degrees C. The power spectral density of the phrenic nerve activity differed from that of the recurrent laryngeal nerve activity because the single fibers in each nerve had different power spectral densities. About 70% of the fibers recorded in a nerve had power spectral densities similar to that of the whole nerve. A minority of the phrenic nerve fibers had the same low spectral peak as the recurrent laryngeal nerve, and conversely, a minority of the recurrent laryngeal fibers had the same low spectral peak as the phrenic nerve. Bilateral removal of the dorsal respiratory group eliminated the high frequency peak in the power spectral density of the phrenic nerve and the peripheral reflexes, but rhythmic bursts of inspiratory activity remained. From these findings we hypothesized that there are two central respiratory pattern generators in the brain stem with parallel pathways to the respiratory motoneurons.

Autonomic nervous system responses during sedative infusions of dexmedetomidine

BACKGROUND The purpose of this study was to determine the effects of dexmedetomidine on systemic and cardiac autonomic reflex responses during rest and during thermal stress. METHODS Volunteers received either placebo or low- or high-dose dexmedetomidine (target plasma concentrations 0.3 or 0.6 ng/ml, respectively) infusions in a prospectively randomized, double-blinded crossover study design. After 1 h, baroreflex sensitivity was assessed, and then core body temperature was raised to the sweating threshold and then lowered to the shivering threshold. Plasma catecholamines and blood pressure were measured, and cardiac autonomic responses were assessed by analysis of heart rate variability. RESULTS Compared with placebo, plasma norepinephrine concentrations, blood pressure, heart rate, and some heart rate variability measures were lower after 1-h infusion of dexmedetomidine, but baroreflex responses did not differ significantly. Dexmedetomidine blunted the systemic and cardiac sympathetic effects of sweating observed during placebo infusion but had no effect on parasympathetic measures. Increases in blood pressure, and systemic catecholamines due to shivering were observed during placebo and dexmedetomidine, but these responses were less with dexmedetomidine. During shivering, dexmedetomidine infusion was associated with higher low-frequency and high-frequency heart rate variability power but lower heart rate compared with the sweating threshold and with the control period, suggesting nonreciprocal cardiac autonomic responses. CONCLUSIONS Infusion of dexmedetomidine results in compensated reductions in systemic sympathetic tone without changes in baroreflex sensitivity. Dexmedetomidine blunts heart rate and the systemic sympathetic activation due to sweating, but it is less effective in blunting cardiac sympathetic responses to shivering. During dexmedetomidine infusion, cardiac sympathetic and parasympathetic tone may have nonreciprocal changes during shivering.

The Effects of Dexmedetomidine on Neuromuscular Blockade in Human Volunteers

UNLABELLED The neuromuscular effects of dexmedetomidine in humans are unknown. We evaluated the effect of dexmedetomidine on neuromuscular block and hemodynamics during propofol/alfentanil anesthesia. During propofol/alfentanil anesthesia, the rocuronium infusion rate was adjusted in 10 volunteers to maintain a stable first response (T1) in the train-of-four sequence at 50% +/- 3% of the pre-rocuronium value. Dexmedetomidine was then administered by computer-controlled infusion, targeting a plasma dexmedetomidine concentration of 0.6 ng/mL for 45 min. The evoked mechanical responses of the adductor pollicis responses (T1 response and T4/T1 ratio), systolic blood pressure (SBP), heart rate (HR), and transmitted light through a fingertip were measured during the dexmedetomidine infusion and compared with predexmedetomidine values using repeated-measures analysis of variance and Dunnetts test. Plasma dexmedetomidine levels ranged from 0.68 to 1.24 ng/mL. T1 values decreased during the infusion, from 51% +/- 2% to 44% +/- 9% (P < 0.0001). T4/T1 values did not change during the infusion. Plasma rocuronium concentrations increased during the infusion (P = 0.02). Dexmedetomidine increased SBP (P < 0.001) and decreased HR (P < 0.001) (5-min median values) during the infusion compared with values before the infusion. Dexmedetomidine increased the transmitted light through the fingertip by up to 41% +/- 8% during the dexmedetomidine infusion (P < 0.001).We demonstrated that dexmedetomidine (0.98 +/- 0.01 microg/kg) increased the plasma rocuronium concentration, decreased T1, increased SBP, and decreased finger blood flow during propofol/alfentanil anesthesia. We conclude that dexmedetomidine-induced vasoconstriction may alter the pharmacokinetics of rocuronium. IMPLICATIONS We studied the effect of an alpha2-agonist (dexmedetomidine) on rocuronium-induced neuromuscular block during propofol/alfentanil anesthesia. We found that the rocuronium concentration increased and the T1 response decreased during the dexmedetomidine administration. Although these effects were statistically significant, it is unlikely that they are of clinical significance.

Effect of Dexmedetomidine on Lumbar Cerebrospinal Fluid Pressure in Humans

Dexmedetomidines potential for analgesia without respiratory depression and its opioid-and anesthetic-sparing properties make it an attractive choice as an anesthetic adjunct for patients undergoing neurosurgery. However, the effects of dexmedetomidine on intracranial pressure are not known. We therefore studied the effect of dexmedetomidine on lumbar cerebrospinal fluid (CSF) pressure in patients after transphenoidal pituitary tumor surgery. Sixteen transphenoidal pituitary tumor surgery patients were randomized to receive placebo (n = 9) or dexmedetomidine (n = 7) for 60 min in the postanesthesia care unit. The study drug was administered by a continuous computer-controlled infusion to achieve an estimated plasma dexmedetomidine concentration of 600 pg/mL, the highest plasma concentration that has been used for clinical purposes. Patient-controlled analgesia was used to administer morphine for postoperative discomfort. Lumbar CSF pressure (via lumbar intrathecal catheter), intraarterial blood pressure, and heart rate were monitored continuously. There was no change in lumbar CSF pressure in either group. The highest values obtained were 19 mm Hg in the dexmedetomidine group and 20 mm Hg in the placebo group. During infusion, mean arterial pressure decreased from 103 +/- 10 mm Hg to 86 +/- 6 mm Hg (P < 0.05), heart rate decreased from 77 +/- 12 bpm to 64 +/- 7 bpm (P < 0.05), and cerebral perfusion pressure decreased from 95 +/- 8 mm Hg to 78 +/- 6 mm Hg (P < 0.05) in the dexmedetomidine group, but not in the placebo group. We conclude that dexmedetomidine does not have an effect on lumbar CSF pressure in patients with normal intracranial pressure who have undergone transphenoidal pituitary hypophysectomy. Implications: The effects of dexmedetomidine (an alpha2-agonist) or placebo on lumbar cerebrospinal fluid pressure, measured via an intrathecal catheter, were studied postoperatively in 16 patients. Dexmedetomidine had no effect on lumbar cerebrospinal fluid pressure. We will continue to investigate the potential utility of dexmedetomidine for neurosurgical anesthesia. (Anesth Analg 1997;85:358-64)

The Effect of α2 Agonist-Induced Sedation and Its Reversal with an α2 Antagonist on Organ Blood Flow in Sheep

We investigated changes in cardiac output and organ blood flow induced by medetomidine in sheep and determined changes in cardiac output and organ blood flow after reversal of medetomidine-induced sedation by atipamezole. Eight sheep were chronically instrumented. Medetomidine was infused IV to target plasma levels of 0, 0.8, 1.6, 3.2, 6.4, and 12.8 ng/mL for 25 min each, followed by a 5-min infusion of atipamezole. Hemodynamic values and organ blood flow (using colored microspheres) were measured just before medetomidine infusion (baseline), at the end of each medetomidine infusion step, and 30 min after the administration of atipamezole. Medetomidine (12.8 ng/mL) decreased cardiac output from 6.3 ± 1.0 to 3.2 ± 0.7 L/min (P < 0.0001) and increased systemic vascular resistance from 1310 ± 207 to 3467 ± 1299 dynes · s−1 · cm−5 (P < 0.0001). Blood flow decreased in the cerebral cortex from 1.29 ± 0.40 to 0.66 ± 0.12 mL · g−1 · min−1 (P < 0.0001), left ventricle from 2.11 ± 0.61 to 1.40 ± 0.40 mL · g−1 · min−1 (P < 0.0001), kidney from 8.28 ± 3.17 to 6.07 ± 2.65 mL · g−1 · min−1 (P < 0.0001), skin from 0.09 ± 0.04 to 0.05 ± 0.02 mL · g−1 · min−1 (P < 0.0001), intestine from 0.56 ± 0.13 to 0.27 ± 0.07 mL · g−1 · min−1 (P < 0.0001), and skeletal muscle from 0.28 ± 0.15 to 0.04 ± 0.01 mL · g−1 · min−1 (P < 0.0001). Blood flow in the liver (hepatic artery) increased from 0.05 ± 0.03 to 0.24 ± 0.16 mL · g−1 · min−1 (P < 0.0001). After atipamezole infusion, cardiac output and systemic vascular resistance returned to baseline, but the cerebral cortex, left ventricle, and renal blood flows remained below baseline at 0.89 ± 0.22, 1.37 ± 0.50, and 6.25 ± 2.76 mL · g−1 · min−1, respectively; skeletal muscle blood flow increased above baseline to 0.44 ± 0.27 mL · g−1 · min−1, spleen blood flow decreased below baseline to 1.65 ± 0.61 mL · g−1 · min−1 (P < 0.0001), and liver, intestine, and lung blood flows returned to baseline values. In conclusion, medetomidine decreased and redistributed organ blood flow in sheep. Atipamezole reversed the medetomidine-induced hemodynamic changes, but redistributed blood flow from the brain, heart, and kidney to the skeletal muscle. Implications The &agr;2 agonist, medetomidine, decreased and redistributed organ blood flow in sheep. Although the highly selective &agr;2 antagonist, atipamezole, reversed medetomidine-induced hemodynamic changes, blood flow to the heart and kidney rmeoaned significantly depressed, whereas skeletal muscle blood flow increased to twice baseline values.

A Comparison of Three Anesthetic Techniques in Patients Undergoing Craniotomy for Supratentorial Intracranial Surgery

Several anesthetic techniques have been used successfully to provide anesthesia for resection of intracranial supratentorial mass lesions. One technique used to enhance recovery involves changing anesthesia from vapor-based to propofol-based for cranial closure. However, there are no data to support a beneficial effect of this approach in the immediate postoperative period after craniotomy. We evaluated 3 anesthetic techniques in 60 patients undergoing elective surgery for supratentorial mass lesions. Patients were randomly assigned to three anesthesia study groups: propofol infusion, isoflurane inhalation, and these two techniques combined. In the combination group, once the dura was closed, isoflurane was discontinued and propofol infusion simultaneously started. We studied intra- and postoperative hemodynamics and several recovery variables for 2 h after the end of anesthesia. Baseline and average intraoperative blood pressure and heart rate values did not differ among the groups. Heart rate and blood pressure increased similarly in all groups in response to intubation and pin placement and postoperatively. None of the recovery event times (open eyes, extubation, follow commands, oriented, Aldrete score) or psychomotor test performance differed significantly. We conclude that the sequential administration of isoflurane and propofol did not provide earlier recovery and cognition than the intraoperative use of isoflurane alone.

Desflurane and Isoflurane Increase Lumbar Cerebrospinal Fluid Pressure in Normocapnic Patients Undergoing Transsphenoidal Hypophysectomy

Background Rapid emergence from anesthesia makes desflurane an attractive choice as an anesthetic for patients having neurosurgery. However, the data on the effect of desflurane on intracranial pressure in humans are still limited and inconclusive. The authors hypothesized that isoflurane and desflurane increase intracranial pressure compared with propofol. Methods Anesthesia was induced with intravenous fentanyl and propofol in 30 patients having transsphenoidal hypophysectomy with no evidence of mass effect, and it was maintained with 70% nitrous oxide in oxygen and a continuous 100 micro gram [centered dot] kg sup -1 [centered dot] min sup -1 infusion of propofol. Patients were assigned to three groups randomized to receive only continued propofol infusion (n = 10), desflurane (n = 10), or isoflurane (n = 10) for 20 min. During the 20-min study period, each patient in the desflurane and isoflurane groups received, in random order, two concentrations (0.5 minimum alveolar concentration [MAC] and 1.0 MAC end-tidal) of desflurane or isoflurane for 10 min each. Lumbar cerebrospinal fluid (CSF) pressure, blood pressure, heart rate, and anesthetic concentrations were monitored continuously. Results Lumbar CSF pressure increased significantly in all patients receiving desflurane or isoflurane. Lumbar CSF pressure increased by 5 +/- 3 mmHg at 1-MAC concentrations of desflurane and by 4 +/- 2 mmHg at 1-MAC concentrations of isoflurane. Cerebral perfusion pressure decreased by 12 +/- 10 mmHg at 1-MAC concentrations of desflurane and by 15 +/- 10 mmHg at 1-MAC concentrations of isoflurane. Heart rate increased by 7 +/- 9 bpm with 0.5 MAC desflurane and by 8 +/- 7 bpm with 1.0 MAC desflurane, and by 5 +/- 11 bpm with 1.0 MAC isoflurane. Systolic blood pressure decreased in all but the patients receiving 1.0 MAC desflurane. To maintain blood pressure within predetermined limits, phenylephrine was administered to six of ten patients in the isoflurane group (range, 25 to 600 micro gram), two of ten patients in the desflurane group (range, 200 to 500 micro gram), and in no patients in the propofol group. Lumbar CSF pressure, heart rate, and systolic blood pressure did not change in the propofol group. Conclusion Desflurane and isoflurane, at 0.5 and 1.0 MAC, increase lumbar CSF pressure.

Sevoflurane increases Lumbar cerebrospinal fluid pressure in normocapnic patients undergoing transsphenoidal hypophysectomy

BACKGROUND The data on the effect of sevoflurane on intracranial pressure in humans are still limited and inconclusive. The authors hypothesized that sevoflurane would increase intracranial pressure as compared to propofoL METHODS: In 20 patients with no evidence of mass effect undergoing transsphenoidal hypophysectomy, anesthesia was induced with intravenous fentanyl and propofol and maintained with 70% nitrous oxide in oxygen and a continuous propofol infusion, 100 microg x kg(-1) x min(-1). The authors assigned patients to two groups randomized to receive only continued propofol infusion (n = 10) or sevoflurane (n = 10) for 20 min. During the 20-min study period, each patient in the sevoflurane group received, in random order, two concentrations (0.5 times the minimum alveolar concentration [MAC] and 1.0 MAC end-tidal) of sevoflurane for 10 min each. The authors continuously monitored lumbar cerebrospinal fluid (CSF) pressure, blood pressure, heart rate, and anesthetic concentrations. RESULTS Lumbar CSF pressure increased by 2+/-2 mmHg (mean+/-SD) with both 0.5 MAC and 1 MAC of sevoflurane. Cerebral perfusion pressure decreased by 11+/-5 mmHg with 0.5 MAC and by 15+/-4 mmHg with 1.0 MAC of sevoflurane. Systolic blood pressure decreased with both concentrations of sevoflurane. To maintain blood pressure within predetermined limits (within+/-20% of baseline value), phenylephrine was administered to 5 of 10 patients in the sevoflurane group (range = 50-300 microg) and no patients in the propofol group. Lumbar CSF pressure, cerebral perfusion pressure, and systolic blood pressure did not change in the propofol group. CONCLUSIONS Sevoflurane, at 0.5 and 1.0 MAC, increases lumbar CSF pressure. The changes produced by 1.0 MAC sevoflurane did not differ from those observed in a previous study with 1.0 MAC isoflurane or desflurane.