Meperidine Decreases the Shivering Threshold Twice as Much as the Vasoconstriction Threshold

Background: Meperidine administration is a more effective treatment for shivering than equianalgesic doses of other opioids. However, it remains unknown whether meperidine also profoundly impairs other thermoregulatory responses, such as sweating or vasoconstriction. Proportional inhibition of vasoconstriction and shivering suggests that the drug acts much like alfentanil and anesthetics but possesses greater thermoregulatory than analgesic potency. In contrast, disproportionate inhibition would imply a special antishivering mechanism. Accordingly, the authors tested the hypothesis that meperidine administration produces a far greater concentration-dependent reduction in the shivering than vasoconstriction threshold.

Methods: Nine volunteers were each studied on three days: 1) control (no opioid); 2) a target total plasma meperidine concentration of 0.6 micro gram/ml (40 mg/h); and 3) a target concentration of 1.8 micro gram/ml (120 mg/h). Each day, skin and core temperatures were increased to provoke sweating and then subsequently reduced to elicit vasoconstriction and shivering. Core-temperature thresholds (at a designated skin temperature of 34 degrees Celsius) were computed using established linear cutaneous contributions to control sweating (10%) and vasoconstriction and shivering (20%). The dose-dependent effects of unbound meperidine on thermoregulatory response thresholds was then determined using linear regression. Results are presented as means +/- SDs.

Results: The unbound meperidine fraction was [nearly equal] 35%. Meperidine administration slightly increased the sweating threshold (0.5 +/- 0.8 degrees Celsius [center dot] micro gram sup -1 [center dot] ml; r2 = 0.51 +/- 0.37) and markedly decreased the vasoconstriction threshold (-3.3 +/- 1.5 degrees Celsius [center dot] micro gram sup -1 [center dot] ml; r sup 2 = 0.92 +/- 0.08). However, meperidine reduced the shivering threshold nearly twice as much as the vasoconstriction threshold (-6.1 +/- 3.0 degrees Celsius [center dot] micro gram sup -1 [center dot] ml; r2 = 0.97 +/- 0.05; P = 0.001).     

Selective Pulmonary Vasodilation by Intravenous Infusion of an Ultrashort Half-life Nucleophile/Nitric Oxide Adduct

Background: PROLI/NO (C5 H7 N3 O4 Na2 [center dot] CH3 OH) is an ultrashort-acting nucleophile/NO adduct that generates NO (half-life 2 s at 37 [degree sign] Celsius and pH 7.4). Because of its short half-life, the authors hypothesized that intravenous administration of this compound would selectively dilate the pulmonary vasculature but cause little or no systemic hypotension.

Methods: In eight awake healthy sheep with pulmonary hypertension induced by 9,11-dideoxy-9 alpha,11 alpha-methanoepoxy prostaglandin F sub 2 alpha, the authors compared PROLI/NO with two reference drugs-inhaled NO, a well-studied selective pulmonary vasodilator, and intravenous sodium nitroprusside (SNP), a nonselective vasodilator. Sheep inhaled 10, 20, 40, and 80 parts per million NO or received intravenous infusions of 0.25, 0.5, 1, 2, and 4 micro gram [center dot] kg sup -1 [center dot] min sup -1 of SNP or 0.75, 1.5, 3, 6, and 12 micro gram [center dot] kg sup -1 [center dot] min sup -1 of PROLI/NO. The order of administration of the vasoactive drugs (NO, SNP, PROLI/NO) and their doses were randomized.

Results: Inhaled NO selectively dilated the pulmonary vasculature. Intravenous SNP induced nonselective vasodilation of the systemic and pulmonary circulation. Intravenous PROLI/NO selectively vasodilated the pulmonary circulation at doses up to 6 micro gram [center dot] kg sup -1 [center dot] min sup -1, which decreased pulmonary vascular resistance by 63% (P < 0.01) from pulmonary hypertensive baseline values without changing systemic vascular resistance. At 12 micro gram [center dot] kg sup -1 [center dot] min sup -1, PROLI/NO decreased systemic and pulmonary vascular resistance and pressure. Exhaled NO concentrations were higher during PROLI/NO infusion than during SNP infusion (P < 0.01 with all data pooled).     

Comparison of Remifentanil and Fentanyl in Patients Undergoing Craniotomy for Supratentorial Space-occupying Lesions

Background: Remifentanil hydrochloride is an ultra-short-acting, esterase-metabolized micro-opioid receptor agonist. This study compared the use of remifentanil or fentanyl during elective supratentorial craniotomy for space-occupying lesions.

Methods: Sixty-three adults gave written informed consent for this prospective, randomized, double-blind, multiple-center trial. Anesthesia was induced with thiopental, pancuronium, nitrous oxide/oxygen, and fentanyl (n = 32; 2 micro gram [center dot] kg [center dot] sup -1 min sup -1) or remifentanil (n = 31; 1 micro [center dot] kg sup -1 [center dot] min sup -1). After tracheal intubation, infusion rates were reduced to 0.03 micro gram [center dot] kg sup -1 [center dot] min sup -1 (fentanyl) or 0.2 micro gram [center dot] kg sup -1 [center dot] min sup -1 (remifentanil) and then adjusted to maintain anesthesia and stable hemodynamics. Isoflurane was given only after specified infusion rate increases had occurred. At the time of the first burr hole, intracranial pressure was measured in a subset of patients. At bone flap replacement either saline (fentanyl group) or remifentanil ([nearly equal] 0.2 micro gram [center dot] kg sup -1 [center dot] min sup -1) were infused until dressing completion. Hemodynamics and time to recovery were monitored for 60 min. Analgesic requirements and nausea and vomiting were observed for 24 h. Neurological examinations were performed before operation and on postoperative days 1 and 7.

Results: Induction hemodynamics were similar. Systolic blood pressure was greater in the patients receiving fentanyl after tracheal intubation (fentanyl = 127 +/- 18 mmHg; remifentanil = 113 +/- 18 mmHg; P = 0.004). Intracranial pressure (fentanyl = 14 +/- 13 mmHg; remifentanil = 13 +/- 10 mmHg) and cerebral perfusion pressure (fentanyl = 76 +/- 19 mmHg; remifentanil = 78 +/- 14 mmHg) were similar. Isoflurane use was greater in the patients who received fentanyl. Median time to tracheal extubation was similar (fentanyl = 4 min: range = -1 to 40 min; remifentanil = 5 min: range = 1 to 15 min). Seven patients receiving fentanyl and none receiving remifentanil required naloxone. Postoperative systolic blood pressure was greater (fentanyl = 134 +/- 16 mmHg; remifentanil = 147 +/- 15 mmHg; P = 0.001) and analgesics were required earlier in patients receiving remifentanil. Incidences of nausea and vomiting were similar.     

Epidural Anesthesia Reduces the Gain and Maximum Intensity of Shivering

Background: Shivering can be characterized by its threshold (triggering core temperature), gain (incremental intensity increase), and maximum intensity. The gain of shivering might be preserved during epidural or spinal anesthesia if control mechanisms compensate for lower-body paralysis by augmenting the activity of upper-body muscles. Conversely, gain will be reduced approximately by half if the thermoregulatory system fails to compensate. Similarly, appropriate regulatory feedback might maintain maximum shivering intensity during regional anesthesia. Accordingly, the gain and maximum intensity of shivering during epidural anesthesia were determined.

Methods: Seven volunteers participated on two randomly ordered study days. On one day (control), no anesthesia was administered; on the other, epidural anesthesia was maintained at a T8 sensory level. Shivering, at a mean skin temperature near 33 [degree sign] Celsius, was provoked by central-venous infusion of cold fluid; core cooling continued until shivering intensity no longer increased. Shivering was evaluated by systemic oxygen consumption and electromyography of two upper-body and two lower-body muscles. The core temperature triggering an increase in oxygen consumption identified the shivering threshold. The slopes of the oxygen consumption versus core temperature and electromyographic intensity versus core temperature regressions identified systemic and regional shivering gains, respectively.

Results: The shivering threshold was reduced by epidural anesthesia by [nearly =] 0.4 [degree sign] Celsius, from 36.7 +/- 0.6 to 36.3 +/- 0.5 [degree sign] Celsius (means +/- SD; P < 0.05). Systemic gain, as determined by oxygen consumption, was reduced from -581 +/- 186 to -215 +/- 154 ml [center dot] min sup -1 [center dot] [degree sign] Celsius sup -1 (P < 0.01). Lower-body gain, as determined electromyographically, was essentially obliterated by paralysis during epidural anesthesia, decreasing from -0.73 +/- 0.85 to -0.04 +/- 0.06 intensity units/[degree sign] Celsius (P < 0.01). However, upper-body gain had no compensatory increase: -1.3 +/- 1.1 units/[degree sign] Celsius control versus -2.0 +/- 2.1 units/[degree sign] Celsius epidural. Maximum oxygen consumption was decreased by one third during epidural anesthesia: 607 +/- 82 versus 412 +/- 50 ml/min (P < 0.05).     

Local Cerebral Blood Flow, Local Cerebral Glucose Utilization, and Flow-Metabolism Coupling during Sevoflurane versus Isoflurane Anesthesia in Rats

Background: Compared to isoflurane, knowledge of local cerebral glucose utilization (LCGU) and local cerebral blood flow (LCBF) during sevoflurane anesthesia is limited.

Methods: LCGU, LCBF, and their overall means were measured in Sprague-Dawley rats (8 groups, n = 6 each) during sevoflurane and isoflurane anesthesia, 1 and 2 MAC, and in conscious control animals (2 groups, n = 6 each) using the autoradiographic 2-[(14) C]deoxy-D-glucose and 4-iodo-N-methyl-[(14) C]antipyrine methods.

Results: During anesthesia, mean cerebral glucose utilization was decreased: control, 56 +/- 5 [micro sign]mol [middle dot] 100 g-1 [middle dot]-1; 1 MAC isoflurane, 32 +/- 4 [micro sign]mol [middle dot] 100 g-1 [middle dot] min-1 (-43%); 1 MAC sevoflurane, 37 +/- 5 [micro sign]mol [middle dot] 100 g-1 [middle dot] min-1 (-34%); 2 MAC isoflurane, 23 +/- 3 [micro sign]mol [middle dot] 100 g-1 [middle dot] min-1 (-58%); 2 MAC sevoflurane, 23 +/- 5 [micro sign]mol [middle dot] 100 g-1 [middle dot] min-1 (-59%). Local analysis showed a reduction in LCGU in the majority of the 40 brain regions analyzed. Mean cerebral blood flow was increased as follows: control, 93 +/- 8 ml [middle dot] 100 g-1 [middle dot] min-1; 1 MAC isoflurane, 119 +/- 19 ml [middle dot] 100 g-1 [middle dot] min-1 (+28%); 1 MAC sevoflurane, 104 +/- 15 ml [middle dot] 100 g-1 [middle dot] min-1 (+12%); 2 MAC isoflurane, 149 +/- 17 ml [middle dot] 100 g-1 [middle dot] min-1 (+60%); 2 MAC sevoflurane, 118 +/- 21 ml [middle dot] 100 g-1 [middle dot] min-1 (+27%). LCBF was increased in most brain structures investigated. Correlation coefficients obtained for the relationship between LCGU and LCBF were as follows: control, 0.93; 1 MAC isoflurane, 0.89; 2 MAC isoflurane, 0.71; 1 MAC sevoflurane, 0.83; 2 MAC sevoflurane, 0.59).     

Sex-related Differences in the Influence of Morphine on Ventilatory Control in Humans

Background: Opiate agonists have different analgesic effects in male and female patients. The authors describe the influence of sex on the respiratory pharmacology of the micro-receptor agonist morphine.

Methods: The study was placebo-controlled, double-blind, and randomized. Steady-state ventilatory responses to carbon dioxide and responses to a step into hypoxia (duration, 3 min; oxygen saturation, [approximately] 82%; end-tidal carbon dioxide tension, 45 mmHg) were obtained before and during intravenous morphine or placebo administration (bolus dose of 100 micro gram/kg, followed by a continuous infusion of 30 micro gram [center dot] kg sup -1 [center dot] h sup -1) in 12 men and 12 women.

Results: In women, morphine reduced the slope of the ventilatory response to carbon dioxide from 1.8 +/- 0.9 to 1.3 +/- 0.7 l [center dot] min sup -1 [center dot] mmHg sup -1 (mean +/- SD; P < 0.05), whereas in men there was no significant effect (control = 2.0 +/- 0.4 vs. morphine = 1.8 +/- 0.4 l [center dot] min sup -1 [center dot] mmHg sup -1). Morphine had no effect on the apneic threshold in women (control = 33.8 +/- 3.8 vs. morphine = 35.3 +/- 5.3 mmHg), but caused an increase in men from 34.5 +/- 2.3 to 38.3 +/- 3 mmHg, P < 0.05). Morphine decreased hypoxic sensitivity in women from 1.0 +/- 0.5 l [center dot] min sup -1 [center dot] % sup -1 to 0.5 +/- 0.4 l [center dot] min sup -1 [center dot] % sup -1 (P < 0.05) but did not cause a decrease in men (control = 1.0 +/- 0.5 l [center dot] min sup -1 [center dot] % sup -1 vs. morphine = 0.9 +/- 0.5 l [center dot] min sup -1 [center dot] % sup -1). Weight, lean body mass, body surface area, and calculated fat mass differed between the sexes, but their inclusion in the analysis as a covariate revealed no influence on the differences between men and women in morphine-induced changes.     

Remifentanil versus Remifentanil/midazolam for Ambulatory Surgery during Monitored Anesthesia Care

Background: This study was designed to define the appropriate dose of remifentanil hydrochloride alone or combined with midazolam to provide satisfactory comfort and maintain adequate respiration for a monitored anesthesia care setting.

Methods: One hundred fifty-nine patients scheduled for outpatient surgery participated in this multicenter, double-blind study. Patients were randomly assigned to one of two groups: remifentanil, 1 micro gram/kg, given over 30 s followed by a continuous infusion of 0.1 micro gram [center dot] kg sup -1 [center dot] min sup -1 (remifentanil); remifentanil, 0.5 micro gram/kg, given over 30 s followed by a continuous infusion of 0.05 micro gram [center dot] kg sup -1 [center dot] min sup -1 (remifentanil + midazolam). Five minutes after the start of the infusion, patients received a loading dose of saline placebo (remifentanil) or midazolam, 1 mg, (remifentanil + midazolam). If patients were not oversedated, a second dose of placebo or midazolam, 1 mg, was given. Remifentanil was titrated (in increments of 50% from the initial rate) to limit patient discomfort or pain intraoperatively, and the infusion was terminated at the completion of skin closure.

Results: At the time of the local anesthetic, most patients in the remifentanil and remifentanil + midazolam groups experienced no pain (66% and 60%, respectively) and no discomfort (66% and 65%, respectively). The final mean (+/- SD) remifentanil infusion rates were 0.12 +/- 0.05 micro gram [center dot] kg sup -1 [center dot] min sup -1 (remifentanil) and 0.07 +/- 0.03 micro gram [center dot] kg sup -1 [center dot] min sup -1 (remifentanil + midazolam). Fewer patients in the remifentanil + midazolam group experienced nausea compared with the remifentanil group (16% vs. 36%, respectively; P < 0.05). Four patients (5%) in the remifentanil group and two patients (2%) in the remifentanil + midazolam group experienced brief periods of oxygen desaturation (SpO2 < 90%) and hypoventilation (< 8 breaths/min).     

Effects of Temperature on Cerebral Tissue Oxygen Tension, Carbon Dioxide Tension, and pH during Transient Global Ischemia in Rabbits

Background: A decrease in brain temperature (Tbrain) causes a decrease in the cerebral metabolic rate for oxygen (CMRO2) and provides potent neuroprotection against ischemic damage. In the present study, the effects of mild to moderate hypothermia on cerebral tissue oxygen tension (PO2 brain), carbon dioxide tension (PCO2 brain), and pH (pHbrain) were monitored during short episodes of global cerebral ischemia.

Methods: After approval by the Animal Care and Use Committee, 10 New Zealand white rabbits were anesthetized (1% halothane in air) and mechanical ventilation was adjusted to maintain the arterial carbon dioxide tension at 35 mmHg (alpha-stat). A sensor to measure PO2 brain, PCO2 brain, pHbrain, and Tbrain was inserted into the brain through a burr hole in the skull. Tbrain was adjusted to 38 [degree sign] Celsius, 34.4 [degree sign] Celsius, and 29.4 [degree sign] Celsius in a random sequence in each animal. PO2 brain, PCO sub 2 brain, and pHbrain (all variables are reported at the actual Tbrain) were recorded every 10 s during a 5-min baseline, 3 min of cerebral ischemia induced by inflation of a neck tourniquet, and 10 min of reperfusion at each level of Tbrain. Analysis of variance and Dunnett's test were used for statistical analysis. Data are presented as means +/- SD.

Results: During ischemia, PO2 brain decreased from 56 +/- 3 to 33 +/- 2 mmHg at 38 [degree sign] Celsius, from 58 +/- 3 to 32 +/- 3 mmHg at 34.4 [degree sign] Celsius, and from 51 +/- 2 to 32 +/- 2 mmHg at 29.4 [degree sign] C (p = NS). PCO2 brain increased by 6.7 +/- 2 mmHg at 38 [degree sign] Celsius, by 5.1 +/- 1.4 mmHg at 34.4 [degree sign] Celsius, and by 2.3 +/- 0.8 mmHg at 29.4 [degree sign] Celsius. pH sub brain inversely followed the trend of PCO2 brain.     

Rapid Rewarming Causes an Increase in the Cerebral Metabolic Rate for Oxygen that Is Temporarily Unmatched by Cerebral Blood Flow: A Study during Cardiopulmonary Bypass in Rabbits

Background: Jugular venous hemoglobin desaturation during the rewarming phase of cardiopulmonary bypass is associated with adverse neuropsychologic outcome and may indicate a pathologic mismatch between cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2). In some studies, rapid rewarming from hypothermic cardiopulmonary bypass results in greater jugular venous hemoglobin desaturation. The authors wished to determine if rewarming rate influences the temperature dependence of CBF and CMRO2.

Methods: Anesthetized New Zealand white rabbits, cooled to 25 degrees Celsius on cardiopulmonary bypass, were randomized to one of two rewarming groups. In the fast group (n = 9), aortic blood temperature was made normothermic over 25 min. Cerebral blood flow (microspheres) and CMRO2 (Fick) were determined at baseline (25 degrees C), and at brain temperatures of 28 degrees, 31 degrees, 34 degrees, and 37 degrees Celsius during rewarming.

Results: Systemic physiologic variables appeared similar between groups. At a brain temperature of 28 degrees C, CMRO2 was 47% greater in the fast rewarming group than in the slow group (2.2 +/-0.5 vs. 1.5+/-0.2 ml O2 *symbol* 100 g sup -1 *symbol* min sup -1, respectively; P = 0.01), whereas CBF did not differ (48+/-18 vs. 49+/-8 ml *symbol* 100 g sup -1 *symbol* min sup -1, respectively; P = 0.47). Throughout rewarming, CBF increased as a function of brain temperature but was indistinguishable between groups. Cerebral metabolic rate for oxygen differences between groups decreased as brain temperatures increased.     

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.     

Interactions between Hypothermia and the Latency to Ischemic Depolarization: Implications for Neuroprotection

Background: The authors postulated that hypothermic neuroprotection can be attributed to a delayed onset of ischemic depolarization.

Methods: Halothane-anesthetized rats were prepared for near-complete forebrain ischemia. Direct current (DC) potential microelectrodes were placed in hippocampal CA1. The pericranial temperature was maintained at 31 [degree sign] Celsius, 33 [degree sign] Celsius, 35 [degree sign] Celsius, or 37 [degree sign]C (n = 6 per group). Bilateral carotid occlusion with systemic hypotension was initiated for 10 min. The time to onset of the DC shift was recorded. In a second experiment, rats were assigned to 37 [degree sign]C or 31 [degree sign]C for 10 min of ischemia, or to 31 [degree sign]C for 14 min of ischemia (n = 8 per group). These durations of ischemia were defined to allow 9 min of ischemic depolarization in the 37 [degree sign] Celsius-10 min and 31 [degree sign] Celsius-14 min groups. Neurologic and histologic outcomes were examined 7 days later.

Results: Hippocampal CA1 time to depolarization increased with decreasing temperature (P < 0.0001). Time to depolarization was increased by approximately 4 min in the rats maintained at 31 [degree sign]C compared with those at 37 [degree sign] Celsius. Time to repolarization during reperfusion was not affected by temperature. Increasing the duration of ischemia from 10 min to 14 min with the pericranial temperature maintained at 31 [degree sign]C resulted in a duration of depolarization that was equivalent in the 37 [degree sign] Celsius-10 min and 31 [degree sign] Celsius-14 min groups. However, hippocampal CA1 damage was not increased (31 [degree sign] Celsius-10 min = 4 +/- 1% dead neurons; 31 [degree sign] Celsius-14 min = 6 +/- 1% dead neurons, 95% CI, -1% to 3%; 37 [degree sign] Celsius-10 min = 90 +/- 17% dead neurons).     

Isoflurane Alters Shivering Patterns and Reduces Maximum Shivering Intensity

Background: Shivering can be characterized by its threshold (triggering core temperature), gain (incremental intensity increase with further core hypothermia), and maximum response intensity. Isoflurane produces a clonic muscular activity that is not a component of normal shivering. To the extent that clonic activity is superimposed on normal thermoregulatory shivering, the gain of shivering might be increased during isoflurane anesthesia. Conversely, volatile anesthetics decrease systemic oxygen consumption and peripherally inhibit skeletal muscle strength, which might limit maximum intensity despite central activation. The purpose of the present study was, therefore, to evaluate the effect of isoflurane shivering patterns and the gain and maximum intensity of shivering.

Methods: Ten volunteers were each studied in two separate protocols: (1) control (no drug) and (2) 0.7% end-tidal isoflurane. On each day, the mean skin temperature was maintained at 31 [degree sign] Celsius. Core temperature was then reduced by infusion of cold fluid until shivering intensity no longer increased. The core temperature triggering the initial increase in oxygen consumption defined the shivering threshold. The gain of shivering was defined by the slope of the core temperature versus oxygen consumption regression. Pectoralis and quadriceps electromyography was used to evaluate anesthetic-induced facilitation of clonic (5-7 Hz) muscular activity.

Results: Isoflurane significantly decreased the shivering threshold from 36.4 +/- 0.3 to 34.2 +/- 0.8 [degree sign] Celsius. The increase in oxygen consumption was linear on the control day and was followed by sustained high-intensity activity. During isoflurane administration, shivering was characterized by bursts of intense shivering separated by quiescent periods. Isoflurane significantly increased the gain of shivering (as calculated from the initial increase), from -684 +/- 266 to -1483 +/- 752 ml [center dot] min sup -1 [center dot] [degree sign] Celsius sup -1. However, isoflurane significantly decreased the maximum intensity of shivering, from 706 +/- 144 to 489 +/- 80 ml/min. Relative electromyographic power in frequencies associated with clonus increased significantly when the volunteers were given isoflurane.     

The Effect of Clonidine on Cerebral Blood Flow Velocity, Carbon Dioxide Cerebral Vasoreactivity, and Response to Increased Arterial Pressure in Human Volunteers

Background: Because patients may be taking clonidine chronically or may be receiving it as a premedication before surgery, the authors investigated its effect on cerebral hemodynamics.

Methods: In nine volunteers, middle cerebral artery mean blood flow velocity (Vm) was measured using transcranial Doppler ultrasonography (TCD). CO2 vasoreactivity was measured before clonidine administration (preclonidine), 90 min after clonidine, 5 micro gram/kg yorally, then following restoration of mean arterial pressure (MAP) to the preclonidine level. In addition, Vm was measured after a phenylephrine-induced 30-mmHg increase in MAP.

Results: After clonidine administration, Vm decreased from 62 +/- 9 to 48 +/- 8 cm/s (P < 0.01), and MAP decreased from 86 +/- 10 to 63 +/- 5 mmHg (P < 0.01; mean +/- SD). Clonidine decreased the CO2 vasoreactivity slope from 2.2 +/- 0.4 to 1.2 +/- 0.5 cm [center dot] s sup -1 [center dot] mmHg sup -1 (P < 0.05); restoring MAP to the preclonidine level increased the slope to 1.60 +/- 0.5 cm [center dot] s sup -1 [center dot] mmHg [center dot] sup -1, still less than the preclonidine slope (P < 0.05). CO2 vasoreactivity expressed as a percentage change in Vm, decreased after clonidine, 3.5 +/- 0.8 versus 2.4 +/- 0.8%/mmHg (P < 0.05); this difference disappeared after restoration of MAP, 3.1 +/- 1.2%/mmHg. With a 30-mmHg increase in MAP, Vm increased by 13% before and after clonidine (P < 0.05).     

Pulsatile Versus Nonpulsatile Flow: No Difference in Cerebral Blood Flow or Metabolism during Normothermic Cardiopulmonary Bypass in Rabbits

Background: Although pulsatile and nonpulsatile cardiopulmonary bypass (CPB) do not differentially affect cerebral blood flow (CBF) or metabolism during hypothermia, studies suggest pulsatile CPB may result in greater CBF than nonpulsatile CPB under normothermic conditions. Consequently, nonpulsatile flow may contribute to poorer neurologic outcome observed in some studies of normothermic CPB. This study compared CBF and cerebral metabolic rate for oxygen (CMRO2) between pulsatile and nonpulsatile CPB at 37 degrees Celsius.

Methods: In experiment A, 16 anesthetized New Zealand white rabbits were randomized to one of two pulsatile CPB groups based on pump systolic ejection period (100 and 140 ms, respectively). Each animal was perfused at 37 degrees Celsius for 30 min at each of two pulse rates (150 and 250 pulse/min, respectively). This scheme created four different arterial pressure waveforms. At the end of each perfusion period, arterial pressure waveform, arterial and cerebral venous oxygen content, CBF (microspheres), and CMRO2 (Fick) were measured. In experiment B, 22 rabbits were randomized to pulsatile (100-ms ejection period, 250 pulse/min) or nonpulsatile CPB at 37 degrees Celsius. At 30 and 60 min of CPB, physiologic measurements were made as before.

Results: In experiment A, CBF and CMRO2 were independent of ejection period and pulse rate. Thus, all four waveforms were physiologically equivalent. In experiment B, CBF did not differ between pulsatile and nonpulsatile CPB (72 plus/minus 6 vs. 77 plus/minus 9 ml *symbol* 100 g sup -1 *symbol* min1, respectively (median plus/minus quartile deviation)). CMRO2 did not differ between pulsatile and nonpulsatile CPB (4.7 plus/minus 0.5 vs. 4.1 plus/minus 0.6 ml Oxygen2 *symbol* 100 g sup -1 *symbol* min1, respectively) and decreased slightly (0.4 plus/minus 0.4 ml Oxygen2 *symbol* 100 g sup -1 *symbol* min1) between measurements.     

Efficacy of Intraoperative Cooling Methods

Background: Patients may require perioperative cooling for a variety of reasons including treatment of a malignant hyperthermia crisis and induction of therapeutic hypothermia for neurosurgery. The authors compared heat transfer and core cooling rates with five cooling methods.

Methods: Six healthy volunteers were anesthetized with desflurane and nitrous oxide. The cooling methods were 1) circulating water (5 [degree sign] Celsius, full-length mattress and cover), 2) forced air (10 [degree sign] Celsius, full-length cover), 3) gastric lavage (500 ml iced water every 10 min), 4) bladder lavage (300 ml iced Ringer's solution every 10 min), and 5) ice-water immersion. Each method was applied for 40 min or until the volunteers' core temperatures approached 34 [degree sign] Celsius. The volunteers were rewarmed to normothermia between treatments. Core cooling rates were evaluated using linear regression.

Results: The first volunteer developed abdominal cramping and diarrhea after gastric lavage. Consequently, the technique was not again attempted. Bladder lavage increased heat loss 10 [nearly =] 10 W and decreased core temperature 0.8 +/- 0.3 [degree sign] Celsius/h (r2 = 0.99 +/- 0.002; means +/- SD). Forced-air and circulating-water cooling comparably increased heat flux, [nearly =] 170 W. Consequently, core cooling rates were similar during the two treatments at 1.7 +/- 0.5 [degree sign] Celsius/h (r2 = 0.99 +/- 0.001) and 1.6 +/- 1.1 [degree sign] Celsius/h (r2 = 0.98 +/- 0.02), respectively. Immersion in an ice water slurry increased heat loss [nearly =] 600-800 W and decreased core temperature 9.7 +/- 4.4 [degree sign] Celsius/h (r sup 2 = 0.98 +/- 0.01). Immersion cooling was associated with an afterdrop of [nearly =] 2 [degree sign] Celsius.     

Influence of Acidosis on Cardiotonic Effects of Milrinone

Background: The present study was designed to determine whether augmentation of cardiac performance by milrinone is affected by acidosis in in vivo canine and in vitro guinea pig preparations, and to elucidate a mechanism in relation to the cyclic adenosine monophosphate (cAMP) formation.

Methods: Halothane-anesthetized, ventilated dogs were randomly assigned to a control group (arterial pH [pHa] [nearly =] 7.4, base excess [BE] > -2 mM; n = 7), mild acidosis group (pHa [nearly =] 7.2, BE < -9 mM; n = 7), or severe acidosis group (pHa < 7, BE < -20 mM; n = 6). Arterial blood pressure, left ventricular pressure (including maximum rate of increase, LV dP/dtmax), and pulmonary blood flow (PBF) were measured. Acidosis was induced by transient hypoxia and maintained with hydrogen chloride infusion. Hemodynamic responses to milrinone infusions at 2 and 5 micro gram [center dot] kg sup -1 [center dot] min were then studied. In addition, left atria and right ventricular strips were dissected from guinea pig hearts and suspended in HEPES-Tyrode solution, with pH values adjusted to 7.4, 7, or 6.6. The concentration-response relation of isometric contractions for milrinone (10 sup -7 to 10 sup -4 M) and 8-bromo-cAP (10 sup -4 to 10 sup -3 M) were determined.

Results: In the control group of dogs, significant increases in LN dP/dtmax (2,674 +/- 822 to 3,999 +/- 1,016 mmHg/s [means +/- SD]) and PBF (2.04 +/- 0.98 to 2.44 +/- 0.96 l/min [means +/- SD]) were seen with a milrinone infusion of 5 micro gram [center dot] kg sup -1 [center dot] min sup -1. In the mild acidosis group, 5 micro gram [center dot] kg sup -1 min sup -1 milrinone also increased LV dP/dtmax and PBF. However, neither LV dP/dtmax nor PBF changed in the severe acidosis group. In in vitro experiments, milrinone exerted a positive inotropic effect in a concentration-dependent manner on the right ventricular preparations at pH 7.4, but not at pH 7 and 6.6, whereas no significant difference was observed in inotropic responses to 8-bromo-cAMP at pH values of 6.6, 7, and 7.4 on the right ventricular strips. In the right ventricular in vitro preparation, 10 sup -4 M milrinone was accompanied by a significant increase in intracellular cAMP content at a pH of 7.4 but not 7.     

Pharmacokinetics Anesthesiologists, and Pharmacodynamics of Remifentanil in Persons with Renal Failure Compared with Healthy Volunteers

Background: Remifentanil is an opioid analgesic for use in anesthesia. An ester linkage renders it susceptible to rapid metabolism by blood and tissue esterases. Thus it was hypothesized that remifentanil elimination would be independent of renal function. Because its principal metabolite (GR90291) is eliminated renally, it would depend on renal function. This study was designed to evaluate the pharmacokinetics and pharmacodynamics of remifentanil and its metabolite in persons with and without renal failure.

Methods: Two groups of volunteers received two-stage infusions of remifentanil: low dose with 0.0125 micro gram [center dot] kg sup -1 [center dot] min sup -1 for 1 h followed by 0.025 micro gram kg sup -1 [center dot] min sup -1 for 3 h; and high dose with 0.025 micro gram [center dot] kg sup -1 [center dot] min sup -1 for 1 h followed by 0.05 micro gram [center dot] kg sup -1 [center dot] min sup -1 for 3 h. Blood samples were collected for analysis of remifentanil and GR90291 concentrations. The pharmacokinetics of remifentanil were fit using a one-compartment pharmacokinetic model. Remifentanil's effect was determined intermittently using minute ventilation during a hypercapnic (7.5% CO2) challenge.

Results: Fifteen patients with renal failure and eight control participants were enrolled. The clearance and volume of distribution of remifentanil were not different between those with renal failure and the controls. Patients with renal failure showed a marked reduction in the elimination of GR90291; the half-life of the metabolite increased from 1.5 h in the controls to more than 26 h in patients with renal failure. The steady-state concentration of GR90291 is likely to be more than 25 times higher in persons with renal failure. There were no obvious differences in opioid effects on minute ventilation in the controls and in patients with renal failure.     

pH-Stat Management Reduces the Cerebral Metabolic Rate for Oxygen during Profound Hypothermia (17 degrees Celsius): A Study during Cardiopulmonary Bypass in Rabbits

Background: Greater cerebral metabolic suppression may increase the brain's tolerance to ischemia. Previous studies examining the magnitude of metabolic suppression afforded by profound hypothermia suggest that the greater arterial carbon dioxide tension of pH-stat management may increase metabolic suppression when compared with alpha-stat management.

Methods: New Zealand White rabbits, anesthetized with fentanyl and diazepam, were maintained during cardiopulmonary bypass (CPB) at a brain temperature of 17 degrees Celsius with alpha-stat (group A, n = 9) or pH-stat (group B, n = 9) management. Measurements of brain temperature, systemic hemodynamics, arterial and cerebral venous blood gases and oxygen content, cerebral blood flow (CBF) (radiolabeled microspheres), and cerebral metabolic rate for oxygen (CMRO2) (Fick) were made in each animal at 65 and 95 min of CPB. To control for arterial pressure and CBF differences between techniques, additional rabbits underwent CPB at 17 degrees Celsius. In group C (alpha-stat, n = 8), arterial pressure was decreased with nitroglycerin to values observed with pH-stat management. In group D (pH-stat, n = 8), arterial pressure was increased with angiotensin II to values observed with alpha-stat management. In groups C and D, CBF and CMRO2 were determined before (65 min of CPB) and after (95 min of CPB) arterial pressure manipulation.

Results: In groups A (alpha-stat) and B (pH-stat), arterial pressure; hemispheric CBF (44 plus/minus 17 vs. 21 plus/minus 4 ml *symbol* 100 g sup -1 *symbol* min sup -1 [median plus/minus quartile deviation]; P = 0.017); and CMRO2 (0.54 plus/minus 0.13 vs. 0.32 plus/minus 0.10 ml Oxygen2 *symbol* 100 g sup -1 *symbol* min sup -1; P = 0.0015) were greater in alpha-stat than in pH-stat animals, respectively. As a result of arterial pressure manipulation, in groups C (alpha-stat) and D (pH-stat) neither arterial pressure (75 plus/minus 2 vs. 78 plus/minus 2 mm Hg) nor hemispheric CBF (40 plus/minus 10 vs. 48 plus/minus 6 ml *symbol* 100 g sup -1 *symbol* min sup -1; P = 0.21) differed between alpha-stat and pH-stat management, respectively. Nevertheless, CMRO2 was greater in alpha-stat than in pH-stat animals (0.71 plus/minus 0.10 vs. 0.45 plus/minus 0.10 ml Oxygen2 *symbol* 100 g sup -1 *symbol* min sup -1, respectively; P = 0.002).     

Experimental Subarachnoid Hemorrhage in Rats: Effect of Intravenous alpha-alpha Diaspirin Crosslinked Hemoglobin on Hypoperfusion and Neuronal Death

Background: Hemodilution with diaspirin crosslinked hemoglobin (DCLHb) ameliorates occlusive cerebral ischemia. However, subarachnoid hemoglobin has been implicated as a cause of cerebral hypoperfusion. The effect of intravenous DCLHb on cerebral perfusion and neuronal death after experimental subarachnoid hemorrhage was evaluated.

Methods: Rats (n = 48) were anesthetized with isoflurane and subarachnoid hemorrhage was induced by injecting 0.3 ml of autologous blood into the cistema magna. Each animal received one of the following regimens: Control, no hematocrit manipulation; DCLHb, hematocrit concentration decreased to 30% with DCLHb; or Alb, hematocrit concentration decreased to 30% with human serum albumin. The experiments had two parts, A and B. In part A, after 20 min, cerebral blood flow (CBF) was assessed with14 C-iodoantipyrine autoradiography. In part B, after 96 h, in separate animals, the number of dead neurons was determined in predetermined coronal sections by hematoxylin and eosin staining.

Results: Cerebral blood flow was greater for the DCLHb group than for the control group; and CBF was greater for the Alb group than the other two groups (P < 0.05). In one section, CBF was 45.5 +/- 10.9 ml [center dot] 100 g sup -1 [center dot] min sup -1 (mean +/- SD) for the control group, 95.3 +/- 16.6 ml [center dot] 100 g sup -1 [center dot] min sup -1 for the DCLHb group, and 138.1 +/- 18.7 ml [center dot] 100 g sup -1 [center dot] min sup -1 for the Alb group. The number of dead neurons was less in the Alb group (611 +/- 84) than in the control group (1,097 +/- 211), and was less in the DCLHb group (305 +/- 38) than in the other two groups (P < 0.05).     

Spinal Anesthesia Speeds Active Postoperative Rewarming

Background: Redistribution of body heat decreases core temperature more during general than regional anesthesia. However, the combination of anesthetic- and sedative-induced inhibition may prevent effective upper-body thermoregulatory responses even during regional anesthesia. The extent to which each type of anesthesia promotes hypothermia thus remains controversial. Accordingly, the authors evaluated intraoperative core hypothermia in patients assigned to receive spinal or general anesthesia. They also tested the hypothesis that the efficacy of active postoperative warming is augmented when spinal anesthesia maintains vasodilation.

Methods: Patients undergoing lower abdominal and leg surgery were randomly assigned to receive general anesthesia (isoflurane and nitrous oxide; n = 20) or spinal anesthesia (bupivacaine; n = 20). Fluids were warmed to 37 [degree sign] Celsius and patients were covered with surgical drapes. However, no other active warming was applied during operation. Ambient temperatures were maintained near 20 [degree sign] Celsius. After operation, patients were warmed with a full-length, forced-air cover set to 43 [degree sign] Celsius. Shivering, when observed, was treated with intravenous meperidine.

Results: The mean spinal analgesia level, which was at the sixth thoracic level during surgery, remained at the T12 dermatome after 90 min after operation. Core temperatures did not differ significantly during surgery and decreased to 34.4 +/- 0.5 [degree sign] Celsius and 34.1 +/- 0.4 [degree sign] Celsius, respectively, in patients given spinal and general anesthesia. After operation, however, core temperatures increased significantly faster (1.2 +/- 0.1 [degree sign] Celsius/h vs. 0.7 +/- 0.2 [degree sign] Celsius/h, mean +/- SD; P <0.001) in patients given spinal anesthesia. Consequently, patients given spinal anesthesia required less time to rewarm to 36.5 [degree sign] Celsius (122 +/- 28 min vs. 199 +/- 28 min; P < 0.001).