Anesthesia Capacity Research Articles

The World Health Organization Program for Emergency Surgical, Obstetric, and Anesthetic Care

This special article provides an introduction to the World Health Organization (WHO) Emergency and Essential Surgical Care (EESC) program. The program was launched by the WHO in December of 2005 to address the lack of adequate surgical capacity as a global public health issue. The overall objective is to reduce death and disability from trauma, burns, pregnancy-related complications, domestic violence, disasters, and other surgically treatable conditions. The program and materials have spread to over 35 countries and focus on providing (1) basic education and training materials; (2) enhancement of surgical infrastructure at the governmental and health facility level; and (3) resources for monitoring and evaluating surgical, obstetrical, and anesthetic capacity. Additionally, a global forum for program members was established that collaborates with ministries of health, WHO country offices, nongovernmental organizations, and academia. The results of the third biennial meeting of global EESC members in Mongolia are outlined as well as future challenges.

Mechanisms of inhibition of CaV3.1 T-type calcium current by aliphatic alcohols

Many aliphatic alcohols modulate activity of various ion channels involved in sensory processing and also exhibit anesthetic capacity in vivo. Although the interaction of one such compound, 1-octanol (octanol) with different T-type calcium channels (T-channels) has been described, the mechanisms of current modulation and its functional significance are not well studied. Using patch-clamp technique, we investigated the mechanisms of inhibition of T-currents by a series of aliphatic alcohols in recombinant human Ca(V)3.1 (alpha1G) T-channel isoform expressed in human embryonic kidney (HEK) 293 cells and thalamocortical (TC) relay neurons in brain slices of young rats. Octanol, 1-heptanol (heptanol) and 1-hexanol (hexanol) inhibited the recombinant Ca(V)3.1 currents in concentration-dependent manner yielding IC(50) values of 362 microM, 1063 microM and 3167 microM, respectively. Octanol similarly inhibited native thalamic Ca(V)3.1 T-currents with an IC(50) of 287 microM and diminished burst firing without significant effect on passive membrane properties of these neurons. Inhibitory effect of octanol on T-currents in both native and recombinant cells was accompanied with accelerated macroscopic inactivation kinetics and hyperpolarizing shift in the steady-state inactivation curve. Additionally, octanol induced a depolarizing shift in steady-state activation curves of T-current in TC neurons. Surprisingly, the recovery from fast inactivation at hyperpolarized membrane potentials was accelerated by octanol up 3-fold in native but not recombinant channels. Given the importance of thalamocortical pathways in providing sleep, arousal, and anesthetic states, modulation of thalamic T-currents may at least contribute to the pharmacological effects of aliphatic alcohols.

Addressing the Millennium Development Goals From a Surgical Perspective

Surgical and anesthetic care is increasingly recognized as a neglected but cost-effective component of primary health care in low- and middle-income countries (LMICs). Strengthening delivery can help achieve Millennium Development Goals 4, 5, and 6. Large gaps in access to essential surgical care in LMICs result in considerable morbidity and mortality. The goal of this study was to provide a baseline overview of essential surgical and anesthetic capacity at district-level health facilities in multiple LMICs. Survey. District-level health facilities in multiple LMICs A standardized World Health Organization tool was used at selected district-level hospitals to assess infrastructure, supplies, and procedures relating to essential surgical and anesthetic capacity. The analysis included facilities from countries that assessed more than 5 health facilities. All data were aggregated and blinded to avoid intercountry comparisons. Data from 132 facilities were analyzed from 8 countries: Democratic Socialist Republic of Sri Lanka (n = 32), Mongolia (n = 31), United Republic of Tanzania (n = 25), Islamic State of Afghanistan (n = 13), Republic of Sierra Leone (n = 11), Republic of Liberia (n = 9), Republic of The Gambia (n = 6), and Democratic Republic of São Tomé and Príncipe (n = 5). Universally, facilities demonstrated shortfalls in basic infrastructure (water, electricity, oxygen) and functioning anesthesia machines. Although 73% of facilities reported performing incision and drainage of abscesses, only 48% were capable of undertaking an appendectomy. In line with Millennium Development Goals 4, 5, and 6, only 32% of facilities performed congenital hernia repairs, 44% of facilities performed cesarean sections, and few facilities always had goggles and aprons to protect surgical health care workers from human immunodeficiency virus. Enormous shortfalls in infrastructure, supplies, and procedures undertaken are common at district-level health facilities in LMICs.

Concentrações de Eugenol para anestesia profunda e toxidade aguda em juvenis de piavuçu (<em>Leporinus macrocephalus</em>)

Three works were undertaken to evaluate the anesthetic capacity of eugenol in “piavuçu” juveniles; the influence of different concentrations on the anaesthetic effect, the acute toxicity (LD 50) and the Time for Lethal Dose (TLD) for the species. Seventy-two fish (1.77 + 0.69 g) were submitted to eight different eugenol concentrations (25; 37.5; 50; 62.5; 75; 100; 125 and 150 mg L-1); 150 fish were submitted to five concentrations (25; 37.5; 50; 62.5; 75 mg L-1) for ten minutes; and 150 fish were submitted to 37.5 mg/L for five time intervals (300; 600; 900; 1200; 1500 seconds). Eugenol concentration had strong influence on the anesthetic effect for the species; LD for 600 seconds of exposure were LD01 25.21 mg L-1, LD50 45.13 mg L-1 and LD99 65.05 mg L-1. The TLD were TLD01 322.8 seconds, TLD50 854.9 seconds and TLD99 1386.9 seconds. For fast and safe anesthesia of piavuçu juveniles, 37.5 mg L-1 of eugenol is recommended.

Blockade of Acetylcholine Receptors Does Not Change the Dose of Etomidate Required to Produce Immobility in Rats

Administration of drugs blocking muscarinic plus neuronal nicotinic acetylcholine receptors (e.g., atropine and mecamylamine) does not affect the MAC of isoflurane. Although this implies that acetylcholine receptors do not mediate the immobility produced by inhaled anesthetics, another interpretation is possible. Sub-MAC concentrations of isoflurane alone profoundly block acetylcholine receptors, allowing for the possibility that atropine and mecamylamine have no effect because the receptors already are blocked. In the present study, we indirectly tested this possibility by measuring the capacity of acetylcholine receptor blockade to decrease the anesthetic requirement for etomidate, an anesthetic thought to act solely by enhancing the effect of gamma-aminobutyric acid on gamma-aminobutyric acid(A) receptors. Administration of 10 mg/kg atropine plus 5 mg/kg mecamylamine did not change the infusion rate of etomidate, or the blood or brain concentrations of etomidate required to produce immobility in rats. Acetylcholine receptors do not mediate the capacity of anesthetics to produce immobility in the face of noxious stimulation.

JMF2-1, a lidocaine derivative acting on airways spasm and lung allergic inflammation in rats

Prior reports show that nebulized lidocaine might be an effective treatment for asthma. We sought to determine the anti-inflammatory and spasmolytic effects of lidocaine and its analogue, JMF2-1, which we have synthesized for reduced local anesthetic activity. Blockade of Na(+) currents was assayed in cultured GH(3) cells by using the patch-clamp technique, whereas anesthesia was assessed in a cutaneous pinching test in rats. Lidocaine and its analogue were nebulized into sensitized rats for evaluation of their effectiveness on airways spasm and inflammation induced by methacholine and allergen, respectively. Tissue histamine release and tracheal spasm triggered by allergen challenge in the absence and presence of these treatments were also examined in vitro. The 50% inhibitory concentration values for blockade of Na(+) currents after treatment with JMF2-1 (25.4 mM) was remarkably higher than that of lidocaine (0.18 mM), which is consistent with the weak anesthetic capacity of this analogue. In contrast, JMF2-1 was more potent than lidocaine in inhibiting allergen-induced histamine release and tracheal spasm. In in vivo settings methacholine-induced increase in lung resistance (145%) significantly reduced to 72% and 47% after lidocaine and JMF2-1 treatment, respectively. Both treatments inhibited by about 81% allergen-evoked eosinophil accumulation into the lung tissue. Replacement of the 2,6-dimethyl radicals by the 2-trifluormethyl group on the benzene ring of lidocaine significantly reduces anesthetic activity, preserving its ability to prevent key aspects of the allergic inflammatory response in the lung. Nebulized JMF2-1 might be a means of achieving the antiasthmatic effects of lidocaine without the anesthetic effects.

Contrasting Roles of the N-Methyl-d-Aspartate Receptor in the Production of Immobilization by Conventional and Aromatic Anesthetics

We hypothesized that N-methyl-d-aspartate (NMDA) receptors mediate some or all of the capacity of inhaled anesthetics to prevent movement in the face of noxious stimulation, and that this capacity to prevent movement correlates directly with the in vitro capacity of such anesthetics to block the NMDA receptor. To test this hypothesis, we measured the effect of IV infusion of the NMDA blockers dizocilpine (MK-801) and (R)-4-(3-phosphonopropyl) piperazine-2-carboxylic acid (CPP) to decrease the MAC (the minimum alveolar concentration of anesthetic that prevents movement in 50% of subjects given a noxious stimulation) of 8 conventional anesthetics (cyclopropane, desflurane, enflurane, halothane, isoflurane, nitrous oxide, sevoflurane, and xenon) and 8 aromatic compounds (benzene, fluorobenzene, o-difluorobenzene, p-difluorobenzene, 1,2,4-trifluorobenzene, 1,3,5-trifluorobenzene, pentafluorobenzene, and hexafluorobenzene) and, for comparison, etomidate. We postulated that MK-801 or CPP infusions would decrease MAC in inverse proportion to the in vitro capacity of these anesthetics to block the NMDA receptor. This notion proved correct for the aromatic inhaled anesthetics, but not for the conventional anesthetics. At the greatest infusion of MK-801 (32 microg x kg(-1) x min(-1)) the MACs of conventional anesthetics decreased by 59.4 +/- 3.4% (mean +/- sd) and at 8 microg x kg(-1) x min(-1) by 45.5 +/- 4.2%, a decrease not significantly different from a 51.4 +/- 19.0% decrease produced in the EC50 for etomidate, an anesthetic that acts solely by enhancing gamma-amino butyric acid (GABA) receptors. We conclude that some aromatic anesthetics may produce immobility in the face of noxious stimulation by blocking the action of glutamate on NMDA receptors but that conventional inhaled anesthetics do not.

What is the value of cystoscopy with hydrodistension for interstitial cystitis?

Objectives To determine the utility of cystoscopy with hydrodistension for the diagnosis and therapy of interstitial cystitis. Cystoscopy with hydrodistension is the most commonly performed diagnostic test and procedure in patients with interstitial cystitis. Methods Eighty-four consecutive patients with interstitial cystitis (68 women and 16 men) were studied retrospectively. The patients underwent history and physical examination, urinalysis, and urine culture and filled in a voiding diary and pain urgency frequency questionnaire. Cystoscopy with hydrodistension was performed in 47 patients. Patients who had and had not undergone hydrodistension were compared. Patients who underwent hydrodistension were characterized and followed up for response. Results The mean patient age was 41 years, mean daily voided volume was 98 mL, mean number of nocturnal episodes was 3, and pain urgency frequency score was 21. Comparing patients undergoing versus not undergoing hydrodistension, pain was reported in 61% versus 25% ( P = 0.03), vaginal pain in 62% versus 32% ( P = 0.02), and dyspareunia or ejaculatory pain in 67% versus 29% ( P <0.01), respectively. All other parameters were statistically similar. Of the patients undergoing hydrodistension, 43 had follow-up and 24 (56%) reported improvement (mean duration of 2 months). Of the patients with and without improvement, no difference was found in mean age (40 versus 46 years, P = 0.20), duration of symptoms (7 versus 7 years, P = 0.92), anesthetic capacity (722 versus 721 mL, P = 0.99), or glomerulation grade ( P = 0.61), respectively. Conclusions Cystoscopy with hydrodistension provided little useful information above and beyond the history and physical examination findings. As therapy, 56% of patients reported improvement, but the duration was short lived.

Are patient symptoms predictive of the diagnostic and/or therapeutic value of hydrodistention?

Hydrodistention (HD) has been utilized as a diagnostic and therapeutic tool in patients with refractory and diverse pelvic floor symptoms, including bladder pain with or without irritative bladder symptoms such as urinary urgency and urinary frequency. We sought to determine whether we could better define in whom HD was a more valuable intervention by stratifying patients according to presenting symptoms. A retrospective review was performed on 185 patients who underwent HD at our institution by a single surgeon between 1/2002-8/2004. Subjects were placed into groups according to their symptoms. Group 1 (G1) patients reported pain with bladder filling that was relieved with emptying, group 2 (G2) reported constant pelvic pain unrelated to bladder filling or emptying, and group 3 (G3) reported urgency and frequency alone with no pain component. Anesthetic capacity, presence and severity of glomerulations post-distention, and follow-up at 1, 3, and 6 months were recorded for each patient. G1 included 40 patients with mean age of 42 (R = 16-77), G2 included 101 patients with mean age of 46 (R = 20-76), and G3 22 patients with mean age of 40 (R = 20-84). The mean anesthetic capacity was 715 ml, 725 ml, and 542 ml for G1, G2, and G3 respectively. ANOVA revealed a statistically significant reduction in the capacity of G3 when compared with the others (P = 0.0072). Glomerulations were present in 74% of G1, 72% of G2, and 86% of G3 patients. 61%, 33%, & 0% of G1 patients reported improvement at 1, 3, and 6 months respectively, 54%, 25%, & 7% of G2 patients reported improvement, and 50%, 19%, & 7% of G3 patients reported improvement. There were no statistically significant differences in the responses amongst the three groups. Although HD is frequently employed for patients with refractory pelvic pain and/or lower urinary tract complaints, results failed to identify any statistically significant differences in post-distention objective findings (anesthetic capacity, glomerulations) or therapeutic benefits when patients are categorized according to presenting symptoms.

Propofol and Sevoflurane Depress Spinal Neurons In Vitro via Different Molecular Targets

The capacity of general anesthetics to produce immobility is primarily spinally mediated. Recently, compelling evidence has been provided that the spinal actions of propofol involve gamma-aminobutyric acid type A (GABAA) receptors, whereas the contribution of glycine receptors remains uncertain. The relevant molecular targets of the commonly used volatile anesthetic sevoflurane in the spinal cord are largely unknown, but indirect evidence suggests a mechanism of action distinct from propofol. The effects of sevoflurane and propofol on spontaneous action potential firing were investigated by extracellular voltage recordings from ventral horn interneurons in cultured spinal cord tissue slices obtained from embryonic rats (embryonic days 14-15). Propofol and sevoflurane reduced spontaneous action potential firing of neurons. Concentrations causing half-maximal effects (0.11 microm propofol, 0.11 mm sevoflurane) were lower than the median effective concentration immobility (1-1.5 microm propofol, 0.35 mm sevoflurane). At higher concentrations, complete inhibition of action potential activity was observed with sevoflurane but not with propofol. Effects of sevoflurane were mediated predominantly by glycine receptors (45%) and GABAA receptors (38%), whereas propofol acted almost exclusively via GABAA receptors (96%). The authors' results suggest that glycine and GABAA receptors are the most important molecular targets mediating depressant effects of sevoflurane in the spinal cord. They provide evidence that sevoflurane causes immobility by a mechanism distinct from the actions of the intravenous anesthetic propofol. The finding that propofol acts exclusively via GABAA receptors can explain its limited capacity to depress spinal neurons in the authors' study.

Halothane, but not the nonimmobilizers perfluoropentane and 1,2-dichlorohexafluorocyclobutane, depresses synaptic transmission in hippocampal CA1 neurons in rats.

Volatile anesthetics may decrease synaptic transmission at central neurons by presynaptic and/or postsynaptic actions. Nonimmobilizers are volatile compounds with lipophilicities that suggest that they should (but do not) prevent motor responses to surgical stimuli. However, nonimmobilizers interfere with learning and memory, and, thus, might be predicted to depress synaptic transmission in areas of the brain mediating memory (e.g., hippocampal CA1 neurons). To test this possibility, we stimulated the Schaffer collaterals of rat hippocampal slices and recorded from stratum pyramidale of CA1 neurons. At approximately 0.5 MAC (MAC is the minimum alveolar anesthetic concentration at one standard atmosphere that is required to eliminate movement in response to noxious stimulation in 50% of subjects), halothane decreased population spike amplitude 37% +/- 21% (mean +/- SD), increased latency 15% +/- 9%, and decreased excitatory postsynaptic potentials 16% +/- 10%. In contrast, at concentrations below (0.4 times) predicted MAC, the nonimmobilizer, 1,2 dichlorohexafluorocyclobutane (2N), slightly (not significantly) increased population spike amplitude, decreased population spike latency 9% +/- 4%, and increased excitatory postsynaptic potentials 22% +/- 16%. At concentrations above (2 times) predicted MAC, 2N did not significantly increase population spike, decreased latency 10% +/- 4%, and did not significantly change excitatory postsynaptic potentials. At 0.1 predicted MAC, a second nonimmobilizer, perfluoropentane, tended (P = 0.05) to increase (11% +/- 9%) population spike amplitude, decreased population spike latency 8% +/- 2%, and tended (P = 0.06) to increase excitatory postsynaptic potentials (9% +/- 8%). We conclude that clinically relevant concentrations of halothane depress synaptic transmission at Schaffer collateral-CA1 synapses and that the nonimmobilizers 2N and perfluoropentane have no effect or are excitatory. The Schaffer collateral-CA1 synapse may serve as a useful model for the production of immobility by volatile anesthetics, but is flawed as a model for the capacity of volatile anesthetics to interfere with memory and learning. Halothane, but not the nonimmobilizers 1,2-dichlorohexafluorocyclobutane and perfluoropentane, inhibits hippocampal synaptic transmission at Schaffer collateral-CA1 synapses.

Halothane, But Not the Nonimmobilizers Perfluoropentane and 1,2-Dichlorohexafluorocyclobutane, Depresses Synaptic Transmission in Hippocampal CA1 Neurons in Rats

Volatile anesthetics may decrease synaptic transmission at central neurons by presynaptic and/or postsynaptic actions. Nonimmobilizers are volatile compounds with lipophilicities that suggest that they should (but do not) prevent motor responses to surgical stimuli. However, nonimmobilizers interfere with learning and memory, and, thus, might be predicted to depress synaptic transmission in areas of the brain mediating memory (e.g., hippocampal CA1 neurons). To test this possibility, we stimulated the Schaffer collaterals of rat hippocampal slices and recorded from stratum pyramidale of CA1 neurons. At approximately 0.5 MAC (MAC is the minimum alveolar anesthetic concentration at one standard atmosphere that is required to eliminate movement in response to noxious stimulation in 50% of subjects), halothane decreased population spike amplitude 37% ± 21% (mean ± SD), increased latency 15% ± 9%, and decreased excitatory postsynaptic potentials 16% ± 10%. In contrast, at concentrations below (0.4 times) predicted MAC, the nonimmobilizer, 1,2 dichlorohexafluorocyclobutane (2N), slightly (not significantly) increased population spike amplitude, decreased population spike latency 9% ± 4%, and increased excitatory postsynaptic potentials 22% ± 16%. At concentrations above (2 times) predicted MAC, 2N did not significantly increase population spike, decreased latency 10% ± 4%, and did not significantly change excitatory postsynaptic potentials. At 0.1 predicted MAC, a second nonimmobilizer, perfluoropentane, tended (P= 0.05) to increase (11% ± 9%) population spike amplitude, decreased population spike latency 8% ± 2%, and tended (P= 0.06) to increase excitatory postsynaptic potentials (9% ± 8%). We conclude that clinically relevant concentrations of halothane depress synaptic transmission at Schaffer collateral-CA1 synapses and that the nonimmobilizers 2N and perfluoropentane have no effect or are excitatory. The Schaffer collateral-CA1 synapse may serve as a useful model for the production of immobility by volatile anesthetics, but is flawed as a model for the capacity of volatile anesthetics to interfere with memory and learning. Implications Halothane, but not the nonimmobilizers 1,2-dichlorohexafluorocyclobutane and perfluoropentane, inhibits hippocampal synaptic transmission at Schaffer collateral-CA1 synapses.

POTASSIUM LEAK TEST PREDICTS OUTCOME IN INTERSTITIAL CYSTITIS

Purpose We tested whether the potassium leak test predicts the outcome of therapy with heparinoids and antidepressants in interstitial cystitis. Materials and Methods We retrospectively reviewed the records of 38 evaluable patients with interstitial cystitis who underwent a potassium leak test at the initial evaluation and who were treated intravesically with heparin or oral sodium pentosan polysulfate for a minimum of 6 months. All but 1 patient were also treated with tricyclic antidepressants. Changes in average pain score during voiding, urinary frequency and nocturia were evaluated. Results The potassium leak test was positive and negative in 23 and 15 patients, respectively. There was no significant difference in the 2 groups at baseline in regard to the male-to-female ratio, patient age, years of symptoms, pain score, urinary frequency, nocturia or anesthetic capacity. After a minimum of 6 months of therapy patients in whom the potassium leak test was positive were more likely to have improvement than those in whom it was negative, as shown by a decrease of greater than 25% in pain score (78 versus 40%, p = 0.01), frequency (83 versus 47%, p = 0.02) and nocturia (83 versus 53%, p = 0.05). However, potassium leak test results showed no significant difference at the 50% decrease level in pain score, frequency or nocturia. Conclusions The potassium leak test may predict outcome in patients with interstitial cystitis who are treated with combined heparinoid and tricyclic antidepressant medication.

Ethanol concentrations approaching minimum alveolar anesthetic concentration are required to suppress learning in a fear-potentiated startle paradigm in rats.

We previously demonstrated that desflurane and two nonimmobilizers dose-dependently decrease learning and memory in rats. This suggests that although they do not suppress movement in response to noxious stimuli, nonimmobilizers act like inhaled anesthetics in their effects on learning and memory. Like most conventional anesthetics, nonimmobilizers have a greater affinity for lipid than for aqueous phases. In the present study, we examined the effect of ethanol on learning and memory to test the hypothesis that a large part of the capacity of anesthetics to affect learning depends on an action on a lipid (nonpolar) phase. Unlike volatile anesthetics and nonimmobilizers, ethanol has a greater affinity for water than for lipids. Thus, if our hypothesis is correct, ethanol should be relatively less potent in its suppression of memory. Rats receiving various doses of ethanol were conditioned to fear a light followed by a footshock. Fear conditioning to the light was subsequently assessed by measurement of potentiation of the acoustic startle reflex in the presence, compared with the absence, of light. Ethanol up to 0.54 minimum alveolar anesthetic concentration (MAC) did not abolish fear, but 0.82 MAC ethanol did abolish learning. Expressed as a fraction of MAC or predicted MAC, ethanol is less potent than desflurane or the nonimmobilizer 1,2-dichlorohexafluorocyclobutane in suppressing learning. This finding is consistent with the hypothesis that the capacity of anesthetics and nonimmobilizers to impair learning and memory depends mostly on an action at a nonpolar site. Abolition of learning and memory is an important property of inhaled anesthetics. This effect primarily results from an action at a lipid (nonpolar) site, rather than a polar site or a water-lipid interface.

Anesthetic implications of epilepsy, status epilepticus, and epilepsy surgery.

Epilepsy is a clinical paroxysmal disorder of recurring seizures, excluding alcohol or drug withdrawal seizures or such recurring exogenous events as repeated insulin-induced hypoglycemia. Epilepsy has a profound impact on each individual diagnosed with this disease. Seizures have been and are thought to arise as a result of abnormalities in (a) neural circuits, (b) excitation/inhibition balance, (c) potassium, and (d) genetic abnormalities. Therapy for epilepsy is either medical, entailing the use of a variety of antiepileptic drugs, or surgical. An urgent approach to seizure control is indicated when status epilepticus occurs. When all standard therapy fails, general anesthesia can be used to control status epilepticus. Surgery is an option in the treatment of epilepsy and requires extensive preoperative evaluation. The primary concerns for the neuroanesthesiologist anesthetizing the patient with epilepsy are the capacity of anesthetics to modulate or potentiate seizure activity and the interaction of anesthetic drugs with antiepileptic drugs. Proconvulsant and anticonvulsant properties have been reported for nearly every anesthetic. If seizure spikes are to be evoked during seizure surgery, then light anesthesia with a proconvulsant anesthetic is used. Conscious analgesia can be used for awake seizure surgery. However, if electrocorticography is not planned, then a general anticonvulsant anesthetic maintenance regimen is used. The latter technique also may be useful in patients whose anesthetic management is complicated by an incidental history of epilepsy.

Pipecuronium-induced neuromuscular blockade during nitrous oxide-fentanyl, enflurane, isoflurane, and halothane anesthesia in surgical patients.

This study was designed to determine the capacity of several anesthetics to augment pipecuronium neuromuscular blockade. The potency of pipecuronium was determined with single-bolus administration of 20-50 micrograms/kg in 160 patients. Patients were anesthetized with N2O/O2 (60:40) supplemented with fentanyl (4-5 micrograms/kg), halothane (0.8%), isoflurane (1.2%), or enflurane (1.7%). Neuromuscular blockade was measured by an acceleration-responsive transducer (the Accelograph, Biometer International, Odense, Denmark). Responses were defined in terms of percent depression in first-twitch height and train-of-four response, and the dose-response curves were constructed after probit transformation of the responses. The dose-response curves were found to be parallel for both first twitch height and train-of-four responses. The dose-response lines for the enflurane and isoflurane groups were displaced significantly (P less than 0.01) to the left of the line for the fentanyl-N2O group. The calculated doses producing 50% depression of first twitch height were 21.9, 21.2, 18.9, and 17.8 micrograms/kg for the N2O-fentanyl, halothane, isoflurane, and enflurane groups, respectively. Corresponding calculated doses for 50% depression of train-of-four response were significantly smaller (15.5, 14.4, 13.7, 11.9 micrograms/kg, respectively). The enhancing effects of the volatile anesthetics were reflected by significant prolongation of the clinical duration of neuromuscular blockade by pipecuronium. It is concluded that the potency of pipecuronium is enhanced more by enflurane and isoflurane than halothane or fentanyl-N2O anesthesia.

Local anaesthesia and immunomodulatory effects of antithyroid drugs

Propylthiouracil (PTU) and propranolol can suppress, while methimazole (MMI) can enhance, mitogenic activation of lymphocytes. The present study investigated whether this effect of PTU, as has been shown for propranolol, relates to local anaesthetic activity. MMI (1 mM) but not PTU (1 mM) reduced the action potential in rat skeletal muscle. Thus, PTU seems to lack local anaesthetic activity. Moreover, the recorded local anaesthetic capacity of MMI hardly explains the stimulatory influence of MMI on lymphocyte activation. Apparently, the interference of MMI and PTU with lymphocyte activation seems to be due to another mechanism than local anaesthetic activity.

Anesthetic pregnanes counteract androgen-induced defeminization.

The capacity of various pregnanes for counteracting androgen-induced defeminization was evaluated in an attempt to define some cellular mechanisms involved in the defeminization process. 5-day-old female rats received 60 microgram testosterone propionate (TP) along with one of various pregnanes: progesterone, 5 beta-pregnandione, 5 beta, 3 alpha-pregnanolone, 5 beta, 3 beta-pregnanolone, 5 alpha-pregnandione, 5 alpha, 3 beta-pregnanolone, 5 alpha, 3 alpha-pregnanolone or chlormadinone acetate. Protection against defeminization was defined as a significantly smaller proportion of anovulatory animals in a group compared to the control TP group. Data were analyzed at 60, 90 and 120 days of age. The anesthetic potency of the pregnanes was evaluated in 5-day-old male rats through the analysis of EEG and EMG records. Anesthetic pregnanes - progesterone, 5 beta-pregnandione and 5 beta, 3 alpha-pregnanolone - counteracted defeminization while nonanesthetic pregnanes - 5 alpha-pregnanes, chlormadinone acetate and 5 beta, 3 beta-pregnanolone - did not. The results show a clear relation between anesthetic capacity and protection against defeminization.

The importance of the hydrophobic interactions of local anesthetics in the displacement of polyvalent cations from artificial lipid membranes

1. 1. Paramagnetic cations such us europium and praseodymium allow the distinction between the NMR signals arising from internal and external trimethylammonium groups of lecithin liposomes, the peak from the external groups being shifted. This effect seems to depend on the binding of the cation to the phosphate groups of lecithin and on the modification of the magnetic properties of the trimethylammonium protons in the neighborhood. 2. 2. The displacement of Pr 3+ away from the membrane surface by different local anesthetics was related to the ability of these compounds to interact hydrophobically with the membrane. 3. 3. Tetracaine, which interacts hydrophobically with zwitterionic lecithin, was able to reverse the paramagnetic induced shift very efficiently, as judged by the complete return of the shifted peak to its original position. Procaine, lidocaine and tetramethylammonium chloride, which do not interact hydrophobically with the liposomes, failed to displace the paramagnetic cation. 4. 4. The property of the local anesthetic to bind hydrophobically to the lipid membrane enables the positively charged group of tetracaine to complete favourably with the polyvalent cation for the lecithin phosphates. The capacity of local anesthetics to displace polyvalent cations away from the artificial membrane surface could be directly related to their anesthetic potency.

Latency between intravenous injection of progestins and the appearance of estrous behavior in estrogen-treated ovariectomized rats

The latency of the lordosis response after different progestins and progesterone metabolites given by the intravenous route was studied in spayed rats pretreated with estradiol benzoate (10 μg/kg sc). Progestins with anesthetic capacity (progesterone, medroxyprogesterone) had a longer latency at high doses than at low. It is suggested that the true latency for these progestins is masked by the anesthetic property even at dose levels which did not give an overt sedative effect. In analogous experiments with isopregnenone, which lacks an anesthetic effect, a median latency of 10–30 min was obtained regardless of doses given (0.5, 5.0 mg). The isopregnenone data suggest that a certain time is required between the treatment and the appearance of lordotic behavior which is longer than could be expected to be due only to transport from the circulation to the brain tissue.