The Performance of an Artificial Neural Network Model in Predicting the Early Distribution Kinetics of Propofol in Morbidly Obese and Lean Subjects.

BACKGROUND: Induction of anesthesia is a phase characterized by rapid changes in both drug concentration and drug effect. Conventional mammillary compartmental models are limited in their ability to accurately describe the early drug distribution kinetics. Recirculatory models have been used to account for intravascular mixing after drug administration. However, these models themselves may be prone to misspecification. Artificial neural networks offer an advantage in that they are flexible and not limited to a specific structure and, therefore, may be superior in modeling complex nonlinear systems. They have been used successfully in the past to model steady-state or near steady-state kinetics, but never have they been used to model induction-phase kinetics using a high-resolution pharmacokinetic dataset. This study is the first to use an artificial neural network to model early- and late-phase kinetics of a drug. METHODS: Twenty morbidly obese and 10 lean subjects were each administered propofol for induction of anesthesia at a rate of 100 mg/kg/h based on lean body weight and total body weight for obese and lean subjects, respectively. High-resolution plasma samples were collected during the induction phase of anesthesia, with the last sample taken at 16 hours after propofol administration for a total of 47 samples per subject. Traditional mammillary compartment models, recirculatory models, and a gated recurrent unit neural network were constructed to model the propofol pharmacokinetics. Model performance was compared. RESULTS: A 4-compartment model, a recirculatory model, and a gated recurrent unit neural network were assessed. The final recirculatory model (mean prediction error: 0.348; mean square error: 23.92) and gated recurrent unit neural network that incorporated ensemble learning (mean prediction error: 0.161; mean square error: 20.83) had similar performance. Each of these models overpredicted propofol concentrations during the induction and elimination phases. Both models had superior performance compared to the 4-compartment model (mean prediction error: 0.108; mean square error: 31.61), which suffered from overprediction bias during the first 5 minutes followed by under-prediction bias after 5 minutes. CONCLUSIONS: A recirculatory model and gated recurrent unit artificial neural network that incorporated ensemble learning both had similar performance and were both superior to a compartmental model in describing our high-resolution pharmacokinetic data of propofol. The potential of neural networks in pharmacokinetic modeling is encouraging but may be limited by the amount of training data available for these models.

Lean body weight scalar for the anesthetic induction dose of propofol in morbidly obese subjects.

BACKGROUND: The unique anesthetic risks associated with the morbidly obese (MO) population have been documented. Pharmacologic management of these patients may be altered because of the physiologic and anthropometric changes associated with obesity. Unfortunately, studies examining the effects of extreme obesity on the pharmacology of anesthetics have been sparse. Although propofol is the induction drug most frequently used in these patients, the appropriate induction dosing scalar for propofol remains controversial in MO subjects. Therefore, we compared different weight-based scalars for dosing propofol for anesthetic induction in MO subjects. METHODS: Sixty MO subjects (body mass index ≥40 kg/m(2)) were randomized to receive a propofol infusion (100 mg · kg(-1) · h(-1)) for induction of anesthesia based on total body weight (TBW) or lean body weight (LBW). Thirty control subjects (body mass index ≤25 kg/m(2)) received a propofol infusion (100 mg · kg(-1) · h(-1)) based on TBW. Syringe drop was used as the marker for loss of consciousness (LOC), at which point the propofol infusion was stopped. The propofol dose required for syringe drop and time to LOC were recorded. RESULTS: Total propofol dose (mg/kg) required for syringe drop and time to LOC were similar between control subjects and MO subjects given propofol based on LBW. MO subjects receiving a propofol infusion based on TBW had a significantly larger propofol dose and significantly shorter time to LOC. There was a strong relationship between LBW and total propofol dose received in all 3 groups. CONCLUSION: LBW is a more appropriate weight-based scalar for propofol infusion for induction of general anesthesia in MO subjects.

Perioperative pharmacology in morbid obesity.

PURPOSE OF REVIEW: Morbid obesity alters drug dose requirement and time course of drug response. In addition, morbid obesity's impact on many organ systems decreases the margin of safety of anesthetic drugs. Consequently, incorrect dosing will increase the rate of perioperative complications. In this review, we will discuss factors that affect the pharmacokinetics and pharmacodynamics of anesthetic agents in the obese population, we specify certain dosing scalars, and we relate our current knowledge of obesity's effects on the clinical pharmacology of anesthetic drugs. RECENT FINDINGS: A morbidly obese individual's increased cardiac output requires administration of higher drug doses than would be required for a standard-size person to attain the same peak-plasma concentration. Lean body weight (LBW) is highly correlated with the increased cardiac output, more so than fat mass or other variables. For most drugs, clearance increases nonlinearly with total body weight but linearly with LBW. Morbid obesity has no clinically significant impact on the uptake of the inhalation anesthetics isoflurane, sevoflurane, and desflurane when used in routine clinical practice. Total body weight dosing of neuromuscular blocking agents will result in a prolonged effect. SUMMARY: For the induction dose of hypnotics and the initial dose of other drugs that have a fast onset of effect, cardiac output or LBW are relevant dosing scalars. For maintenance dosing, LBW seems to be a more appropriate dosing scalar than total body weight.

Is it more difficult to cannulate the right internal jugular vein in morbidly obese patients than in nonobese patients?

BACKGROUND: The placement of an internal jugular vein (IJV) catheter is considered to be more difficult in morbidly obese patients. The objective of this study was to compare the success of simulated IJV puncture between morbidly obese patients and a nonobese control group. METHODS: Thirty-four morbidly obese patients with body mass index (BMI, kg/m(2)) >/=40 were compared with 36 patients with BMI < 30. Right IJV puncture was simulated using an ultrasound probe directed towards the sternal notch at the midpoint between the sternal notch and the mastoid process. The investigator placing the probe was blinded as to the image being created on the ultrasound machine. Success rate was assessed at three different head rotation angles from midline; 0 degrees , 30 degrees , and 60 degrees . RESULTS: There was no statistically significant difference in successful simulated IJV puncture between two groups for any of the head positions. However, there was a higher incidence of the carotid artery (CA) puncture in the morbidly obese patient group when the head rotation was advanced from neutral position to 60 degrees (p < 0.05). In addition, the ultrasound showed significantly more overlapping of the IJV over the CA in morbidly obese patients at 0 degrees (p < 0.05) and 30 degrees (p < 0.05). Our results show no statistically significant difference in success rate of IJV puncture between morbidly obese patients and nonobese patients. Keeping the head in a neutral position in morbidly obese patients minimizes the overlapping of the IJV over the CA and the risk of CA puncture. CONCLUSION: However, due to the fact that even in the neutral position there is a significant increase in overlap between IJV and CA, we recommend the use of ultrasound guidance for IJV cannulation in obese patients.

Obesity modestly affects inhaled anesthetic kinetics in humans.

BACKGROUND: Few studies have determined the effect of obesity on inhaled anesthetic pharmacokinetics. We hypothesized that the solubility of potent inhaled anesthetics in fat and increased body mass index (BMI) in obese patients interact to increase anesthetic uptake and decrease the rate at which the delivered (FD) and inspired (FI) concentrations of an inhaled anesthetic approach a constantly maintained alveolar concentration (end-tidal or FA). This hypothesis implies that the effect of obesity would be greater with a more soluble anesthetic such as isoflurane versus desflurane. METHODS: In 107 ASA physical status I-III patients, anesthesia was induced with propofol, tracheal intubation facilitated with neuromuscular blockade, and ventilation controlled with 50% nitrous oxide in oxygen to maintain end-tidal carbon dioxide concentrations between 35 and 45 mm Hg. Isoflurane or desflurane was administered in a 1 L/min inflow rate at FD concentrations sufficient to maintain FA at 0.6 minimum alveolar anesthetic concentration (0.7% or 3.7%, respectively). FD, FI, and FA were measured 5, 10, 20, 40, 60, 90, 120,150, and 180 min after starting potent inhaled anesthetic delivery. RESULTS: Fifty-nine patients received isoflurane and 48 received desflurane. BMI ranged between 18 and 63 kg/m(2) and demographic variables did not differ between anesthetic groups. For isoflurane, FD/FA or FI/FA weakly (but significantly) correlated with BMI at 9/18 time points whereas for desflurane FD/FA or FI/FA correlated significantly with BMI at only one time point (P < 0.01). After dividing each group into nonobese (BMI < 30) and obese (BMI > or = 30) patients, with isoflurane, FD/FA or FI/FA was higher in obese patients at four time points whereas there was no difference between nonobese and obese patients for desflurane. Patients receiving isoflurane took longer to respond to command after discontinuing anesthesia but obesity did not increase or decrease awakening time for either isoflurane or desflurane. When BMI was used to normalize FI/FA and FD/FA the median values for isoflurane consistently exceeded the median value for desflurane by factors ranging from 3 to 5, values comparable to the ratios of their blood/gas (3.1), muscle/gas (4.6), and fat/gas (5.4) partition coefficients. CONCLUSION: BMI modestly affects FD/FA and FI/FA, and this effect is most apparent for an anesthetic having a greater solubility in all tissues. An increased BMI increases anesthetic uptake and, thus, the need for delivered anesthetic to sustain a constant alveolar anesthetic concentration, particularly with a more soluble anesthetic. However, the increase with an increased body mass is small.

The effect of deliberate hypercapnia and hypocapnia on intraoperative blood loss and quality of surgical field during functional endoscopic sinus surgery.

BACKGROUND: Anesthetic management during functional endoscopic sinus surgery is aimed at minimizing bleeding and establishing a near-perfect surgical field. We investigated whether deliberate intraoperative hypercapnia and hypocapnia may affect blood loss and quality of surgical field through a proposed modulating effect of different carbon dioxide (CO2) tension levels on nasal vasculature. METHODS: One hundred and eighty patients were randomly assigned to normocapnia (end-tidal CO2 [ETco2] 37 +/- 2 mm Hg), hypercapnia (ETco2 60 +/- 2 mm Hg), and hypocapnia (ETco2 27 +/- 2 mm Hg) groups. Anesthetic management was with propofol and remifentanil infusions, nitrous oxide, and moderate controlled hypotension. Blood loss and operating conditions were assessed by the surgeon who was blinded to group assignment. Differences among the study groups, the effect of the study group and time on ETco2 levels and hemodynamic variables, and the association of blood loss with surgical covariates were analyzed. RESULTS: There were no differences in blood loss and quality of surgical field among the study groups. Patients in the hypocapnia group demonstrated the highest, and in the hypercapnia group, the lowest, requirements for remifentanil, labetalol, and administration of the antihypertensive medications in general. The computed tomography-graded severity of sinonasal disease and duration of surgery were the only independent predictors of intraoperative blood loss. CONCLUSIONS: CO2 management during functional endoscopic sinus surgery does not influence operating conditions or blood loss.

The ideal oxygen/nitrous oxide fresh gas flow sequence with the Anesthesia Delivery Unit machine.

STUDY OBJECTIVE: To determine whether early reduction of oxygen and nitrous oxide fresh gas flow from 6 L/min to 0.7 L/min could be accomplished while maintaining end-expired nitrous oxide concentration > or =50% with an Anesthesia Delivery Unit anesthesia machine. STUDY DESIGN: Prospective, randomized clinical study. SETTING: Large teaching hospital in Belgium. PATIENTS: 53 ASA physical status I and II patients requiring general endotracheal anesthesia and controlled mechanical ventilation. INTERVENTIONS: Patients were randomly assigned to one of 4 groups depending on the duration of high oxygen/nitrous oxide fresh gas flow (two and 4 L/min, respectively) before lowering total fresh gas flow to 0.7 L/min (0.3 and 0.4 L/min oxygen and nitrous oxide, respectively): one, two, three, or 5 minutes (1-minute group, 2-minute group, 3-minute group, and 5-minute group), with n = 10, 12, 13, and 8, respectively. The course of the end-expired nitrous oxide concentration and bellows volume deficit at end-expiration was compared among the 4 groups during the first 30 minutes. RESULTS: At the end of the high-flow period the end-expired nitrous oxide concentration was 35.6 +/- 6.2%, 48.4 +/- 4.8%, 53.7 +/- 8.7%, and 57.3 +/- 1.6% in the 4 groups, respectively. Thereafter, the end-expired nitrous oxide concentration decreased to a nadir of 36.1 +/- 4.5%, 45.4 +/- 3.8%, 50.9 +/- 6.1%, and 55.4 +/- 2.8% after three, 4, 6, and 8 minutes after flows were lowered in the 1- to 5-minute groups, respectively. A decrease in bellows volume was observed in most patients, but was most pronounced in the 2-minute group. The bellows volume deficit gradually faded within 15 to 20 minutes in all 4 groups. CONCLUSIONS: A 3-minute high-flow period (oxygen and nitrous oxide fresh gas flow of 2 and 4 L/min, respectively) suffices to attain and maintain end-expired nitrous oxide concentration > or =50% and ensures an adequate bellows volume during the ensuing low-flow period.

Enriched analgesic efficacy studies: an assessment by clinical trial simulation.

BACKGROUND AND OBJECTIVE: Enrichment strategies which select subjects who appear to respond to the drug have been used in drug studies to demonstrate clinical efficacy. We have used clinical trial simulation techniques to examine factors that are relevant in clinical trial design based on enrichment where poor responders are excluded from the double-blind phase of the study. METHODS: Simulations were performed for an analgesic trial design involving an open-dose titration phase (enrichment phase) followed by a double-blind, randomized, placebo-controlled maintenance phase. Enrichment was examined by excluding subjects above a predefined pain score (cutoff) from analysis of efficacy for the maintenance phase. Cutoff pain scores ranging from 4 to 7 on a 0 to 10 categorical scale were examined. A database consisting of chronic pain patients who participated in studies with a new formulation of buprenorphine was used to build the simulation model. Since no data were available for the key model variable "correlation between treatment and placebo response", values of 0.25, 0.5, and 0.75 were used for the simulations. RESULTS: A correlation between treatment and placebo effect ranging from 0.75 to 0.25 will cause the likelihood of trial success to vary from 50% to 95%. This model also shows that recruitment efficiency will decrease with the use of lower cutoff pain scores. CONCLUSION: Prior to using enrichment techniques, investigators must consider the correlation between treatment effect and placebo response to optimize clinical trial design.

The role of the craniospinal nerves in mediating the antinociceptive effect of transcranial electrostimulation in the rat.

Transcranial electrostimulation (TES) has been reported to elicit significant analgesia, but its mechanism of action has not been elucidated. In a recently introduced clinically relevant rat model of TES we have validated and characterized the TES antinociceptive effect, suggesting involvement of the sensory nerves of the rat's scalp in mediating that effect. In this study, we have further investigated the role of the craniospinal nerves by attempting to block the TES antinociceptive effect with local anesthetic injected under the TES electrodes. We also applied different transcutaneous electrical nerve stimulation modalities through the TES electrodes and compared the elicited antinociceptive effect to that of TES. The antinociceptive effect was assessed by measuring nociceptive thresholds in the tail-flick latency test in awake, unrestrained male rats. Data were analyzed by one-way analysis of variance followed by the Bonferroni t-test. The TES antinociceptive effect was significantly reduced after local anesthetic injection, and administration of 100 Hz transcutaneous electrical nerve stimulation was, over time, capable of eliciting the same degree of antinociceptive effect as TES. We conclude that sensory craniospinal nerves play a critical role in mediating the TES antinociceptive action and offer a hypothesis on the underlying mechanism(s) responsible for this action.

Do distribution volumes and clearances relate to tissue volumes and blood flows? A computer simulation.

BACKGROUND: Kinetics of inhaled agents are often described by physiological models. However, many pharmacokinetic concepts, such as context-sensitive half-times, have been developed for drugs described by classical compartmental models. We derived classical compartmental models that describe the course of the alveolar concentrations (FA) generated by the physiological uptake and distribution models used by the Gas Man program, and describe how distribution volumes and clearances relate to tissue volumes and blood flows. METHODS: Gas Man was used to generate FA vs. time curves during the wash-in and wash-out period of 115 min each with a high fresh gas flow (8 L x min(-1)), a constant alveolar minute ventilation (4 L x min(-1)), and a constant inspired concentration (FI) of halothane (0.75%), isoflurane (1.15%), sevoflurane (2%), or desflurane (6%). With each of these FI, simulations were ran for a 70 kg patient with 5 different cardiac outputs (CO) (2, 3, 5, 8 and 10 L x min(-1)) and for 5 patients with different weights (40, 55, 70, 85, and 100 kg) but the same CO (5 L x min(-1)). Two and three compartmental models were fitted to FA of the individual 9 runs using NONMEM. After testing for parsimony, goodness of fit was evaluated using median prediction error (MDPE) and median absolute prediction error (MDAPE). The model was tested prospectively for a virtual 62 kg patient with a cardiac output of 4.5 L x min(-1) for three different durations (wash-in and wash-out period of 10, 60, and 180 min each) with an FI of 1.5% halothane, 1.5% isoflurane, sevoflurane 4%, or desflurane 12%. RESULTS: A three-compartment model fitted the data best (MDPE = 0% and MDAPE < or = 0.074%) and performed equally well when tested prospectively (MDPE < or = 0.51% and MDAPE < or = 1.51%). The relationship between CO and body weight and the distribution volumes and clearances is complex. CONCLUSION: The kinetics of anesthetic gases can be adequately described e by a mammilary compartmental model. Therefore, concepts that are traditionally thought of as being applicable to the kinetics of intravenous agents can be equally well applied to anesthetic gases. Distribution volumes and clearances cannot be equated to tissue volumes and blood flows respectively.

Anesthetic drugs and bariatric surgery.

The prevalence of obesity is increasing worldwide. For severely obese patients, bariatric surgery is the only effective option for sustained weight loss and associated health improvement. As a consequence, the number of bariatric surgical procedures being performed is growing exponentially. Systematic knowledge regarding the effect of obesity on the pharmacokinetics and pharmacodynamics of anesthetic agents is generally lacking, and data for morbidly obese (body mass index [BMI] 40-49 kg/m2)) and super-obese patients (BMI > 50 kg/m2) are almost completely non-existent. Most drug-dosing guidelines are based on results from relatively small studies in moderately obese patients. Future systematic pharmacological research is needed for improved and more rational peri-operative care of morbidly obese patients.

Verification of endotracheal tube placement by prehospital providers: is a portable fiberoptic bronchoscope of value?

INTRODUCTION: This study was designed to examine whether a handheld, battery-operated fiberoptic bronchoscope (FOB) used to verify endotracheal tube (ETT) placement would be as sensitive and specific as other modes and whether a combination of multiple modes would further enhance the sensitivity and specificity of ETT placement verification. SETTING: An academic hospital-based air medical program. METHODS: This was a prospective, randomized study examining surgical patients undergoing general endotracheal anesthesia. Eighteen critical care transport (CCT) nurses, previously unfamiliar with FOB, were asked to identify intratracheal and intraesophageal ETTs by using misting, end-tidal carbon dioxide concentration (ETCO(2)), and FOB alone or with a combination of all three modes. The sensitivity and specificity of single and multimode verification were calculated and compared. RESULTS: Comparison of ETT verification by single mode alone revealed a rank order of sensitivity with ETCO(2) (0.97) > FOB (0.87) > misting (0.84), whereas all three modes had similar specificities (0.93-0.94). However, the use of the three-mode combination revealed a sensitivity and specificity of 1.0. CONCLUSIONS: As a single mode for ETT verification, use of a handheld, battery-operated FOB device allowed for direct visualization and had an 87% sensitivity and 93% specificity. When combined with misting and ETCO(2), FOB allowed 100% successful verification of ETT placement.

The antinociceptive effect of transcranial electrostimulation with combined direct and alternating current in freely moving rats.

UNLABELLED: Transcranial electrostimulation (TES) has been reported to elicit significant analgesia, allowing a substantial reduction of intraoperative opioids. Acceptance of TES into clinical practice is hampered by lack of controlled clinical trials and inconclusive animal data regarding the TES antinociceptive action. This inconclusive data may be explained, in part, by failure in rat experiments to simulate the variables used in humans when TES electrodes are positioned on the skin. In this study we validated the TES antinociceptive effect in a novel animal model of cutaneously administered TES, when the stimulating conditions mimic the ones used in clinical practice. The antinociceptive effect was assessed by measuring nociceptive thresholds in the tail-flick and hot-plate latency tests in awake, unrestrained male rats. Data were analyzed by analysis of variance and mixed-effects population modeling. The administration of TES at 2.25 mA produced an almost immediate, sustained, frequency-dependent (40-60 Hz) antinociceptive effect, reaching approximately 50% of the maximal possible value. We conclude that an antinociceptive effect of cutaneously administered TES can be demonstrated in the rat. Some characteristics of the effect suggest an important role of the sensory nerves of the rat's scalp in mediating the TES antinociceptive response. IMPLICATIONS: Transcranial electrostimulation produces a significant, frequency-dependent antinociceptive effect that may be mediated by cutaneous nerves of the scalp.