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PubMed2003

[Hemothorax as complication of laparoscopic technique].

A 69-year-old woman with a hiatal hernia and esophagitis caused by reflux was scheduled for laparoscopic Nissen fundoplication. Anesthetic induction was accomplished with fentanyl, propofol and rocuronium and maintenance with sevoflurane and rocoronium. Hemodynamics were stable until the end of surgery, when a sudden decrease in blood pressure to 40/20 mm Hg and arterial carbon dioxide tension to 14 mm Hg were observed. Anesthetic insufflation was stopped and physiological saline solution and ephedrine were administered. Hemothorax and air embolism were ruled out. After hemodynamic recovery, renewal of anesthetic insufflation was contraindicated, laparoscopy was halted, and hemoperitoneum was ruled out. After extubation, the patient was transferred to the recovery room, where hemodynamic instability worsened progressively. A chest radiograph suggest left hemothorax and an emergency thoracotomy was performed. After evacuation of multiple clots from the pleural cavity, the point of hemorrhage was located at the right crus of the diaphragm and bleeding was arrested. Postoperative recovery continued with no further events. The most common complications of laparoscopy are pneumothorax, gastroesophageal perforation and hemorrhage. However, given the complexity of the technique, the possibility of bleeding in the pleural cavity, as occurred in this case, should be considered. This case highlights the importance of rigorous intraoperative monitoring and postoperative surveillance by the anesthesiologist.

Aged↗
PubMed2003

[Early extubation with caudal morphine after pediatric heart surgery].

OBJECTIVES: To analyze the viability of immediate extubation of children after corrective surgery for congenital heart defects with extracorporeal membrane oxygenation using an anesthetic technique involving caudal morphine, and to study the effect on length of stay in the pediatric intensive care unit (PICU) or elsewhere in the hospital. MATERIAL AND METHODS: Twenty-nine ASA I-II patients without coagulation alterations undergoing surgery to correct simple heart defects were selected for extubation after surgery. Anesthesia was provided with with sevoflurane, midazolam, rocuronium, fentanil (maximum dose 10 micrograms/Kg) and a bolus of caudal morphine (50-60 micrograms/Kg) after anesthetic induction. Patient characteristics, type of surgery, times of extracorporeal circulation and of ischemia, arterial blood gases upon arrival in the PICU, postoperative complications and quality of analgesia were the variables analyzed. We also compared length of stay in the PICU and hospital for the study group and for a historical control group of 23 patients who had no received caudal morphine or been selected for early extubation. RESULTS: All patients were extubated satisfactorily in the operating room. None required reintubation or reoperation. Postoperative pain was controlled with metamizol alone for 79.3%. No episodes of respiratory depression or neurological complications were observed. PICU and hospital stays were significantly shorter in the study group than in the control group. CONCLUSIONS: Of patients undergoing simple corrective heart surgery with extracorporeal membrane oxygenation immediate extubation did not increase postoperative morbimortality and shortened the hospital stay. A single dose of caudal morphine provided optimum conditions for extubation and good control of postoperative pain. Strict measures must be taken, however, to avoid postpuncture bleeding.

Analgesics, Non-Narcotic↗
PubMed2003

Off-pump coronary artery bypass surgery: evaluation of extubation time and predictors of failed early extubation.

Anesthesia during and after off-pump surgery is critical for the outcome of the procedure. Intubation time has been shown to correlate with ICU time and length of stay. This study is to evaluate the extubation time and predictors of prolonged extubation in this institution. One hundred and sixty consecutive patients during Jan 2001-June 2002, excluding pre-operative tracheostomy (n = 1) were retrospectively reviewed. Anesthetic agents include fentanyl, rocuronium Bromide, midazolam and sevoflurane. Phenylephrine and nitroglycerine were used to maintain adequate arterial pressures. Post-operative pain control was mainly with intravenous fentanyl and oral pain medications. The extubation time was divided into 4 groups; 0-2 h, n = 76, mean = 1.11 +/- 0.5 h; 2-4 h, n = 30, mean = 2.91 +/- 0.5 h; 4-24 h, n = 39, mean = 11.44 +/- 7.3 h; > 24 h, n = 5, mean = 33.3 +/- 21 h. The data were collected and analyzed following the guidelines of National STS cardiac surgery database. All pre-operative risk factors included: Age (> 70 yrs vs < or = 70 yrs), gender (male vs female), diabetes (yes vs no), hypertension (yes vs no), morbid obesity (yes vs no), renal insufficiency (yes vs no), chronic obstructive lung disease (yes vs no), history of cerebrovascular accident (yes vs no), smoking (yes vs no), dyslipidemia (yes vs no), history of myocardial infarction (MI) (yes vs no), history of congestive heart failure (CHF) (yes vs no), unstable angina (yes vs no), left ventricular ejection fraction (LVEF) (> 40% vs < or = 40%), left main (LM) lesion (LM > 50% vs LM < or = 50%), intra-aortic balloon pump (IABP) used (yes vs no) and time between operating and closing (> 4.30 h vs < or = 4.30 h) were used to predict failed early extubation (2 h). More than 50 per cent of the patients were extubated in less than 2 h (1.11 +/- 0.5 h) and only 5 patients were extubated after 24 h. Univariate analysis revealed old age, diabetes, MI, CHF, LVEF < or = 0.4 and the use of IABP are the predictors (p < 0.05) of failed early extubation. Multivariate analysis of these variables revealed old age with adjusted odds ratio of 4.6 (95% CI = 1.5-13.7) p < 0.01, diabetes with adjusted odds ratio of 3.2 (95% CI = 1.3-7.5) p < 0.01 and IABP used with adjusted odds ratio of 4.3 (95% CI = 1.3-14.6) p = 0.02 are the predictors of fail early extubation. The findings suggested early extubation is possible in OPCAB surgery and attention should be made when operate in patients who have old age, diabetes, and IABP used.

Adult↗
PubMed2002

[Placement of a double-lumen tube using a 6 mm diameter fibro-bronchoscope and a Cook exchange catheter in a patient with unforeseen tracheal intubation difficulty].

The trachea of a 74-year-old man undergoing left pneumonectomy could not be intubated in two attempts after induction of anesthesia with midazolam, fentanyl, propofol and rocuronium. Difficult intubation had not been foreseen, but inspection through the laryngoscope revealed Cormack and Lehane grade IV conditions. Because a small-caliber fiberoptic bronchoscope was unavailable for intubation with a double-lumen endobronchial tube, we inserted a No. 9 orotracheal tube with a 6 mm bronchoscope as far as the left main bronchus. Intubation was aided by a universal adaptor for fiberoptics with a face mask and a Williams cannula. We were then able to ventilate the patient manually with 100% oxygen during bronchoscopy. As selective ventilation was required during surgery, a No. 11 Cook-type airway exchange catheter was inserted into the left main bronchus, the tracheal tube was removed, and was used to guide a No. 39F left double-lumen endobronchial tube through the bronchus. Insertion was uncomplicated and selective ventilation was satisfactory. The technique described is a new application for the Cook exchange catheter that allows selective bronchial in difficult cases when a small-caliber fiberoptic bronchoscope is unavailable.

Aged↗
PubMed2004

Immediate Extubation after Aortic Valve Surgery Using High Thoracic Epidural Anesthesia.

Abstract Purpose: Fast-track anesthesia has gained widespread use in cardiac centers around the world. No study has focused on immediate extubation after aortic valve surgery. This study examines the feasibility and hemodynamic stability of immediate extubation after simple or combined aortic valve surgery using thoracic epidural anesthesia. Methods: Thirty patients undergoing aortic valve surgery with an ejection fraction of more than 30% were included in this prospective audit. After insertion of a high thoracic epidural catheter, induction with fentanyl 2 to 4 microg/kg, administration of propofol 1 to 2 mg/kg, and endotracheal intubation facilitated by rocuronium, anesthesia was maintained with sevoflurane titrated according to bispectral index (target, 50). Perioperative analgesia was provided by high thoracic epidural analgesia (TEA) (bupivacaine 0.125% 6-14 mL/h). Hemodynamic data were compared by Friedman test. P <.05 was considered to show a significant difference. Data are presented as median (25th-75th percentile). Results: Patients underwent simple aortic valve surgery (n = 17) or combined aortic valve surgery (n = 13) with additional coronary artery bypass grafting (n = 8), replacement of the ascending aorta (Bentall procedure) (n = 4), and repair of open foramen ovale (n = 1). All 30 patients were extubated within 15 minutes after surgery at 36.5 degrees C (36.4 degrees C-36.6 degrees C). There was no need for reintubation. Pain scores were low immediately after surgery and 6, 24, and 48 hours after surgery at 0 (0-3.5), 0 (0-2), 0 (0-2), and 0 (0-2), respectively. During and up to 6 hours after surgery, there was no significant hemodynamic change due to TEA. Fifteen of 30 patients needed temporary pacemaker activation. There were no complications related to TEA. Conclusions: Immediate extubation is feasible after aortic valve surgery with high thoracic epidural analgesia and maintenance of hemodynamic stability throughout surgery. Immediate extubation after aortic valve surgery is a promising new path in cardiac anesthesia.

Journal Article↗
PubMed2004

Peri-intubation cardiovascular response during low dose remifentanil or sufentanil administration in association with propofol TCI. A double blind comparison.

AIM: The aim of this study was to compare the effects on cardiovascular modifications induced by tracheal intubation when low dose infusion of remifentanil or sufentanil are used in association with propofol target controlled infusion. METHODS: Sixty normotensive, ASA I-II-III, Mallampati Score <3 undergoing general anaesthesia for major elective abdominal surgery, received i.m. midazolam (0.05 mg/kg) and atropine (0.01 mg/kg) 30 min before induction. They were randomly divided in a double-blind fashion into two groups receiving for induction respectively target controlled infusion of propofol (site-effect 3.0 microg/ml) and sufentanil (0.01 microg/kg/min) or remifentanil (0.1 microg/kg/ min) infusion. Rocuronium (0.6 mg/kg) was administered. Following intubation, the lungs were mechanically ventilated with an oxygen/air mixture. RESULTS: Bispectral index score and haemodynamic variables were recorded at baseline, after induction, during intubation and 1-3-5 min after the trachea was intubated. No differences in systolic and diastolic arterial pressure were observed in the sufentanil group, while the remifentanil group showed transient systolic and diastolic variations after intubating manoeuvers. The heart rate and bispectral index score were not affected in either group. CONCLUSION: In healthy normotensive patients the use of a small dose of either remifentanil or sufentanil after standard midazolam premedication, proved to be an effective strategy to blunt the cardiovascular response to intubation.

Anesthetics, Combined↗
PubMed2004

[Cesarean delivery and exeresis of a pheochromocytoma performed under epidural and general anesthesia].

A 33-year-old pregnant woman with episodes of nocturnal tachycardia and anxiety diagnosed with extra-renal pheochromocytoma in her 28th month of gestation was admitted in her 38th week for an alpha-adrenergic block prior to elective cesarean section and tumor exeresis. The cesarean section was performed with the patient given an epidural lumbar block, and immediately after delivery of the fetus total intravenous anesthesia (with propofol, remifentanil, and rocuronium) was administered in addition to the continuous epidural analgesia used during tumor resection and postoperatively. No complications developed during surgery or recovery and the clinical courses were satisfactory for both mother and child. The use of propofol and remifentanil in combination with epidural anesthesia is not common in our clinical context. We point out that the multimodal technique affords good hemodynamic stability, guarantees satisfactory analgesia, and reduces the need for vasoactive drugs.

Adrenal Gland Neoplasms↗
PubMedDate not supplied

Bispectral Index System (BIS) monitoring reduces time to discharge in children requiring intramuscular sedation and general anesthesia for outpatient dental rehabilitation.

PURPOSE: Pediatric patients who receive both intramuscular (i.m.) sedation and general anesthesia (GA) for oral rehabilitation occasionally experience prolonged sedation and delayed discharge. The Bispectral Index System (BIS) is an EEG monitor that measures the level of sedation. The authors compared discharge times of patients who had BIS monitoring to those who did not to determine if the use of BIS speeded discharge. METHODS: After IRB approval, 20 children were enrolled. BIS was monitored continuously from admission until discharge. Each child received ketamine, midazolam, and glycopyrrolate i.m. Once sedated, the patient was transferred to the operating room, monitored, and i.v. access was established. GA proceeded with sevoflurane, rocuronium, and fentanyl. Randomly, in half the patients, the anesthesiologist knew and maintained the BIS at GA level of sedation by adjusting sevoflurane. In the rest, the anesthesiologist did not know BIS. Time from turning of sevoflurane to discharge was noted and compared. RESULTS: Patients where the BIS was known and used were discharged 60+/-13 minutes after the end of GA. Patients where BIS was unknown were discharged 90+/-11 minutes after the end of GA (P<.001). CONCLUSIONS: Based on the data, the authors recommend the use of BIS to facilitate faster discharge of pediatric patients who require i.m. sedation and GA for oral rehabilitation.

Adjuvants, Anesthesia↗
PubMed2005

Desflurane and sevoflurane in elderly patients during general anesthesia: a double blind comparison.

AIM: To investigate pulmonary wash-out of sevoflurane and desflurane and the quality of recovery from anesthesia in elderly patients. METHODS: Thirty-six patients aged >65 years, ASA II, were assigned in a double blind fashion to either desflurane (n=18) or sevoflurane (n=18) anesthesia. All received propofol 2 mg/kg and remifentanil 0.2 microg/kg/min for induction and 0.6 mg/kg of rocuronium. When the trachea was intubated volatile anaesthetic was administered. All data were recorded 1, 3, 5, 15, 30 min after intubation and then every 15 min. All data were recorded 1, 2, 3, 4, 5 min after suspension of all agents. Once extubated simple orders and questions were given every minute, times of appropriate response were noted. The patients were then transferred to the recovery room, until discharge to the floor. Postoperative pain control was obtained by a continuous iv infusion of ketorolac 60 mg and tramadol 100 mg. The latter was incremented by supplemental boluses of 50 mg according to patient needs (VAS <4) up to a maximum of 300 mg/24h. RESULTS: The F(A)/F(A0) ratio was lower in the desflurane group after halogenated agent suspension (p= or <0.05). Desflurane proved to have a faster wash out curve with respect to sevoflurane. Early recovery, as indicated by the time necessary to appropriately answer simple questions after the discontinuation of anesthetics, showed a significant advantage for desflurane (p= or <0.05). VAS was higher in the desflurane group as well as the needs for postoperative analgesia. CONCLUSIONS: Patients receiving desflurane reported faster recovery from anesthesia but an earlier and more intense perception of pain after surgery.

Aged↗
PubMed2005

Near-miss injection of an anesthetic agent into a cerebrospinal fluid external ventricular drain: special report.

OBJECTIVE AND IMPORTANCE: Human error has been increasingly recognized as a cause of patient morbidity and mortality. One method of error prevention is the reporting of a near-miss event. We report that intravenous anesthetic agents were nearly injected into the external ventricular drainage (EVD) of a patient during an emergency shunt procedure. CLINICAL PRESENTATION: A 3-year-old male patient with multiple cerebrospinal fluid shunts and shunt infection had an external ventricular drain catheter tunneled to exit just inferior to the left clavicle during a previous procedure. The exit site was covered by an occlusive dressing. This particular system, the Codman external drainage system II collection bag and tubing set (Codman & Shurtleff, Inc., Raynham, MA), contains two access ports (a three-way stoppered port and an angled rubber stoppered injection port). At induction of anesthesia, the EVD system was mistaken for a central venous line and was nearly injected with propofol and rocuronium. Fortunately, the error was quickly recognized and the patient came to no harm. INTERVENTION AND TECHNIQUE: A modified EVD system has recently been released that does not include the three-way port, and features an embedded bright green stripe in the tubing to distinguish it from intravenous tubing. CONCLUSION: We recommend using caution when tunneling EVDs to sites that might be confused with central venous access sites. EVD system tubing should be designed so it can be easily distinguished from intravenous tubing, and it should be clearly labeled as an EVD line.

Anesthetics↗
PubMedDate not supplied

Bispectral index system (BIS) monitoring reduces time to extubation and discharge in children requiring oral presedation and general anesthesia for outpatient dental rehabilitation.

PURPOSE: Pediatric oral rehabilitation patients who receive presedation with oral Versed and general anesthesia (GA) occasionally experience prolonged sedation and delayed discharge. The Bispectral Index System (BIS) is an EEG monitor that measures the anesthesia level. The purpose of this study was to compare the effects of monitoring the BIS to not monitoring the BIS on time from discontinuation of GA to extubation and to discharge. METHODS: Twenty-nine children were enrolled. BIS was monitored from admission until discharge. Each child received 0.7 mg/kg of oral Versed. In the operating room, GA with sevoflurane (IH), rocuronium 1 mg/kg (IV), fentanyl 1 microg/kg (IV), and ondansetron 0.15 mg/kg (IV) was administered. Randomly, in half the patients, the anesthesiologist maintained the level of anesthesia and BIS by adjusting sevoflurane. In the rest, the anesthesiologist did not know BIS. The time from turning off sevoflurane to discharge was compared. RESULTS: Group 1 patients were extubated 5+/-2 minutes sooner than group 2 patients (P=.04). The post-anesthesia care unit stay for group 1 patients was 47+/-17 minutes compared to 63+/-17 minutes in group 2. (p=0.02). CONCLUSIONS: Monitoring anesthesia with BIS promotes earlier extubation and discharge for pediatric dental patients who receive oral Versed and sevoflurane GA.

Administration, Oral↗
PubMed2006

[The agents related to anesthetic practice: preface and comments].

Every new agent appears from necessity, and a medical agent is not an exception. In the history of anesthesia, intravenous anesthetic agents with such properties as rapid onset and short acting, appear necessarily. Remifentanyl is an example. An agent with less adverse effect for reversal of nondepolarizing neuromuscular agents is expected to appear. It is cyclodextrin, Org25969 which entraps rocuronium resulting in its reversal. Two kinds of beta-blockers are in our hand to control perioperative cardiac events and they also show anti-stress effect at the same time. The newly biosynthesized antirheumatic agents will give patients relief from intolerable joints pain of rheumatic arthritis.

Anesthesia↗
PubMed2006

Anaesthetic management in asthma.

Anaesthetic management in asthmatic patients has been focused on avoiding bronchoconstriction and inducing bronchodilation. However, the definition of asthma has changed over the past decade. Asthma has been defined as a clinical syndrome characterized by an inflammatory process that extends beyond the central airways to the distal airways and lung parenchyma. With this concept in mind, and knowing that asthma is a common disorder with increasing prevalence rates and severity worldwide, a rational choice of anaesthetic agents and procedures is mandatory. Thus, we pursued an update on the pharmacologic and technical anaesthetic approach for the asthmatic patient. When feasible, regional anaesthesia should be preferred because it reduces airway irritation and postoperative complications. If general anaesthesia is unavoidable, a laryngeal mask airway is safer than endotracheal intubation. Lidocaine inhalation, alone or combined with albuterol, minimizes histamine-induced bronchoconstriction. Propofol and ketamine inhibit bronchoconstriction, decreasing the risk of bronchospasm during anaesthesia induction. Propofol yields central airway dilation and is more reliable than etomidate or thiopental. Halothane, enflurane, and isoflurane are potent bronchodilators and can be helpful even in status asthmaticus. Sevoflurane has shown controversial results in asthmatic patients. Vecuronium, rocuronium, cisatracurium, and pancuronium do not induce bronchospasm, while atracurium and mivacurium can dose-dependently release histamine and should be cautiously administered in those patients. Further knowledge about the sites of action of anaesthetic agents in the lung, allied with our understanding of asthma pathophysiology, will establish the best anaesthetic approach for people with asthma.

Analgesics, Opioid↗
PubMedDate not supplied

[Anaphylactic reaction as a side-effect of administration of general anesthetics and neuromuscular blocking agents].

The incidence of anaphylactic reactions during anesthesia is between 1:5000 and 1:25000 anesthetics. During the IgE-mediated anaphylactic reaction mast cells release proteases such as tryptase, histamine and vasoactive mediators. The release of mediators from the mast cells and basophils is responsible for the immediate clinical manifestations of anaphylaxis. Anaphylactoid reactions can be caused directly by a release of histamine and other mediators from mast cells and basophils and they don't depend on interaction of IgE antibodies with antigen. The most frequent agents that cause anaphylactic and anaphylactoid reactions during anesthesia are neuromuscular blocking agents (among them the highest percent refers to rocuronium and succinylcholine), some general anesthetics, antibiotics, blood and blood products, opioids and latex. Increased tryptase concentration in serum is a marker for systemic mast cell activation. Skin tests (in vivo) are used for verification of specific hypersensitivity to drugs in patients after anaphylactic reaction. In vitro tests prove the presence of specific IgE antibodies for drugs. The plan for the treatment of anaphylactic reactions must be established before the event. Airway maintenance, 100% oxygen administration, intravascular volume expansion and epinephrine are essential to treat the hypotension and hypoxia that result from vasodilatation, increased capillary permeability and bronchospasm. As soon as the diagnosis has been made the adrenalin should be given intravenously 1 to 3 ml of 1:10000 aqueous solution (0.1 mg/ml) over 10 minutes. Prevention is possible with methylprednisolone 125 mg i.v. 1 hour before administering of anesthetics and neuromuscular blocking agents with or without antihistaminic chlorpiramine-chloride 1 amp i.v. few minutes before anesthesia.

Anaphylaxis↗
PubMedDate not supplied

[Calculated and measured blood propofol concentrations during target-control infusion by means of a Diprifusor system during operations under extracorporeal circulation].

The study was undertaken to compare measured versus calculated propofol concentrations (C(m) and C(c), respectively), by using Diprifusor technology in cardiac surgery with cardiopulmonary bypass (CPB). The study included 10 NYHA II-III patients (aged 27-45 years) undergoing mitral valve replacement. Propofol (Diprivan PFS 50 ml, AstraZeneca) was target-control infused (TCI) by the Diprifusor system (Graseby 3500). C(c) was titrated to maintain the BIS value close to 40. Propofol in doses of 2.1 +/- 0.05 mg/kg was required for induction. Anesthesia before, during, and after CPB required propofol in doses of 5.4 +/- 0.3, 3.9 +/- 0.2, and 3.1 +/- 0.2 mg/kg/h, respectively. The doses of fentanyl were 4.4 +/- 0.1 microg/kg for induction of anesthesia and 4.5 +/- 0.4, 2.4 +/- 0.2, and 0.2 +/- 0.1 mg/kg/h for its maintenance before, during, and after CPB, respectively. The patients received rocuronium in the standard doses for neuromuscular relation. C(m) was determined by high-performance liquid chromatography with ultraviolet detection (Agilent 1100, column C18, Altima). Blood propofol concentrations were measured at: 1) intubation; 2) skin incision; 3) sternotomy; 4) aortic cannulation; 5) 30 min of CPB; 6) 60 min of CPB; 7) the end of CPB; 8) 30 min following CPB; 9) skin closure; 10) awakening. Data were expressed as mean +/- SEM. The values were compared by linear regression. Student's t-test was used with p < 0.05. C(m) was 2 times higher than C(c) at all stages. A close correlation was found between C(m) and C(c): r = 0.83, p = 0.038. It is concluded that Marsh's PK/PD model predicts the trend in blood propofol concentrations during uncomplicated operations on the open heart satisfactorily, but C(c) was constantly 2 times less than C(m).

Adult↗
PubMed1993

Speed of action of various muscle relaxants at the neuromuscular junction binding vs. buffering hypothesis.

The speed of action of several nondepolarizing muscle relaxants (gallamine, rocuronium, D-tubocurarine, atracurium, vecuronium, pancuronium and doxacurium) was tested iontophoretically at the frog cutaneous pectoris neuromuscular junction at various temperatures. If differences in rate of onset and offset are due to different molecular rates of binding (and unbinding), and of resulting conformational changes, they should be strongly temperature dependent. In contrast, if differences are due to differences in buffered diffusion, temperature dependence should be low to moderate. The onset and recovery time constants of inhibition of brief acetylcholine pulses, caused by long pulses of relaxants for all of the muscle relaxants, were inversely related to apparent dissociation constants (KD values), that ranged from 4.56 microM (gallamine) to 0.11 microM (doxacurium). The kinetics showed only modest temperature dependence (Q10 values of 1/time constant of offset were typically < 1.4). Because KD values of all muscle relaxants were even less temperature dependent (Q10 < 1.3), this suggests that the kinetics of inhibition is probably determined by the extent of buffering in the synaptic cleft, and not by binding and unbinding. Diffusion of relaxants from the synaptic cleft is expected to be strongly buffered, because the nerve terminal presents a physical barrier to diffusion, and because of extremely high density of acetylcholine receptors. The density of acetylcholine receptors can be calculated from the time constant of offset and KD values of various relaxants, assuming that buffer diffusion is determining the kinetics of action of muscle relaxants.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Structure-pharmacodynamic-pharmacokinetic relationships of steroidal neuromuscular blocking agents.

Several new steroidal non-depolarizing muscle relaxants have been synthesized and tested in humans recently. Results from these studies suggest that the differences in time-course of action between these compounds are mainly, if not totally, related to differences in biodisposition. Biodisposition, in turn, is determined largely by the physico-chemical characteristics of the drug, such as degree of lipophilicity and protein binding. The various pharmacodynamic and pharmacokinetic variables of a series of structurally related steroidal relaxants, varying in the ester substituent at the 17th position of the androstane skeleton, have been related to the degree of lipophilicity. Significant positive relationships could be shown between lipophilicity (logP at pH 7.4) and, among other things, potency (ED90), effective concentration (EC50), unbound plasma clearance (CLupl) and rate constant of transport between plasma and biophase (ke0). The aforementioned relationships between lipophilicity and pharmacokinetic variables resulted in significant inverse relationships between lipophilicity and time course parameters, such as onset time and duration of neuromuscular blocking effects. It is concluded that changes in the molecular structure of steroidal relaxants which enhance lipophilicity coincide with a decrease of (intrinsic) potency and a shorter time course of action. Protein binding appears to be of minor importance for the biodisposition and time course characteristics, since there were only small differences in degree of protein binding between most of the investigated compounds. However, the surprisingly fast initial rate of block development observed with rocuronium may in part result from its relatively high unbound fraction in plasma.

Adolescent↗
PubMed1995

Research and development of aminosteroid neuromuscular blocking agents: past and future.

This article attempts to summarize more than 25 years of chemistry and pharmacology research aimed at the search for clinically useful muscle relaxants based on an amino-androstane skeleton. This research strategy has produced three clinically useful drugs (pancuronium, vecuronium and rocuronium), and in addition has demonstrated that it is indeed possible to design a non-depolarizing neuromuscular blocker with the onset/offset characteristics of suxamethonium. Lastly, much has been learned about the variable clinical predictiveness of data obtained in various animal species with these compounds. This factor is probably mainly responsible for the difficulties and delay in producing the non-depolarizing suxamethonium equivalent.

Animals↗