The impact of deep versus standard neuromuscular block on intraoperative safety during laparoscopic surgery: an international multicenter randomized controlled double-blind strategy trial - EURO-RELAX TRIAL.

BACKGROUND: Muscle relaxants are routinely used during anesthesia to facilitate endotracheal intubation and to optimize surgical conditions. However, controversy remains about the required depth of neuromuscular block (NMB) needed for optimal surgical working conditions and how this relates to other outcomes. For instance, a deep neuromuscular block yields superior surgical working conditions compared to a standard NMB in laparoscopic surgery, however, a robust association to other (safety) outcomes has not yet been established. METHODS: Trial design: an international multicenter randomized controlled double-blind strategy trial. Trial population: 922 patients planned for elective, laparoscopic or robotic, abdominal surgery. INTERVENTION: Patients will be randomized to a deep NMB (post-tetanic count 1-2 twitches) or standard care (single-dose muscle relaxant administration at induction and repeated only if warranted by surgical team). Main trial endpoints: Primary endpoint is the difference in incidence of intraoperative adverse events during laparoscopic surgery graded according to ClassIntra® classification (i.e., ClassIntra® grade ≥ 2) between both groups. Secondary endpoints include the surgical working conditions, 30-day postoperative complications, and patients' quality of recovery. DISCUSSION: This trial was designed to analyze the effect of deep neuromuscular block compared to standard neuromuscular block on intra- and postoperative adverse events in patients undergoing laparoscopic surgery. TRIAL REGISTRATION: ClinicalTrials.gov NCT04124757 (EURO-RELAX); registration URL: https://clinicaltrials.gov/ct2/show/NCT04124757 , registered on October 11th, 2019.

Postoperative respiratory state assessment using the Integrated Pulmonary Index (IPI) and resultant nurse interventions in the post-anesthesia care unit: a randomized controlled trial.

Although postoperative adverse respiratory events, defined by a decrease in respiratory rate (RR) and/or a drop in oxygen saturation (SpO2), occur frequently, many of such events are missed. The purpose of the current study was to assess whether continuous monitoring of the integrated pulmonary index (IPI), a composite index of SpO2, RR, end-tidal PCO2 and heart rate, alters our ability to identify and prevent adverse respiratory events in postoperative patients. Eighty postoperative patients were subjected to continuous respiratory monitoring during the first postoperative night using RR and pulse oximetry and the IPI monitor. Patients were randomized to receive intervention based on standard care (observational) or based on the IPI monitor (interventional). Nurses were asked to respond to adverse respiratory events with an intervention to improve the patient's respiratory condition. There was no difference in the number of patients that experienced at least one adverse respiratory event: 21 and 16 in observational and interventional group, respectively (p = 0.218). Compared to the observational group, the use of the IPI monitor led to an increase in the number of interventions performed by nurses to improve the respiratory status of the patient (average 13 versus 39 interventions, p < 0.001). This difference was associated with a significant reduction of the median number of events per patient (2.5 versus 6, p < 0.05) and a shorter median duration of events (62 s versus 75 s, p < 0.001). The use of the IPI monitor in postoperative patients did not result in a reduction of the number of patients experiencing adverse respiratory events, compared to standard clinical care. However, it did lead to an increased number of nurse interventions and a decreased number and duration of respiratory events in patients that experienced postoperative adverse respiratory events.

Combining opioids and benzodiazepines: effects on mortality and severe adverse respiratory events.

Opioids and benzodiazepines are increasingly used alone or in combination. However, the combined use of these agents increases the risk for potentially lethal respiratory depression. This review summarizes current evidence on the effects of the combined use of opioids and benzodiazepines on mortality and severe respiratory adverse events. The results of 29 included manuscripts showed that concomitant use of opioids and benzodiazepines increased the risk for these outcomes in most of clinical and non-clinical settings. However, the risk for harm and benefit of the drug combination strongly correlates to its context and there are situations, such as in the hospice setting, where benefits may outweigh the risks.

Reversal of Partial Neuromuscular Block and the Ventilatory Response to Hypoxia: A Randomized Controlled Trial in Healthy Volunteers.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: The ventilatory response to hypoxia is a critical reflex that is impaired by neuromuscular blocking drugs. However, the degree to which this reflex is restored after reversal of blockade is unknown. WHAT THIS ARTICLE TELLS US THAT IS NEW: Despite full reversal of neuromuscular blockade at the thumb using different drug classes, this hypoxic chemoreflex is not fully restored. BACKGROUND: The ventilatory response to hypoxia is a life-saving chemoreflex originating at the carotid bodies that is impaired by nondepolarizing neuromuscular blocking agents. This study evaluated the effect of three strategies for reversal of a partial neuromuscular block on ventilatory control in 34 healthy male volunteers on the chemoreflex. The hypothesis was that the hypoxic ventilatory response is fully restored following the return to a train-of-four ratio of 1. METHODS: In this single-center, experimental, randomized, controlled trial, ventilatory responses to 5-min hypoxia (oxygen saturation, 80 ± 2%) and ventilation at hyperoxic isohypercapnia (end-tidal carbon dioxide concentration, 55 mmHg) were obtained at baseline, during rocuronium-induced partial neuromuscular block (train-of-four ratio of 0.7 measured at the adductor pollicis muscle by electromyography), and following reversal until the train-of-four ratio reached unity with placebo (n = 12), 1 mg neostigmine/0.5 mg atropine (n = 11), or 2 mg/kg sugammadex (n = 11). RESULTS: This study confirmed that low-dose rocuronium reduced the ventilatory response to hypoxia from 0.55 ± 0.22 (baseline) to 0.31 ± 0.21 l · min · % (train-of-four ratio, 0.7; P < 0.001). Following full reversal as measured at the thumb, there was persistent residual blunting of the hypoxic ventilatory response (0.45 ± 0.16 l · min · %; train-of-four ratio, 1.0; P < 0.001). Treatment effect was not significant (analysis of covariance, P = 0.299) with chemoreflex impairment in 5 (45%) subjects following sugammadex reversal, in 7 subjects (64%) following neostigmine reversal, and in 10 subjects (83%) after spontaneous reversal to a train-of-four ratio of 1. CONCLUSIONS: Despite full reversal of partial neuromuscular block at the thumb, impairment of the peripheral chemoreflex may persist at train-of-four ratios greater than 0.9 following reversal with neostigmine and sugammadex or spontaneous recovery of the neuromuscular block.

Nociception-guided versus Standard Care during Remifentanil-Propofol Anesthesia: A Randomized Controlled Trial.

BACKGROUND: The multidimensional index of nociception, the nociception level, outperforms blood pressure and heart rate in detection of nociceptive events during anesthesia. We hypothesized that nociception level-guided analgesia reduces opioid consumption and suboptimal anesthesia events such as low blood pressure and use of vasoactive medication. METHODS: In this single-blinded randomized study, 80 American Society of Anesthesiologists class I-III adult patients of either sex, scheduled for major abdominal procedures under remifentanil/propofol anesthesia by target-controlled infusion, were included. During the procedure nociception level, noninvasive blood pressure, and heart rate were monitored. Patients were randomized to receive standard clinical care or nociception level-guided analgesia. In the nociception level-guided group, remifentanil concentration was reduced when index values were less than 10 or increased when values were above 25 for at least 1 min, in steps of 0.5 to 1.0 ng/ml. Propofol was titrated to bispectral index values between 45 and 55. The primary outcomes of the study were remifentanil and propofol consumption and inadequate anesthesia events. RESULTS: Compared with standard care, remifentanil administration was reduced in nociception level-guided patients from (mean ± SD) 0.119 ± 0.033 to 0.086 ± 0.032 µg · kg · min (mean difference, 0.039 µg · kg · min; 95% CI, 0.025-0.052 µg · kg · min; P < 0.001). Among nociception level-guided patients, 2 of 40 (5%) experienced a hypotensive event (mean arterial pressure values less than 55 mm Hg) versus 11 of 40 (28%) patients in the control group (relative risk, 0.271; 95% CI, 0.08-0.77; P = 0.006). In the nociception level-guided group, 16 of 40 (40%) patients received vasoactive medication versus 25 of 40 (63%) patients in the standard care group (relative risk, 0.64; 95% CI, 0.40-0.99; P = 0.044). CONCLUSIONS: Nociception level-guided analgesia during major abdominal surgery resulted in 30% less remifentanil consumption.

A Pragmatic Utility Function to Describe the Risk-Benefit Composite of Opioid and Nonopioid Analgesic Medication.

It is not straightforward to simultaneously evaluate the beneficial and harmful effects of pain management, since different drugs may possess different analgesia and adverse effect profiles. Utility functions, derived from the pharmacokinetics and pharmacodynamics of individual outcome parameters, have been constructed to address this problem. Here, we construct "pragmatic" utility functions based on measurements of benefit and harm, but without making assumptions about the underlying pharmacokinetics and pharmacodynamics. Using data from two previous studies, utility functions were designed by estimating the probability of occurrence of benefit and harm and combining these into one function. Study 1 was a clinical trial on the effect of oral pregabalin on pain relief in chronic pancreatitis patients, with endpoint analgesia and dizziness monitored for 21 days. Study 2 was an experimental study on the effect of intravenous fentanyl on antinociception and respiratory depression in healthy volunteers. From study 1, the utility function was negative the first week of treatment, indicative of the greater probability of dizziness than analgesia, but positive thereafter. From study 2, the utility function showed a nadir 30 minutes after dosing, after which the probability function slowly increased toward zero. A pragmatic utility function based on the probability of two binary outcomes, analgesia and adverse effect, was successfully constructed using data from the two previous studies. The results yielded valuable insights into the utility of treatment and may be highly educative for physicians and potentially used in development of potent analgesics without serious side effects.

Frequent respiratory events in postoperative patients aged 60 years and above.

There is limited information on the occurrence of respiratory events in postoperative patients after discharge from the postanesthesia care unit. We studied the respiratory rate (RR) of 68 patients aged 60 years and above during the first 6 hours following elective surgery under general anesthesia to assess the frequency of respiratory events in the care unit and on the ward. RR was derived from the continuous RR counter RespiR8, measuring RR by quantifying the humidity of exhaled air. One-minute-averaged RRs were collected and analyzed to assess the frequency of postoperative bradypnea (RR 1-6 breaths/minute) and apnea (cessation of inspiratory flow ≥60 seconds). Values were median (interquartile range) or mean (SD). The median RR was 13 (10-15) breaths/minute. In the 6-hour postoperative period, 78% and 57% of patients experienced at least one bradypnea or apnea event, respectively. A median of ten (3.5-24) bradypnea and three (1-11) apnea events were detected per patient. The occurrence of respiratory events in the postanesthesia care unit (PACU) was a predictor of events on the ward (bradypnea, r2=0.4, P<0.001; apnea, r2=0.2, P<0.001). Morphine consumption correlated weakly with respiratory events in the PACU, but not on the ward. Patients with apnea had significantly larger neck circumference than patients without (39.6 [0.7] versus 37.4 [0.8] cm, P<0.05). Bradypneic or apneic respiratory events are frequent in postoperative elderly patients and even occur relatively late after surgery. Continuous respiratory monitoring on the ward, especially in patients with risk factors, such as early occurrence of events, opioid use, and larger neck circumference, is likely warranted.

Ability of the nociception level, a multiparameter composite of autonomic signals, to detect noxious stimuli during propofol-remifentanil anesthesia.

BACKGROUND: A novel multidimensional index of nociception, the nociception level (NoL) index, derived from the nonlinear composite of heart rate (HR), HR variability, amplitude of the photoplethysmogram, skin conductance, fluctuations in skin conductance, and their time derivatives, was used to assess nociception during anesthesia. METHODS: Seventy-two American Society of Anesthesiologists I to III patients received propofol (target bispectral index, 45) and one of six remifentanil target concentrations in the range of 0 to 5 ng/ml. The NoL, mean arterial pressure (MAP; derived from a beat-to-beat finger cuff measurement), and HR were measured during nonnoxious, moderate noxious (skin incision), and intense noxious (intubation) stimulation. Values are represented as average (95% CI). RESULTS: NoL, HR, and MAP did not change during nonnoxious events. Incision increased HR by 1.3/min (-0.46 to 3.1/min; not significant), MAP by 7.9 mmHg (-1.9 to 13.0 mmHg; not significant), and NoL by 8.0 (0.4 to 16.0; P < 0.001). Intubation increased HR by 7.0/min (1.4 to 12.0/min; P < 0.001), MAP by 13.0 mmHg (3.1 to 20 mmHg; P < 0.001), and NoL by 18.0 (7.8 to 29.0; P < 0.001). The ΔNoL area under the curve (0.95) of the receiver operating characteristic curve was greater compared with ΔHR (0.84, P < 0.001) and ΔMAP (0.78, P < 0.001). Under nonnociceptive conditions, remifentanil had no effect on NoL, in contrast to HR and MAP that showed a dose-dependent decrease. CONCLUSIONS: The NoL is a reliable measure of moderate and intense noxious stimulation and outperforms HR and MAP in differentiating noxious from nonnoxious stimuli. In contrast to HR and MAP, the NoL was not affected by hemodynamic effects of remifentanil.