Tsuneo Tatara

A solid-solution theory of anesthetic interaction with lipid membranes: temperature span of the main phase transition

Anesthetics (or any other small additives) depress the temperature of the main phase transition of phospholipid bilayers. Certain anesthetics widen the temperature span of the transition, whereas others do not. The widening in a first-order phase transition is intriguing. In this report, the effects of additive molecules on the temperature and its span were explained by the solid-solution theory. By assuming coexistence of the liquid-crystal and solid-gel phases of lipid membranes at phase transition, the phase boundary is determined from the distribution of anesthetic molecules between the liquid-crystal membrane versus water and between the solid-gel membrane versus water. The theory shows that when the lipid concentration is large or when the lipid solubility of the drug is large, the width of the transition temperature increases, and vice versa. Highly lipid-soluble molecules, such as long-chain alkanols and volatile anesthetics, increase the width of the transition temperature when the lipid:water ratio is large, whereas highly water-soluble molecules, such as methanol and ethanol, do not. The aqueous phase serves as the reservoir for anesthetics. Depletion of the additive molecules from the aqueous phase is the cause of the widening. When the reservoir capacity is large, the temperature width does not increase. The theory also predicts asymmetry of the specific heat profile at the transition.

The α-helix to β-sheet transition in poly(l-lysine): Effects of anesthetics and high pressure

Poly( l -lysine) exists in a random-coil formation at a low pH, α-helix at a pH above 10.6, and transforms into β-sheet when the α-helix polylysine is heated. Each conformation is clearly distinguishable in the amide-I band of the infrared spectrum. The thermotropic α-to-β transition was studied by using differential scanning calorimetry. At pH 10.6, the transition temperature was 43.5°C and the transition enthalpy was 170 cal/mol residue. At pH 11.85, the measurements were 36.7°C and 910 cal/mol residue, respectively. Volatile anesthetics (chloroform, halothane, isoflurane and enflurane) partially transformed α-helix polylysine into β-sheet. The transformation was reversed by the application of hydrostatic pressure in the range of 100–350 atm. Apparently, the α-to-β transition was induced by anesthetics through partial dehydration of the peptide side-chains (β-sheet surface is less hydrated than α-helix). High pressure reserved this process by re-hydrating the peptide. Because the membrane spanning domains of channel and receptor proteins are predominantly in the α-helix conformation, anesthetics may suppress the activity of excitable cells by transforming them into a less than optimal structure for electrogenic ion transport and neurotransmission. Proteins and lipid membranes maintain their structural integrity by interaction with water. That which attenuates the interaction will destabilize the structure. These data suggest that anesthetics alter macromolecular conformations essentially by a solvent effect, thereby destroying the solvation water shell surrounding macromolecules.

Structure-selective anesthetic action of steroids : anesthetic potency and effects on lipid and protein

Alphaxalone was a clinically used steroid anesthetic. Its analog δ16-alphaxalone is nonanesthetic. The only difference between the two is the presence of a double bond at the hydrophobic end of the δ16-alphaxalone molecule. This study determined the anesthetic potency of alphaxalone and δ16-alphaxalone in goldfish and compared it with their effects on dipalmitoylphos-phatidylcholine (DPPC) membranes and an α-helix polypeptide, poly(L-lysine). The goldfish EC50 values were: alphaxalone 5 μmol/L and δ16-alphaxalone 80 μmol/L. Because these steroids are insoluble to water, the bulk of the steroid in water is absorbed by the fish. Larger containers hold more steroids than smaller containers at the same steroid concentrations. Then, EC50 values vary according to the size of the container. By assuming that the total amount of steroids in the container is distributed into the fish, the EC50 values expressed by the concentration in the fish body become 1.9 mmol/L for alphaxalone, and 30.5 mmol/L for δ16-alphaxalone. A monoamino acid peptide, poly(L-lysine), can be formed into random-coil, α-helix, or β-sheet. Addition of 0.07 mmol/L alphaxalone to the α-helix poly(L-lysine) partially transformed it to a β-sheet structure. An equivalent change was observed with 3.0 mmol/L δ16-alphaxalone. These values translate into 3.5 mmol/L for alphaxalone and 0.15 mol/L for δ16-alphaxalone, when expressed by the concentration in the peptide. The change from α-helix to β-sheet is accompanied by dehydration of the surface of poly(L-lysine). The steroids decreased the phase-transition temperature of DPPC membrane. At 1:10 steroid:DPPC mole ratio, alphaxalone and δ16-alphaxalone decreased the main transition temperature 0.6 and 0.2°C, respectively, and the pretransition temperature 4.5 and 1.0°C, respectively. When expressed by the steroid concentration in DPPC, 1:10 mole ratio equals 0.14 mmol/L. Addition of alphaxalone to the DPPC membrane released water molecules from the membrane surface. δ16-Alphaxalone did not. Lipid membranes cannot be formed without water. A string of amino acids transforms into biologically meaningful protein structure only when it is dissolved in water. These structures are supported by water molecules hydrogen-bonded to the macromolecular surfaces. We contend that the debate on the anesthetic action site between proteins and lipid membranes is futile. Although the affinity of anesthetics to neuroreceptors may vary, the basic interaction force is the tendency to be excluded from water to bind hydrophobic surfaces of proteins and lipid membranes. The present study demonstrated that alphaxalone induces nonspecific conformational changes of lipid membranes and proteins by releasing the supporting water molecules.

Quantitative analysis of fluid balance during abdominal surgery

BACKGROUND: Surgical injury causes acute sequestration of interstitial fluid in injured tissue. Fluid sequestration treated with IV fluid administration can lead to postoperative complications related to excessive intravascular volume. Quantitative prediction of interstitial fluid sequestration may foster a better understanding of the relationship between fluid administered and the resulting balance between intra- and extravascular fluid. METHODS: We developed a mathematical model describing the dynamic distribution and transport of fluid and proteins with the goal of quantifying the balance of fluid between intra- and extravascular compartments. Fluid volume changes in the plasma, interstitial and urine compartments were calculated for a simulated 4 h abdominal surgery in a 70 kg male. To validate the model, we compared the results obtained with those measured by segmental bioelectrical impedance on 30 patients undergoing elective abdominal surgery. RESULTS: The model predicted that, compared to the normal state, surgical injury would result in the sequestration of 705 mL of interstitial fluid in injured tissue, whereas plasma volume would undergo a 356 mL decrease. During surgery, it was not possible to obtain a normal plasma volume, even with fluid replacement at a rate of almost 20 mL · kg−1 · h−1. Bias and limit of agreement on interstitial fluid volume changes in body segments between bioelectrical impedance and model prediction were −131 and 325 mL, respectively for limbs, and −157 and 834 mL for the trunk. CONCLUSIONS: The model shows that increasing the fluid replacement rate above 10 mL · kg−1 · h−1 does not have the desired effect on plasma volume but instead increases the interstitial volume.

The effect of duration of surgery on fluid balance during abdominal surgery: a mathematical model.

BACKGROUND: There is controversy regarding which fluid management regimen provides the best postoperative outcome. Interstitial fluid accumulation may adversely affect postoperative outcome, but the effect of surgical duration on fluid balance is unknown. In this study, we used a mathematical model to describe fluid distribution. METHODS: Previously published data from bioimpedance analysis in patients undergoing abdominal surgery were used to calculate changes to interstitial volume (&Dgr;VIT, percent change relative to baseline) in uninjured and injured tissues. Ratios of &Dgr;VIT in uninjured and injured tissues at the end of surgery to total fluid volume infused during surgery (VINF, mL/kg) were compared between surgeries of duration <3 h (n = 5) and ≥3 h (n = 25). Critical values for change in plasma volume (&Dgr;VPL, percent change relative to baseline) and &Dgr;VIT, which give rise to adverse outcome, were calculated from previously published data on the physiological effects of IV fluid administration in healthy volunteers. Finally, simulated abdominal surgery in a 70 kg man for 1–8 h was used to determine the effect of crystalloid infusion rate between 2 and 30 mL · kg−1 · h−1 on &Dgr;VPL and &Dgr;VIT. Fluid infusion rates that maintained &Dgr;VPL and &Dgr;VIT in uninjured tissue within critical values were then computationally determined as a function of duration of surgery. RESULTS: Bioimpedance data showed that the differences in &Dgr;VIT/VINF ratios between uninjured and injured tissues were significant only for surgical duration ≥3 h (0.30 ± 0.17% · kg/mL vs 1.55 ± 0.73% · kg/mL, P < 0.0001). Differences of &Dgr;VIT/VINF ratios between surgical durations <3 and ≥3 h were found only for injured tissue (0.45 ± 0.35% · kg/mL vs 1.55 ± 0.73% · kg/mL, P = 0.003). The range of fluid infusion rates required to maintain &Dgr;VPL and &Dgr;VIT within the critical values (>−15% and <20%, respectively) was wide for short-duration surgery (2–18.5 mL · kg−1 · h−1 for a 2 h-surgery), whereas it was narrow for long-duration surgery (5–8 mL · kg−1 · h−1 for a 6 h-surgery). CONCLUSIONS: Based on our model, it should be possible to increase the fluid infusion rate without significant interstitial edema for abdominal surgery of <3 h duration. However, our model predicts that restrictive fluid management should be used in abdominal surgery of >6 h duration to avoid excessive interstitial edema.

Hydration status after overnight fasting as measured by urine osmolality does not alter the magnitude of hypotension during general anesthesia in low risk patients.

BACKGROUND: The increased distribution of crystalloid solution into the interstitial space may decrease the effectiveness of intravascular volume loading in patients. We investigated whether preoperative hydration status after overnight fasting affects interstitial fluid redistribution and thus the magnitude of hypotension during general anesthesia. METHODS: Sixty ASA physical status I/II patients undergoing tympanoplasty fasted from midnight. Anesthesia was induced by fentanyl and propofol and maintained with sevoflurane and remifentanil. Coinciding with the induction of anesthesia, 15 mL/kg acetated Ringer solution was infused IV over 60 minutes followed by 1 mL/kg acetated Ringer solution over the next 30 minutes. Urine osmolalities after induction of anesthesia and during the study period (pre-Uosm, post-Uosm) and percent decreases of whole-body bioelectrical resistance for extracellular fluid relative to baseline at the end of the study period (&Dgr;Re) were measured. Patients with a pre-Uosm < the 25th percentile or with a pre-Uosm > the 75th percentile of pre-Uosm were categorized in the hydrated or the dehydrated group, respectively. A range of variables, including mean arterial blood pressure during the 30- to 90-minute period relative to baseline, and &Dgr;Re, were compared between the groups. RESULTS: The dehydrated group (pre-Uosm >759.5 mOsm/kg, n = 15) had a lower age (44 vs 52 years, P = 0.049) and had a higher post-Uosm (181 vs 55 mOsm/kg, P = 0.001) compared with the hydrated group (pre-Uosm <378.5 mOsm/kg, n = 15). Mean arterial blood pressure during the 30- to 90-minute period relative to baseline (0.67 vs 0.67, P = 0.85) with 95% confidence interval for the difference of means (−0.070 to 0.084) and &Dgr;Re (5.6% vs 6.0%, P = 0.58) with 95% confidence interval for the difference of means (−1.85% to 1.06%) were similar for the hydrated and dehydrated groups. CONCLUSIONS: Preoperative dehydration after overnight fasting as measured by urine osmolality did not alter the magnitude of hypotension during general anesthesia. This finding suggests that intravascular volume loading with crystalloid solution to prevent hypotension during general anesthesia is an unfounded practice for low risk patients after overnight fasting.

Myristate, a 14-carbon fatty acid, effectively reverses anesthesia.

THE pressure reversal of anesthesia was discovered in the light intensity of bacterial luciferase. 1 This in vitro study implies that the partial molar volume of the luciferase is greater during anesthesia than during the awake state. 1 This observation was confirmed in vivo in tadpoles, 2 newts, 3 and rats. 4 We found that the light intensity of firefly luciferase (FFL) also responds to high pressure. 5 We also measured the effects of anesthetics and myristate (a 14-carbon fatty acid, neutralized by NaOH) on the volume of FFL. 6 Halothane 0.5 mM increased the FFL volume by 3.93 cm 3 mol -1 whereas myristate 2.5 μM decreased it by 7.66 cm 3 mol -1 . We hypothesized that if the molar volume of FFL determines depth of anesthesia, myristate may antagonize anesthesia. As expected, our preliminary study showed that myristate antagonized anesthesia in goldfish. 7 Contrary to the general belief that fatty acids are toxic to mammals, the intravenous hyperalimentation fluids, Intralipid (Baxter, Deerfield, IL), and others are composed of a variety of long-chain fatty acids: linoleic, oleic, palmitic, linolenic, stearic acids, and so on. These fatty acids are neutralized by triglycerides. They are called essential fatty acids (EFA), and are well tolerated by debilitated patients. The generally held idea among anesthesiologists that fatty acids do not cross the blood-brain barrier is contradicted by oleamide (18-carbon fatty acid, oleic acid, neutralized by NH 4 OH) which crosses the blood-brain barrier and induces sleep. 8,9 .

Pulmonary edema after long-term beta-adrenergic therapy and cesarean section.

P -Adrenergic agonists, such as ritodrine and terbutaline, have been widely used for the inhibition of premature uterine contraction in preterm patients (1,2). However, these drugs can cause pulmonary edema during the initial phase of tocolytic therapy, probably secondary to excessive intravascular fluid administration, cardiac failure (l-4), and/or pulmonary capillary endothelial damage (5,6). We describe a patient who received 11 wk of ritodrine administration prior to cesarean section and developed pulmonary edema, unlikely related to excessive intravascular fluid volume, after the surgery.

Effect of inhalation anesthetics on swimming activity of artemia salina

The swimming movement of artemia salina in the artificial sea water was measured by using the video camera system in the absence and the presence of anesthetics, i.e. enfiurane, halothane, and isofiurane. The movement of artemia looked random at a glance but the obtained distribution curve for the swimming speed was skewed toward the high speed side somewhat resembling a Maxwellian distribution curve seen in the statistics of ideal gases. When anesthetics were added, the distribution curve became sharpened and shifted to the low speed side, which is similar to a behavior of ideal gasses when they are cooled down. The mean swimming-speed was decreased eventually leading to an irreversible death with increasing the anesthetic dose. The activity was analyzed by using the hydrodynamic equation. The ED50, which is a dose that causes a 50% reduction in the activity, of all anesthetics used in this study was quite similar to the MAC values for human. It was also suggested that an interaction between anesthetics and artemia was highly cooperative since the large Hill coefficients were obtained for all three anesthetics used.

C-reactive Protein Level on Postoperative Day One is Associated with Chronic Postsurgical Pain After Mastectomy

Background C-reactive protein (CRP) is an acute phase reactant released in response to inflammation or tissue injury. Inflammation is one of the pathogenic factors related to transition from acute postsurgical pain (APSP) to chronic postsurgical pain (CPSP). Although several risk factors are reportedly associated with CPSP, the effects of CRP levels on CPSP have not been examined. Objectives The present study investigated the relationship between perioperative risk factors, including CRP levels on postoperative day one and CPSP, in patients undergoing mastectomy. Methods Preoperative anxiety and depression levels were evaluated in female patients undergoing mastectomy under general anesthesia, with or without peripheral nerve block. Patients with chronic preoperative pain and/or preoperative breast pain were excluded. The intensity of postoperative pain was prospectively examined one and six days, and three and twelve months after surgery using a numerical rating scale (NRS). Results The current researchers conducted univariate and multivariate linear regression analyses to explore risk factors for CPSP in 36 patients. Patient demographics, preoperative psychological states, and anesthetic managements showed no relationship with CPSP. On the other hand, pain intensity of APSP and CRP levels on postoperative day one was significantly associated with the pain intensity of CPSP. Conclusions Postoperative CRP level is likely to be associated with the development of CPSP after mastectomy.