Comparison of two pharmacokinetic-pharmacodynamic models of rocuronium bromide during profound neuromuscular block: analysis of estimated and measured post-tetanic count effect.

BACKGROUND: Profound neuromuscular block (NMB) is important in surgeries where complete immobility is considered essential to improve tracheal intubation and surgical conditions. Rocuronium bromide is a commonly used NMB agent. This work describes a noninvasive approach for estimation of post-tetanic count (PTC) based on two pharmacokinetic (PK) models, the Saldien and the De Haes models. The aim was to investigate the rocuronium bromide PK-pharmacodynamic (PD) relationship in estimating the PTC effect during profound NMB. METHODS: In this prospective, non-randomised, observational study, an induction bolus of rocuronium bromide was administered followed by continuous infusion for maintenance of a PTC of 1-2. measured every 3 min. Measurements were analysed as discrete categorical data and by applying the nonlinear mixed-effect modelling approach. Performance of the selected models was evaluated through simulation model-based diagnostics, further assessing the precision of the parameter estimates and the performance of the models at the individual level. RESULTS: Data from 30 adult patients undergoing elective abdominal or neurosurgical procedures were included. Post-tetanic count response profiles during rocuronium bromide infusion were successfully characterised using the population PD analysis. The models showed a good performance for all PTC categories, albeit with a moderate over-prediction of PTC >6. CONCLUSIONS: Our findings indicate that using plasma concentrations of rocuronium bromide estimated with either of the two models, combined with a PD model, provides equal model performance when predicting PTC. These promising results may provide an important advance in guiding rocuronium bromide administration when profound NMB in routine clinical practice is desired.

Semimechanistic models to relate noxious stimulation, movement, and pupillary dilation responses in the presence of opioids.

Intraoperative targeting of the analgesic effect still lacks an optimal solution. Opioids are currently the main drug used to achieve antinociception, and although underdosing can lead to an increased stress response, overdose can also lead to undesirable adverse effects. To better understand how to achieve the optimal analgesic effect of opioids, we studied the influence of remifentanil on the pupillary reflex dilation (PRD) and its relationship with the reflex movement response to a standardized noxious stimulus. The main objective was to generate population pharmacodynamic models relating remifentanil predicted concentrations to movement and to pupillary dilation during general anesthesia. A total of 78 patients undergoing gynecological surgery under general anesthesia were recruited for the study. PRD and movement response to a tetanic stimulus were measured multiple times before and after surgery. We used nonlinear mixed effects modeling to generate a population pharmacodynamic model to describe both the time profiles of PRD and movement responses to noxious stimulation. Our model demonstrated that movement and PRD are equally depressed by remifentanil. Using the developed model, we changed the intensity of stimulation and simulated remifentanil predicted concentrations maximizing the probability of absence of movement response. An estimated effect site concentration of 2 ng/ml of remifentanil was found to inhibit movement to a tetanic stimulation with a probability of 81%.

Foreseeing postoperative pain in neurosurgical patients: pupillometry predicts postoperative pain ratings-an observational study.

Pupillary reflex dilation (PRD) is triggered by noxious stimuli and diminished by opioid administration. In the postoperative period, PRD has been shown to be correlated with pain reporting and a useful tool to guide opioid administration. In this study we assessed whether pupillary measurements taken before extubation were related with the patient's reported pain in the Post-Anesthesia Care Unit (PACU) using the Numerical Rating Scale (NRS). Our objective was to evaluate the correlation of PRD and pupillary variables measured intraoperatively with postoperative pain under the same opioid concentration. This was a prospective observational study of 26 neurosurgical patients undergoing general anesthesia exclusively with propofol and remifentanil. A portable infrared pupillometer was used to provide an objective measure of pupil size and PRD (using the Pupillary Pain Index) before extubation. Pain ratings were obtained from patients after recovery of consciousness, while remifentanil was maintained at 2 ng/mL. A significant correlation was observed between NRS scores and pre-extubation PPI (rS = 0.62; P = 0.002), as well as between NRS scores and pupil diameter before tetanic stimulation PPI (rS = 0.56, P = 0.006). We also found a negative correlation between pupil diameter and age (rS = - 0.42, P = 0.04). The statistically significant correlation between pre-extubation PPI scores and NRS scores, as well as between the pupillary diameter before tetanic stimulation and NRS scores suggest the possibility of titrating analgesia at the end of the intraoperative period based on individual responses. This could allow clinicians to identify the ideal remifentanil concentration for the postoperative period.

Effects of varying remifentanil concentrations on Analgesia Nociception Index® under propofol: an observational study.

Analgesia Nociception Index monitor provides a measurement of the nociception and anti-nociception balance based on heart-rate variability. The aim was to assess the ability of Analgesia Nociception Index (ANI) to detect standard noxious stimulation during anesthesia at different opioid concentrations in comparison to hemodynamic and Bispectral Index parameters. Sixteen patients undergoing general anesthesia with propofol and remifentanil. Standardized tetanic electrical stimulation was applied without any other concurrent stimuli, while different effect site concentrations of remifentanil were increased step-by-step (0.5, 1.5, 3.0, 5 and 7 ng/ml). For each tetanic stimulus, values of the different variables 60 s before and 120 s following the stimulus were analyzed. ANI values decreased significantly 120 s after the stimulus when compared to the mean ANI 60 s before the stimulus (P < 0.01). At lower remifentanil concentrations (0.5 ng/ml), all variables except electromyogram from the Bispectral Index significantly changed after the stimulus but in the higher concentrations (5.0 and 7.0 ng/ml) there was not a significant change. The other variables did not change significantly after the noxious stimulation. ANI was the only variable that positively correlated with the different remifentanil concentrations (R = 0.959, P = 0.01). Our study showed that there was a significant decrease in Analgesia Nociception Index after a tetanic stimulation while hemodynamic and BIS parameters did not change, suggesting that the Analgesia Nociception Index may perform better than traditional hemodynamic parameters at reflecting noxious stimulation. Analgesia Nociception Index significantly changed at lower, but not at higher, remifentanil concentrations.

Systematic Review on Rocuronium Continuous Infusion for Deep Neuromuscular Blockade.

BACKGROUND: Rocuronium is a muscle relaxant with increased use due to its binding relation with the reversal agent sugammadex. The purpose of this review entails the investigation of its use for the maintenance of Deep Neuromuscular Block (NMB) via continuous infusion. METHODS: Based on PRISMA systematic search guidelines, databases included PubMed, ISI Web of Science, Cochrane Library and Google Scholar. This comprehensive search addresses surgical patients under deep muscle relaxation via continuous rocuronium infusion. The main indicators were the rocuronium administration, NMB monitoring approaches and effects in order to maintain the deep level of relaxation, as well as reversal time after a standard dose of sugammadex. RESULTS: Despite the variance in approaches found in the literature, findings show the overall maintenance of deep NMB requires approximately 0.758 mg.kg-1h-1 of rocuronium (according to the PTC target of 0-10, 0-5 and 1-2, mean estimates are 0.445, 0.65 and 0.833 mg.kg-1h-1 respectively), suggesting that a lower range and a smaller maximum of PTC response require higher amount of rocuronium for its maintenance. The standard dose of sugammadex (4 mg/kg), administered at the end of the surgery takes longer [2.85 (1.17) min] than when they are administered after moderate NMB recovery [1.68 (0.47) min]. CONCLUSION: Continuous infusion for deep NMB presents inherent advantages in terms of maintenance and stability of muscle relaxation. Monitoring and rocuronium administration approaches are fundamental and intrinsically connected to provide a stable and improved maintenance of deep NMB.

Electromyographic assessment of blink reflex throughout the transition from responsiveness to unresponsiveness during induction with propofol and remifentanil.

General anesthesia is a reversible drug-induced state of altered arousal characterized by loss of responsiveness due to brainstem inactivation. Precise identification of the moment in which responsiveness is lost during the induction of general anesthesia is extremely important to provide information regarding an individual's anesthetic requirements and help intraoperative drug titration. To characterize the transition from responsiveness to unresponsiveness more objectively, we studied neurophysiologic-derived parameters of electromyographic records of electrically evoked blink reflex as a means of identifying the precise moment of loss of responsiveness. Twenty-five patients received a slow infusion of propofol until loss of corneal reflex while successive blink reflexes were elicited and recorded every 6 s. The level of anesthesia was assessed using an adapted version of the Richmond Agitation-Sedation Scale. Different variables of the blink reflex components were calculated and compared to the adapted version of the Richmond Agitation-Sedation score and the estimated effect-site propofol concentration. Baselines of the blink reflex responses were similar to those in literature. After propofol infusion started, the most susceptible component of the blink reflex to propofol was R2 (EC50 = 1.358 (95% CI 1.321, 1.396) µg/mL) and the most resistant was R1 (EC50 = 3.025 (95% CI 2.960, 3.090) µg/mL). Most of the patients (24 out of 25) lost the R1 component when they were still responsive to shaking and shouting and corneal reflex could be elicited clinically (time = 102.48 ± 33.00 s). Habituation was present in R2 but not in R1. The R1 component of the blink reflex was found to have a strong correlation with the adapted version of the Richmond Agitation-Sedation Scale, with amplitude correlating better than areas (ρ = - 0.721 (0.123) versus ρ = - 0.688 (0.165)). We found a strong correlation between the R1 component with the estimated propofol effect-site concentration, with amplitude correlating better than areas (ρ = - 0.838 (0.113) versus ρ = - 0.823 (0.153)) and between the clinical scale and the propofol concentration (ρ = 0.856 (0.060)). The area and amplitude of the R1 component showed to be indicators of predicting different levels of anesthesia (Pk = 0.672 (0.183) versus Pk = 0.709 (0.134)) and these are connected to the propofol concentrations (Pk = 0.593 (0.10)). Our results suggest that electrically evoked blink reflex could be used during the induction of anesthesia as a surrogate of the Richmond Agitation-Sedation Scale to provide an objective endpoint as far as a - 4. At this point, at the moment of loss of R1, the propofol infusion may be stopped, as overshooting increases slightly the effect-site concentration afterward and eventually reaching loss of responsiveness. If the desired target is not achieved, the infusion can then be resumed.

Association Among Preoperative Cognitive Performance, Regional Cerebral Oxygen Saturation, and Postoperative Delirium in Older Portuguese Patients.

BACKGROUND: Postoperative delirium is common among older patients and preoperative identification of high-risk patients is widely recommended. The aim of this study was to assess whether preoperative cognitive performance using brief screening tools or regional cerebral oxygen saturation (Scto2) was associated with the development of postoperative delirium in older Portuguese patients undergoing elective surgery. METHODS: Prospective observational cohort study where preoperative cognitive screening tools (Mini-Cog, Mini-Mental State Examination, verbal fluency) and Scto2 (INVOS 5100C; Medtronic, Ireland) were assessed in 238 patients ≥65 years old undergoing elective surgery between July 2017 and May 2019 at a tertiary academic center in Portugal. The primary outcome was postoperative delirium detected by the 3D-Confusion Assessment Method. Data were analyzed by univariate analysis and multivariable logistic regression. RESULTS: Delirium was identified in 53 patients (22%); 162 patients (68%) had completed only 4 years of education. On multivariable analysis, probable cognitive impairment tested by the Mini-Cog (odds ratio [OR] = 1.57; 95% confidence interval [CI], 0.70-3.53; corrected P value >.999), by the Mini-Mental State Examination (OR = 2.75; 95% CI, 1.23-6.13; corrected P value = .052), and by the animal verbal fluency test (OR = 1.24; 95% CI, 0.49-3.16; corrected P value >.999) were not significantly associated with the development of postoperative delirium. In contrast, lower preoperative Scto2 (OR = 1.08; 95% CI, 1.02-1.14; corrected P value = .024 for each point decrease in Scto2) was associated with postoperative delirium. CONCLUSIONS: We did not find enough evidence to suggest that poor preoperative cognitive performance was significantly associated with the development of postoperative delirium in an older Portuguese surgical population with an overall low level of formal education, but rather that preoperative Scto2 may be helpful in identifying patients at risk for delirium.

Performance of blink reflex in patients during anesthesia induction with propofol and remifentanil: prediction probabilities and multinomial logistic analysis.

BACKGROUND: The amount of propofol needed to induce loss of responsiveness varied widely among patients, and they usually required less than the initial dose recommended by the drug package inserts. Identifying precisely the moment of loss of responsiveness will determine the amount of propofol each patient needs. Currently, methods to decide the exact moment of loss of responsiveness are based on subjective analysis, and the monitors that use objective methods fail in precision. Based on previous studies, we believe that the blink reflex can be useful to characterize, more objectively, the transition from responsiveness to unresponsiveness. The purpose of this study is to investigate the relation between the electrically evoked blink reflex and the level of sedation/anesthesia measured with an adapted version of the Richmond Agitation-Sedation Scale, during the induction phase of general anesthesia with propofol and remifentanil. Adding the blink reflex to other variables may allow a more objective assessment of the exact moment of loss of responsiveness and a more personalized approach to anesthesia induction. RESULTS: The electromyographic-derived features proved to be good predictors to estimate the different levels of sedation/anesthesia. The results of the multinomial analysis showed a reasonable performance of the model, explaining almost 70% of the adapted Richmond Agitation-Sedation Scale variance. The overall predictive accuracy for the model was 73.6%, suggesting that it is useful to predict loss of responsiveness. CONCLUSIONS: Our developed model was based on the information of the electromyographic-derived features from the blink reflex responses. It was able to predict the drug effect in patients undergoing general anesthesia, which can be helpful for the anesthesiologists to reduce the overwhelming variability observed between patients and avoid many cases of overdosing and associated risks. Despite this, future research is needed to account for variabilities in the clinical response of the patients and with the interactions between propofol and remifentanil. Nevertheless, a method that could allow for an automatic prediction/detection of loss of responsiveness is a step forward for personalized medicine.

Clinical implications of using non-invasive haemoglobin monitoring for red blood cell transfusion decision in hip arthroplasty.

INTRODUCTION: The decision to transfuse red blood cells requires accurate haemoglobin concentration values. In this study, we evaluated if continuous non-invasive haemoglobin (SpHb) measurement could substitute laboratory determined haemoglobin (LabHb) in patients undergoing elective hip replacement. As secondary objective, we analyzed the trend of the difference between techniques. MATERIALS/METHODS: LabHb measurements were done using an automated analyser and SpHb measurements were acquired using Radical-7®. In randomly selected patients undergoing hip replacement, whenever blood was collected for LabHb, concomitant SpHb was recorded. Correlation, bias and accuracy of SpHb were calculated in comparison with LabHb. RESULTS: 108 paired measurements were obtained from 43 patients. The Pearson R of the correlation between SpHb and LabHb was 0.7 (p < 0.001). Bland-Altman test revealed a bias of 1 ± 1.4 g dL-1, meaning Lab Hb was recurrently higher than SpHb. Limits of agreement were [-1.7; 3.8]. Considering RBC transfusion threshold of 8 g dL-1, we found that in two situations transfusion decision would differ based on the measurement considered. Trending ability of SpHb study showed a significant difference between preoperative and postoperative LabHb-SpHb. DISCUSSION: There was a good correlation between SpHb and LabHb, while bias and limits of agreement were higher than those in literature. There was a limited trending ability of SpHb during the perioperative period. Despite this, using SpHb instead of LabHb for decision making regarding transfusion would only change the decision in 1.9 % of our cases. Our findings suggest that this device could be used as a reference but cannot replace venous puncture as gold standard.

Pharmacodynamic modelling of the effect of remifentanil using the Pupillary Pain Index.

Using a targeted controlled infusion of remifentanil during total intravenous anesthesia, we investigated the effect-site concentrations of remifentanil that correlate with different values of the Pupillary Pain Index and which concentrations were necessary for achieving a Pupillary Pain Index ≤ 4 and its usefulness in titrating opioids. The Pupillary Pain Index was measured in 54 patients prior to surgery under different remifentanil effect-site concentrations and subsequently modeled. One hundred and twenty-eight measurements were taken at different remifentanil concentrations while titrating propofol for a similar depth of hypnosis using a BIS monitor. Our modeled Hill equation revealed a remifentanil of 2.96 ng/mL for a PPI of 4, and the probability model a Ce of 3.22 ng/mL for the probability of 50% of patients achieving a PPI score ≤ 4. For the probability of 80% of patients achieving a PPI score ≤ 4 the Ce of remifentanil was 4.39 ng/mL. We conclude that concentrations of remifentanil that have been shown to suppress movement in response to noxious stimulation correspond to a Pupillary Pain Index ≤ 4.

Patterns of Hysteresis Between Induction and Emergence of Neuroanesthesia Are Present in Spinal and Intracranial Surgeries.

BACKGROUND: Recovery of consciousness is usually seen as a passive process, with emergence from anesthesia depicted as the inverse process of induction resulting from the elimination of anesthetic drugs from their central nervous system sites of action. However, that need not be the case. Recently it has been argued that we might encounter hysteresis to changes in the state of consciousness, known as neural inertia. This phenomenon has been debated in neuroanesthesia, as manipulation of the brain might further influence recovery of consciousness. The present study is aimed at assessing hysteresis between induction and emergence under propofol-opioid neuroanesthesia in humans using estimated propofol concentrations in both spinal and intracranial surgeries. METHODS: We identified the moments of loss (LOR) and recovery of responsiveness (ROR) in 21 craniotomies and 25 spinal surgeries. Propofol was given slowly until loss of responsiveness and stopped at the end of surgery. An opioid was present at induction and recovery. Propofol infused was recorded and plasma and effect-site concentrations were estimated using 2 pharmacokinetic models. Dose-response curves were generated. Estimated propofol plasma and effect-site concentrations were compared to assess hysteresis. RESULTS: Estimated propofol concentrations at LOR and ROR showed hysteresis. Whether for spinal or intracranial surgeries, the EC50 of propofol at which half of the patients entered and exited the state of responsiveness was significantly different. CONCLUSIONS: Hysteresis was observed between propofol concentrations at LOR and ROR, in both patients presenting for spinal and intracranial surgeries. Manipulation of the brain does not appear to change patterns of hysteresis, suggesting that neural inertia may occur in humans, in a way similar to that found in animal species. These findings justify performing a clinical study in patients using measured propofol concentrations to assess neural inertia.

Rocuronium Continuous Infusion for Profound Neuromuscular Blockade: A Systematic Review and Meta-analysis.

OBJECTIVES: Rocuronium is a muscle relaxant with increased use, because of the binding relation with the reversal agent sugammadex. Its continuous infusion benefits the maintenance of deeper levels of neuromuscular blockade (NMB) ensuring an improved and stable solution for daily surgical anesthesia. This is systematic review on current approaches on rocuronium infusion and monitoring parameters when using rocuronium continuous infusion for profound muscle relaxation (0-2 posttetanic count). METHODS: Database search included publications worldwide until February 28, 2019. Main outcomes studied were the amount of rocuronium used, surgical conditions, and time of recovery after standard sugammadex dose. Secondary assessments include methodological features of rocuronium administration and blockade monitoring. Meta-analysis was conducted to assess the effect means difference of surgical conditions, followed by heterogeneity and sensitive analysis. RESULTS: Eight randomized trials were identified as eligible. Three studies allowed to account that maintenance of profound muscle relaxation a mean difference of 0.251 mg/kg per hour (95% confidence interval = 0.169-0.334) of rocuronium is required, in relation to moderate NMB, significantly improving surgical conditions (mean difference = 0.653, 95% confidence interval = 0.451-0.856, in a 5-point scale, including data from 6 trials). Only 2 studies presented results on reversal after sugammadex; therefore, no significant results were yielded regarding the time required to complete NMB recovery. CONCLUSIONS: Rocuronium continuous infusion for profound neuromuscular blockade presents inherent advantages in terms of maintenance and stability of the paralysis. Further studies should address the methodological approaches and benefits/drawbacks of this approach.Registration number: CRD42018106626.

Tools to screen and measure cognitive impairment after surgery and anesthesia.

Cognition is essential to all aspects of our everyday life. Although we take our cognitive function for granted, the perioperative period is prone to several aggressions that might impair it. Postoperative cognitive dysfunction, has been the aim of many studies recently, and was shown to be very common with an incidence that can reach 40%, yielding not only impairment in cognition, but also longer hospital stays, higher costs and greater mortality. While several studies have revealed some of the mechanisms contributing to postoperative cognitive dysfunction, the search for the perfect instrument to screen and measure cognitive (dys)function has proven more elusive. The present paper aims to review several cognitive evaluation methods, discussing their advantages and disadvantages as well as their potential clinical applications in evaluating the dynamics of the recovery of cognitive function after anesthesia and surgery. The current availability of easy to use computerized tests might provide the tools necessary to identify patients at risk, and promptly provide them with the adequate course of action.

Effects of Ketamine on Pupillary Reflex Dilation: A Case Report.

Ketamine is an important component of multimodal treatment and a commonly used anesthetic drug. However, its analgesic effects have not been fully assessed intraoperatively because of difficulties in measuring this effect. In this case report, a woman underwent general anesthesia with ketamine and its pupillary reflexes were measured to detect autonomic changes in response to pain. With increasing doses of ketamine, the pupillary light reflex and the pupillary dilation response decreased. This could be caused by N-methyl-D-aspartate receptor antagonism in the pupillary reflexes pathway or by the analgesic effects of ketamine.

Hyperbaric oxygen therapy as an adjuvant to source control in necrotizing soft tissue infections.

INTRODUCTION: Necrotizing soft tissue infections (NSTI) are rare but potentially lethal disorders, and adequate management is time- and resource-demanding. This study aims to assess whether variations in the treatment modalities - surgery, hyperbaric oxygen (HBO2) therapy and negative pressure wound therapy - had an impact on the length to definitive source control in NSTI patients who underwent HBO2. METHODS: This is a retrospective study of all NSTI patients treated with hyperbaric oxygen therapy between March 2007 and May 2015 at Unidade Local de Saúde de Matosinhos (ULSM) Hyperbaric Unit. A multiple linear regression model was used to assess the impact of different treatment modalities in the posdiagnosis time until source control. RESULTS: 58 patients were included; overall mortality was 13.8%. Mean time until source control was 10.4 days (±5.4). All patients were under empiric and broad-spectrum antibiotics on the day of diagnosis. Patients underwent an average of 0.62 (±0.29) surgical interventions and 1.06 (±0.52) HBO2 sessions per day. The regression model (R2=0.86) showed that after adjusting for other covariates, doubling the number of HBO2 sessions per day shortened source control by five days (? ß = -5.25; 95% CI -6.49 to 4.01), and for each day that HBO2 was delayed, source control was achieved one day later (ß = 1.03; 95% CI 0.82 to 1.24). CONCLUSIONS: More intensive HBO2 protocols with earlier and more frequent sessions shorten the time until definitive source control in necrotizing soft tissue infections, potentially lowering the impact of systemic effects of infection and complications associated with organ dysfunction.