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Biomedical subjects

R B Weiskopf

Publications and source records attributed to R B Weiskopf.

At least 37 records · Page 2Linked to original sources
PubMed1997

Nephrotoxicity of sevoflurane versus desflurane anesthesia in volunteers.

Present package labeling for sevoflurane recommends the use of fresh gas flow rates of 2 L/min or more when delivering anesthesia with sevoflurane. This recommendation resulted from a concern about the potential nephrotoxicity of a degradation product of sevoflurane, "Compound A," produced by the action of carbon dioxide absorbents on sevoflurane. To assess the adequacy of this recommendation, we compared the nephrotoxicity of 8 h of 1.25 minimum alveolar anesthetic concentration (MAC) sevoflurane (n = 10) versus desflurane (n = 9) in fluid-restricted (i.e., nothing by mouth overnight) volunteers when the anesthetic was given in a standard circle absorber anesthetic system at 2 L/min. Subjects were tested for markers of renal injury (urinary albumin, glucose, alpha-glutathione-S-transferase [GST], and pi-GST; and serum creatinine and blood urea nitrogen [BUN]) before and 1, 2, 3, and/or 5-7 days after anesthesia. Desflurane did not produce renal injury. Rebreathing of sevoflurane produced average inspired concentrations of Compound A of 41 +/- 3 ppm (mean +/- SD). Sevoflurane was associated with transient injury to: 1) the glomerulus, as revealed by postanesthetic albuminuria; 2) the proximal tubule, as revealed by postanesthetic glucosuria and increased urinary alpha-GST; and 3) the distal tubule, as revealed by postanesthetic increased urinary pi-GST. These effects varied greatly (e.g., on postanesthesia Day 3, the 24-h albumin excretion was < 0.03 g (normal) for one volunteer; 0.03-1 g for five others; 1-2 g for two others; 2.1 g for one volunteer; and 4.4 g for another volunteer). Neither anesthetic affected serum creatinine or BUN, nor changed the ability of the kidney to concentrate urine in response to vasopressin, 5 U/70 kg subcutaneously (i.e., these measures failed to reveal the injury produced). In addition, sevoflurane, but not desflurane, caused small postanesthetic increases in serum alanine aminotransferase (ALT), suggesting mild, transient hepatic injury.

Adult↗
PubMed1997

Baralyme dehydration increases and soda lime dehydration decreases the concentration of compound A resulting from sevoflurane degradation in a standard anesthetic circuit.

UNLABELLED: Soda lime and Baralyme brand carbon dioxide absorbents degrade sevoflurane to CF2 = C(CF3)OCH2F, a potentially nephrotoxic vinyl ether called Compound A. Dehydration of these absorbents increases both the degradation of sevoflurane to Compound A and the degradation of Compound A. The balance between sevoflurane degradation and Compound A degradation determines the concentration of Compound A issuing from the absorbent (the net production of Compound A). We studied the effect of dehydration on the net production of Compound A in a simulated anesthetic circuit. Mimicking continuing oxygen delivery for 1, 2, or 3 days after completion of an anesthetic, we directed a "conditioning" fresh gas flow of 5 L/min or 10 L/min retrograde through fresh absorbent in situ in a standard absorbent system for 16, 40, and/or 64 h. The conditioned absorbent was subsequently used (without mixing of the granules) in a standard anesthetic circuit in which a 3-L rebreathing bag substituted for the lung. Metabolism was mimicked by introducing 250 mL/min carbon dioxide into the "lung," and the lung was ventilated with a minute ventilation of 10 L/ min. At the same time, we introduced sevoflurane in a fresh gas inflow of 2 L/min at a concentration sufficient to produce an inspired concentration of 3.2%. Because of increased sevoflurane destruction by the absorbent, progressively longer periods of conditioning (dehydration) and/or higher inflow rates increased the delivered (vaporizer) concentration of sevoflurane required to sustain a 3.2% concentration. Dehydration of Baralyme increased the inspired concentration of Compound A by up to sevenfold, whereas dehydration of soda lime markedly decreased the inspired concentration of Compound A. IMPLICATIONS: Economical delivery of modern inhaled anesthetics requires rebreathing of exhaled gases after removal of carbon dioxide. However, carbon dioxide absorbents (Baralyme/soda lime) may degrade anesthetics to toxic substances. Baralyme dehydration increases, and soda lime dehydration decreases, degradation of the inhaled anesthetic sevoflurane to the toxic substance, Compound A.

Anesthetics, Inhalation↗
PubMed1997

Dose-related biochemical markers of renal injury after sevoflurane versus desflurane anesthesia in volunteers.

UNLABELLED: Sevoflurane (CH2F-O-CH[CF3]2) reacts with carbon dioxide absorbents to produce Compound A (CH2F-O-C[=CF2][CF3]). Because of concern about the potential nephrotoxicity of Compound A, the United States package label (but not that of several other countries) for sevoflurane recommends the use of fresh gas flow rates of 2 L/min or more. We previously demonstrated in humans that a 2-L/min flow rate delivery of 1.25 minimum alveolar anesthetic concentration (MAC) sevoflurane for 8 h can injure glomeruli (i.e., produce albuminuria) and proximal tubules (i.e., produce glucosuria and urinary excretion of alpha-glutathione-S-transferase [alpha-GST]). The present report extends this investigation to fasting volunteers given 4 h (n = 9) or 2 h (n = 7) of 1.25 MAC sevoflurane versus desflurane at 2 L/min via a standard circle absorber anesthetic system (all subjects given both anesthetics). Markers of renal injury (urinary creatinine, albumin, glucose, alpha-GST, and blood urea nitrogen) did not reveal significant injury after anesthesia with desflurane. Sevoflurane degradation with a 2-L/min fresh gas inflow rate produced average inspired concentrations of Compound A of 40 +/- 4 ppm (mean +/- SD, 8-h exposure [data from previous study]), 42 +/- 2 ppm (4 h), and 40 +/- 5 ppm (2 h). Relative to desflurane, sevoflurane given for 4 h caused statistically significant transient injury to glomeruli (slightly increased urinary albumin and serum creatinine) and to proximal tubules (increased urinary alpha-GST). Other measures of injury did not differ significantly between anesthetics. Neither anesthetic given for 2 h at 1.25 MAC produced injury. We conclude that 1.25 MAC sevoflurane plus Compound A produces dose-related glomerular and tubular injury with a threshold between 80 and 168 ppm/h of exposure to Compound A. This threshold for renal injury in normal humans approximates that found previously in normal rats. IMPLICATIONS: Human (and rat) kidneys are injured by a reactive compound (Compound A) produced by degradation of the clinical inhaled anesthetic, sevoflurane. Injury increases with increasing duration of exposure to a given concentration of Compound A. The response to Compound A has several implications, as discussed in the article.

Adult↗
PubMed1997

Quantitative differences in the production and toxicity of CF2=BrCl versus CH2F-O-C(=CF2)(CF3) (compound A): the safety of halothane does not indicate the safety of sevoflurane.

UNLABELLED: Carbon dioxide absorbents degrade both halothane and sevoflurane to toxic unsaturated compounds (CF2=CBrCl and CH2F-O-C[=CF2][CF3] [i.e., Compound A], respectively). Given the long history of safe administration of halothane, comparable toxicities of these degradation products would imply a similar safety of sevoflurane. We therefore examined CF2=CBrCl in the context of four issues relevant to previous studies of the toxicity of Compound A: 1) reactivity of the degradation product in vitro; 2) rate of its production in vitro; 3) its in vivo toxicity; 4) importance of the beta-lyase pathway to the toxicity in vivo. We found the following. 1) CF2=CBrCl is less reactive than Compound A, degrading in human serum albumin at one-fifth the rate of Compound A. 2) Over a 3-h period of "anesthesia," a standard circle system containing Baralyme (Allied Healthcare Products, Inc., St. Louis, MO) produces 30 times as much Compound A from a minimum alveolar anesthetic concentration (MAC) concentration of sevoflurane as CF2=CBrCl from a MAC concentration of halothane; with soda lime, the difference is 60-fold. Correcting for differences in uptake of halothane versus sevoflurane decreases the differences to 20-40 times. 3) For a 3-h administration to rats, the partial pressure of Compound A causing minimal renal injury or necrosis of half the affected tubule cells exceeds the partial pressure of CF2=CBrCl causing minimal injury or necrosis of half the affected tubule cells by a factor of approximately 4-6. Thus, the ratio of production (Item 2 above) to the partial pressure causing injury with CF2=CBrCl is approximately a quarter of that ratio for Compound A. 4) Compounds that block the beta-lyase pathway either do not change (acivicin) or decrease (aminooxyacetic acid; AOAA) renal injury from CF2=CBrCl in rats, whereas these compounds increase (acivicin) or do not change (AOAA) injury from Compound A. We conclude that the safety of halothane cannot be used to support the safety of sevoflurane. IMPLICATIONS: Carbon dioxide absorbents degrade halothane and sevoflurane to unsaturated compounds nephrotoxic to rats. Relative to sevoflurane's degradation product, halothane's degradation product has less toxicity relative to production, less reactivity, and a different mechanism of injury. The clinical absence of halothane nephrotoxicity does not necessarily indicate a similar absence for sevoflurane.

Absorption↗
PubMed1997

Dehydration of Baralyme increases compound A resulting from sevoflurane degradation in a standard anesthetic circuit used to anesthetize swine.

UNLABELLED: In a model anesthetic circuit, dehydration of Baralyme brand carbon dioxide absorbent increases degradation of sevoflurane to CF2=C(CF3)OCH2F, a nephrotoxic vinyl ether called Compound A. In the present study, we quantified this increase using "conditioned" Baralyme in a circle absorbent system to deliver sevoflurane anesthesia to swine. Mimicking continuing oxygen delivery for 2 days after completion of an anesthetic, we directed a conditioning fresh gas flow of 5 L/min retrograde through fresh absorbent in situ in a standard absorbent system for 40 h. The conditioned absorbent was subsequently used (without mixing of the granules) in a standard anesthetic circuit to deliver sevoflurane to swine weighing 78 +/- 2 kg. The initial inflow rate of fresh gas flow was set at 10 L/min with the vaporizer at 8% to achieve the target end-tidal concentration of 3.0%-3.2% sevoflurane in approximately 20 min. The flow was later decreased to 2 L/min, and the vaporizer concentration was decreased to sustain the 3.0%-3.2% value for a total of 2 h (three pigs) or 4 h (eight pigs). Inspired Compound A increased over the first 30 +/- 60 min to a peak concentration of 357 +/- 49 ppm (mean +/- SD), slowly decreasing thereafter to 74 +/- 6 ppm at 4 h. The average concentration over 2 h was 208 +/- 25 ppm, and the average concentration over 4 h was 153 +/- 19 ppm. Pigs were killed 1 or 4 days after anesthesia. The kidneys from pigs anesthetized for both 2 h and 4 h showed mild inflammation but little or no tubular necrosis. These results suggest that dehydration of Baralyme may produce concentrations of Compound A that would have nephrotoxic effects in humans in a shorter time than would be the case with normally hydrated Baralyme. IMPLICATIONS: The vapor known as Compound A can injure the kidney. Dehydration of Baralyme, a standard absorbent of carbon dioxide in inhaled anesthetic delivery systems, can cause a 5- to 10-fold increase in Compound A concentrations produced from the inhaled anesthetic, sevoflurane, given at anesthetizing concentrations in a conventional anesthetic system.

Anesthesia, Closed-Circuit↗
PubMed1997

Recombinant human hemoglobin does not affect renal function in humans: analysis of safety and pharmacokinetics.

BACKGROUND: Recombinant human hemoglobin (OptroD; rHb1.1) is a genetically engineered protein produced in Escherichia coli. The two alpha-globin polypeptides are genetically joined, resulting in a stable tetramer that does not dissociate into dimers or monomers. Historically, infusion in humans of acellular hemoglobin preparations has resulted in renal toxicity. This study was performed to evaluate the safety and pharmacokinetics of rHb1.1 when infused in humans. METHODS: After giving informed consent, 48 healthy male volunteers were randomly assigned to receive either 0.015-0.32 g/kg 5% rHb1.1 (n = 34) or an equivalent amount of 5% human serum albumin (HSA; n = 14) infused intravenously over 0.8-1.9 h. Serum creatinine, creatinine clearance, urine N-acetyl-beta-glucosaminidase, and serum rHb1.1 concentrations were measured before and at timed intervals after infusion. RESULTS: Postinfusion urine N-acetyl-beta-glucosaminidase activity did not exceed preinfusion values at any interval in either group. Serum creatinine did not differ from preinfusion values at 1 day, 2-3 days, or 7 days after infusion for either group. Creatinine clearance increased significantly for the HSA group 12 h after infusion (138 +/- 16 ml/min, means +/- SE) and in the rHb1.1 group 1 day after infusion (112 +/- 5 ml/min; P < 0.05). Values for creatinine clearance did not differ from preinfusion values for either group at any other postinfusion interval; serum creatinine and creatinine clearance did not differ between groups at any time. The amount of hemoglobin excreted in the urine did not exceed approximately 0.04% of the administered rHb1.1 dose in any volunteer. Plasma clearance of rHb1.1 decreased and half-life increased as a function of increasing plasma concentration (e.g., the half-life was 2.8 h at a plasma concentration of 0.5 mg/ml and 12 h at 5 mg/ml). The incidence of gastrointestinal symptoms, fever, and chills was greater after infusion of rHb1.1 than after HSA (P < 0.05). CONCLUSIONS: No evidence for rHb1.1-mediated nephrotoxicity was observed in volunteers given doses of rHb1.1 as large as 0.32 g/kg. Because the clearance of rHb1.1 varies inversely with its concentration, additional studies with larger doses are necessary to determine the half-life expected in clinical use. Administration of rHb1.1 to conscious humans is associated with some side effects, such as gastrointestinal upset, fever, chills, headache, and backache.

Adolescent↗
PubMed1997

Recovery and kinetic characteristics of desflurane and sevoflurane in volunteers after 8-h exposure, including kinetics of degradation products.

BACKGROUND: Desflurane and sevoflurane permit speedier changes in anesthetic partial pressures than do older halogenated anesthetics. The authors determined the kinetic characteristics of desflurane and sevoflurane and those of compound A [CH2F-O-C(=CF2)(CF3)], a nephrotoxic degradation product of sevoflurane. METHODS: Volunteers received 1.25 minimum alveolar concentration of desflurane or sevoflurane, each administered for 8 h in a fresh gas inflow of 2 l/min. Inspired (F(I)) and end-tidal (F(A)) concentrations of anesthetic and compound A were measured during administration, and F(A) relative to F(A0) (the last end-tidal concentration during administration) during elimination. The indices of recovery were also measured. RESULTS: The ratio F(I)/F(A) rapidly approached 1.0, with values greater for sevoflurane (desflurane 1.06 +/- 0.01 vs. sevoflurane 1.11 +/- 0.02, mean +/- SD). The ratio F(A)/F(I) for compound A was approximately 0.8. The F(A)/F(A0) ratio decreased slightly more rapidly with desflurane than with sevoflurane, and objective measures indicated faster recovery with desflurane: The initial response to command (14 +/- 4 min vs. 28 +/- 8 min [means +/- SD]) and orientation (19 +/- 4 vs. 33 +/- 9 min) was quicker, and recovery was faster as defined by results of the Digit Symbol Substitution, P-deletion, and Trieger tests. Desflurane produced less vomiting (1 [0.5, 3]; median [quartiles] episodes) than did sevoflurane (5 [2.5, 7.5] episodes). The F(A)/F(A0) ratio for compound A decreased within 5 min to a constant value of 0.1. CONCLUSIONS: These anesthetics have kinetics consistent with their solubilities. Sevoflurane's greater biodegradation probably increases F(I)/F(A) differences during anesthetic administration and decreases F(A)/F(A0) differences during elimination. The F(A) for compound A differs from F(I) by 20% (F(A)/F(I) = 0.8) because of substantial degradation. Recovery from anesthesia proceeds nearly twice as fast with desflurane than with sevoflurane. Differences in ventilation, or alveolar or tissue elimination, do not completely explain the slower recovery with sevoflurane.

Anesthetics, Inhalation↗
PubMed1996

Compound A: solubility in saline and olive oil; destruction by blood.

Compound A is a degradation product of sevoflurane. Knowledge of the solubility of Compound A, CH2F-O-C(=CF2)(CF3), in blood and other solvents would aid in the definition of its kinetics. Accordingly, we determined solvent/gas partition coefficients of Compound A for saline (0.166 +/- 0.002 [mean +/- SD; n = 4]) and olive oil (20.1 +/- 1.1 [n = 4]). Measurement of solubility in blood was confounded by degradation of Compound A in blood and blood components. If a mixture of 99.3% saline and 0.7% oil provides the solubility equivalent to that possessed by blood (as it does for the parent compound, sevoflurane), then blood solubility and solubility in plasma, albumin, red blood cells, or pure hemoglobin is approximately 0.31. The order of Compound A degradation was human plasma = rat blood > whole human blood >5% human serum albumin = washed human red blood cells (hematocrit 50%) = 5% pure hemoglobin. Presuming a solvent/gas partition coefficient of 0.31, respective approximate times for 50% degradation equaled 2.7, 2.8, 4.6, 9.9, 11.0, and 12 min. The accuracy of these approximations was limited by the need to estimate, rather than determine, the solubility of Compound A in such solvents. Pasteurization (heating to 60 degrees C for 12 h) or pretreatment with N-ethylmaleimide (a compound that reversibly binds to sulfhydryl groups) decreased the degradation rate in plasma. These results suggest that degradation arises, at least in part, from reaction of Compound A with proteins in blood, possibly from covalent reaction of Compound A with protein and/or from an enzymatically mediated reaction. The products of degradation, the binding sites, and the clinical implications of such binding and degradation remain to be determined.

Anesthetics, Inhalation↗
PubMed1996

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.kg-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.kg-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.ml-1 to 279 +/- 51 pg.ml-1; P < 0.05). There was no significant change in norepinephrine concentration (from 198 +/- 37 pg.ml-1 to 277 +/- 46 pg.ml-1). The peak plasma epinephrine concentration was attenuated by each propofol pretreatment (158 +/- 35 pg.ml-1, propofol given 2 min before, and 146 + 41 pg.ml-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.kg-1 propofol does no attenuate the transient cardiovascular response to a rapid increase in desflurane concentration to greater than 1 MAC.

Adult↗
PubMed1995

Mathematical analysis of isovolemic hemodilution indicates that it can decrease the need for allogeneic blood transfusion.

BACKGROUND: The implementation of acute isovolemic hemodilution prior to surgical blood loss is a strategy used in an attempt to diminish the need for or obviate allogeneic transfusion and to avert the potential, attendant complications. Studies examining the efficacy of this technique have produced conflicting results. STUDY DESIGN AND METHODS: The present mathematical analysis was undertaken to resolve these conflicts by determining the efficacy of hemodilution and examining the influence of the variables affecting the outcome. Efficacy was defined as the volume of additional blood loss permitted and the volume and number of units of allogeneic blood saved from transfusion. A mathematical analysis evaluated the impact of circulating blood volume and initial and target hematocrits on the efficacy of isovolemic hemodilution. It was assumed that 1) hemodilution was completed before surgical blood loss; 2) transfusion of removed blood was begun when the target hematocrit was reached and lost surgical blood was replaced at a rate that maintained the target hematocrit; 3) allogeneic transfusion was begun after all autologous blood drawn was transfused; 4) normovolemia was maintained; and 5) a unit of allogeneic blood contains 175 mL of red cells. RESULTS: The analysis showed that isovolemic hemodilution can result in substantial additional allowable surgical blood loss that can diminish the need for or obviate allogeneic transfusion of red cells. Larger circulating blood volume, higher initial hematocrits, and lower target hematocrits increase the efficacy of hemodilution. Removal and isovolemic replacement of 1 to 2 units of blood provide minimal potential savings, as does hemodilution to a circulating (target) hematocrit of 30 percent. The extension of hemodilution to a hematocrit of (or below) 20 percent allows a disproportionately greater surgical blood loss and diminishes the need for allogeneic transfusion. It allows, for example, an additional 4.5 L of surgical blood loss, which represents a savings of 4 units of allogeneic blood when a patient with an initial blood volume of 5.0 L and a hematocrit of 45 percent undergoes isovolemic hemodilution to a hematocrit of 15 percent. CONCLUSION: Isovolemic hemodilution can diminish or in some circumstances eliminate the need for allogeneic transfusion.

Blood Transfusion↗
PubMed1995

Subanesthetic concentrations of desflurane and isoflurane suppress explicit and implicit learning.

The capacity of desflurane to suppress learning is unknown. We investigated whether a subanesthetic concentration of desflurane (0.6 minimum alevolar anesthetic concentration [MAC]) suppressed learning as much as the same concentration of isoflurane, and whether such suppression differed with increasing duration of anesthesia and intervening changes in anesthetic concentration. Using a cross-over-design study in 18-30 yr-old human volunteers, we supplied answers to Trivial Pursuit (Selchow & Righter Co., Bay Shore, NY)-like questions at 0.6 MAC desflurane and isoflurane before and after imposing a half-hour period at 1.7 MAC of each anesthetic, and behavioral directions and a category-example task at 0.6 MAC after the period at 1.7 MAC. These volunteers had a third anesthesia in which no information was supplied (control). After anesthesia, we tested whether the provision of answers during anesthesia increased the number of correct answers to Trivial Pursuit questions. We tested for the number of correct answers for information presented before versus after the 1.7-MAC period, for increased evocation of examples of categories presented during anesthesia, and for exhibition of a behavior suggested during anesthesia. We found that 0.6 MAC of both anesthetics prevented explicit and implicit learning before and after the period at 1.7 MAC.

Adolescent↗
PubMed1995

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 N2O, 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% N2O; five received fentanyl 1.5 micrograms/kg or 4.5 micrograms/kg intravenously 5 min before 4%-8% desflurane; four received clonidine 4.3 micrograms/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). N2O produced a higher peak (6.2 +/- 0.7 mm). Fentanyl 1.5 micrograms/kg and 4.5 micrograms/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. N2O augments, fentanyl and clonidine attenuate, and esmolol does not affect the response.

Administration, Inhalation↗
PubMed1995

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. METHODS: After placement of a double-lumen endotracheal tube in four volunteers and establishment of a steady-state level of 4% desflurane in both lungs, the desflurane concentration was rapidly increased from 4% to 8% in one lung while decreasing it in the other, thereby obviating any increase in the systemic desflurane blood concentration (confirmed by analysis). After returning the desflurane end-tidal concentration to 4% in both lungs, this process was repeated for the contralateral lung thereby having exposed both lungs to 8% desflurane without increasing the systemic desflurane concentration. After returning desflurane concentration to 4%, it was increased in both lungs simultaneously to 8% and consequently in blood to 8% of an atm. RESULTS: Rapid increases in desflurane concentrations in either lung, but not blood, significantly increased heart rate (17 +/- 5 beats/min, mean +/- SE, P < 0.05) and mean arterial blood pressure (15 +/- 5 mmHg, P < 0.05), but a greater increase in heart rate (43 +/- 5 beats/min, P < 0.05) and mean arterial blood pressure (46 +/- 11 mmHg, P < 0.05) occurred when both lungs were exposed simultaneously to rapidly increased desflurane concentration for the second time within 90 min. This result did not differ from the increase occurring on another day when both lungs and blood were exposed for the first time that day to 8% desflurane (heart rate 40 +/- 7 beats/min, P = 0.8; mean arterial blood pressure 40 +/- 3 mmHg, P = 0.5). CONCLUSIONS: It was concluded that at least two sites respond to a rapid increase in desflurane concentrations greater than 6%: one site in the airways and/or lungs, and at least one other in a highly perfused tissue(s). The systemic site contributes more importantly.

Adult↗
PubMed1995

Implications of chemical and physical properties of desflurane for longer surgery.

Increased duration of anaesthetic administration has implications for recovery from anaesthesia, has cardiovascular effects, and potential for toxicity through metabolism and breakdown of the anaesthetics. Recovery of function after desflurane or sevoflurane anaesthesia, because of the low blood gas and tissue solubilities of these agents, is more rapid than after halothane, isoflurane or enflurane, with recovery being most rapid after desflurane. Increased duration of anaesthesia amplifies the differences in rate of recovery because of the additional anaesthetic (greater with more soluble agents) dissolved in tissues. Increased duration of anaesthesia lessens the cardiovascular depression associated with most halogenated inhaled anaesthetics including desflurane, but not isoflurane. Increased duration of anaesthesia allows for greater metabolism of anaesthetics and greater exposure to metabolites and potentially toxic breakdown products. Desflurane is the least metabolised of the available anaesthetics and is stable in soda lime and Baralyme. Thus, it has exceedingly low potential for toxicity. Sevoflurane undergoes considerable metabolism, producing free fluoride ion, with plasma concentrations proportional to dose and duration of anaesthesia exceeding 50 microM in approximately 7% of patients. In rats, the effects of a toxic breakdown product of sevoflurane, CF2 = C(CF3)OCH2F (compound A), are also dose- and duration-dependent, with lower concentrations producing toxic effects as duration of exposure increases. The clinical importance of the metabolism and in vitro breakdown of sevoflurane has still to be adequately tested.

Anesthesia Recovery Period↗
PubMed1995

Cardiovascular effects of desflurane in experimental animals and volunteers.

Desflurane (difluoromethyl-1-fluoro-2,2,2-trifluoroethyl ether [I-653]) was introduced into clinical practice in 1992. The present review summarises the current state of knowledge of the cardiovascular effects of desflurane, with emphasis on investigations published in the past 2 years, and compares desflurane's effects with those of isoflurane, and where available, sevoflurane. Desflurane produces two distinct cardiovascular actions. First, desflurane decreases left ventricular systolic and diastolic function to an extent similar to that of isoflurane. It decreases systemic vascular resistance and mean arterial blood pressure in a dose-dependent fashion. Heart rate is unchanged at lower steady-state concentrations, but increases with higher concentrations. Addition of nitrous oxide maintains heart rate unchanged, increases systemic vascular resistance and mean arterial blood pressure, but decreases cardiac output. Secondly, when the end-tidal concentration of desflurane is very rapidly increased to concentrations exceeding 1 MAC, in the absence of premedication, desflurane increases sympathetic activity, heart rate and mean arterial blood pressure. Prior administration of fentanyl, esmolol or clonidine blunts this response. The response and the ability of fentanyl to blunt it probably account for the disparate results in published studies on the use of desflurane in patients undergoing coronary artery bypass graft surgery.

Anesthetics, Inhalation↗
PubMed1994

What can we learn about the need for transfusion from patients who refuse blood? The experience with Jehovah's Witnesses.

BACKGROUND: A transfusion threshold of 7 g per dL (70 g/L) of hemoglobin has been proposed for patients, although scant human data are available to support this recommendation. STUDY DESIGN AND METHODS: The medical community's experience with Jehovah's Witnesses was examined, in order to assess the lowest tolerable hemoglobin concentration and the lower transfusion threshold of 7 g per dL (70 g/L) of hemoglobin. A MEDLINE search was conducted to capture medical and surgical reports involving Jehovah's Witnesses from 1970 through early 1993. RESULTS: Sixty-one reports of untransfused Jehovah's Witnesses with hemoglobin concentrations < or = 8 g per dL (80 g/L) or hematocrits < or = 24 percent (0.24) were identified. Of 50 reported deaths, 23, as stated in the original reports, were primarily due to anemia. Except for three patients who died after cardiac surgery, all patients whose deaths were attributed to anemia died with hemoglobin concentrations < or = 5 g per dL (50 g/L). Twenty-five survivors were reported with hemoglobin < or = 5 g per dL (50 g/L). CONCLUSION: These data have significant limitations but suggest that survival, without transfusion, is possible at low hemoglobin concentrations, while mortality with an unknown incidence is encountered at hemoglobin concentrations below 5 g per dL (50 g/L).

Anemia↗