Mind the Gap

BackgroundInduction agents are administered to decrease the risk of discomfort, awareness, and psychological sequelae during procedural paralysis (eg, rapid sequence intubation RSI). The expected duration of nondepolarizing neuromuscular blocking agents exceeds that of induction sedatives. The resulting sedation gap may increase the risk of awake paralysis. Research QuestionThe objective of this study was to elucidate the prevalence and duration of sedation gaps in critically ill patients undergoing bedside procedural paralysis. Study Design and MethodsThis was a retrospective cross-sectional study of critically ill adults who received rocuronium for a bedside procedure. The primary outcome was the sedation gap, which was the cumulative time of inadequate sedation during presumed paralysis (ie, 60 min after rocuronium). Secondary outcomes included the sedation gap when a pharmacist was present at the bedside. Descriptive statistics were used for baseline characteristics and the primary outcome. Log-rank and Mann-Whitney U tests were used to analyze secondary outcomes. ResultsEighty patients were included in the final analysis. The average age was 60 years and 57% of patients were male. The most common indication for procedural paralysis was RSI (99%). Most procedures were performed in the ED (55%), followed by the ICU (43. 8%). Eighty-five percent of patients experienced a sedation gap of any duration. The median sedation gap was 19 min (interquartile range IQR, 4-47. 5 min). The probability of initiating adequate sedation was higher when a pharmacist was present at the bedside (hazard ratio, 1. 49 95% CI, 1. 42-1. 55, bootstrapping log-rank test). The median sedation gap with a pharmacist (11 min IQR, 3-27. 5 min) was significantly lower than without a pharmacist (40 min IQR, 17-55 min; P =. 0115, Mann-Whitney U test). InterpretationIn this critically ill cohort, a substantial prevalence and duration of inadequate sedation was experienced after receiving rocuronium for bedside procedures. Further study is needed to identify if sedation gaps correlate with an increased risk of psychological morbidities. Induction agents are administered to decrease the risk of discomfort, awareness, and psychological sequelae during procedural paralysis (eg, rapid sequence intubation RSI). The expected duration of nondepolarizing neuromuscular blocking agents exceeds that of induction sedatives. The resulting sedation gap may increase the risk of awake paralysis. The objective of this study was to elucidate the prevalence and duration of sedation gaps in critically ill patients undergoing bedside procedural paralysis. This was a retrospective cross-sectional study of critically ill adults who received rocuronium for a bedside procedure. The primary outcome was the sedation gap, which was the cumulative time of inadequate sedation during presumed paralysis (ie, 60 min after rocuronium). Secondary outcomes included the sedation gap when a pharmacist was present at the bedside. Descriptive statistics were used for baseline characteristics and the primary outcome. Log-rank and Mann-Whitney U tests were used to analyze secondary outcomes. Eighty patients were included in the final analysis. The average age was 60 years and 57% of patients were male. The most common indication for procedural paralysis was RSI (99%). Most procedures were performed in the ED (55%), followed by the ICU (43. 8%). Eighty-five percent of patients experienced a sedation gap of any duration. The median sedation gap was 19 min (interquartile range IQR, 4-47. 5 min). The probability of initiating adequate sedation was higher when a pharmacist was present at the bedside (hazard ratio, 1. 49 95% CI, 1. 42-1. 55, bootstrapping log-rank test). The median sedation gap with a pharmacist (11 min IQR, 3-27. 5 min) was significantly lower than without a pharmacist (40 min IQR, 17-55 min; P =. 0115, Mann-Whitney U test). In this critically ill cohort, a substantial prevalence and duration of inadequate sedation was experienced after receiving rocuronium for bedside procedures. Further study is needed to identify if sedation gaps correlate with an increased risk of psychological morbidities. Take-home PointsStudy Question: What are the prevalence and duration of sedation gaps after neuromuscular blockade for bedside procedures in critically ill patients? What is the effect of bedside critical care pharmacists on this outcome associated with these procedures? Results: A retrospective cross-sectional study demonstrated that sedation gaps occurred in 85% of patients who received neuromuscular blockade for a bedside procedure. The median sedation gap was 19 min. Duration of inadequate sedation was reduced substantially when an ICU pharmacist was present. Interpretation: A substantial proportion of patients experienced sedation gaps, during which an increased risk of awake paralysis and associated sequalae may be present. A need for further research to understand who is at risk of inadequate sedation and for development of strategies to improve patient care remains. Study Question: What are the prevalence and duration of sedation gaps after neuromuscular blockade for bedside procedures in critically ill patients? What is the effect of bedside critical care pharmacists on this outcome associated with these procedures? Results: A retrospective cross-sectional study demonstrated that sedation gaps occurred in 85% of patients who received neuromuscular blockade for a bedside procedure. The median sedation gap was 19 min. Duration of inadequate sedation was reduced substantially when an ICU pharmacist was present. Interpretation: A substantial proportion of patients experienced sedation gaps, during which an increased risk of awake paralysis and associated sequalae may be present. A need for further research to understand who is at risk of inadequate sedation and for development of strategies to improve patient care remains. Neuromuscular blocking agents (NMBAs) are administered commonly to facilitate bedside procedures such as rapid sequence intubation (RSI). In the United States, > 650, 000 intubations are performed outside of the operating room annually. 1Turner J. S. Bucca A. W. Propst S. L. et al. Association of checklist use in endotracheal intubation with clinically important outcomes: a systematic review and meta-analysis. JAMA Netw Open. 2020; 3e209278Crossref Scopus (36) Google Scholar Induction agents (eg, etomidate, midazolam, ketamine) are administered concurrently to optimize intubating conditions, to provide immediate sedation, and to decrease the risk of discomfort and awareness during procedural paralysis. The incidence of awareness with paralysis is as high as 0. 2% in patients after general anesthesia2Ballard N. Robley L. Barrett D. Fraser D. Mendoza I. Patients' recollections of therapeutic paralysis in the intensive care unit. Am J Crit Care. 2006; 15: 86-95Crossref PubMed Google Scholar and as high as 5. 5% to 7. 4% in patients who receive rocuronium for RSI in the ED. 3Pappal R. D. Roberts B. W. Mohr N. M. et al. The ED-AWARENESS study: a prospective, observational cohort study of awareness with paralysis in mechanically ventilated patients admitted from the emergency department. Ann Emerg Med. 2021; 77: 532-544Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 4Driver B. E. Prekker M. E. Wagner E. et al. Recall of awareness during paralysis among ED patients undergoing tracheal intubation. Chest. 2023; 163: 313-323Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar A higher prevalence of awareness with paralysis as well as greater delays in sedative initiation also is associated with rocuronium as compared with succinylcholine during RSI. 3Pappal R. D. Roberts B. W. Mohr N. M. et al. The ED-AWARENESS study: a prospective, observational cohort study of awareness with paralysis in mechanically ventilated patients admitted from the emergency department. Ann Emerg Med. 2021; 77: 532-544Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 5Johnson E. G. Meier A. Shirakbari A. Weant K. Baker Justice S. Impact of rocuronium and succinylcholine on sedation initiation after rapid sequence intubation. J Emerg Med. 2015; 49: 43-49Abstract Full Text Full Text PDF PubMed Google Scholar, 6Watt J. M. Amini A. Traylor B. R. Amini R. Sakles J. C. Patanwala A. E. Effect of paralytic type on time to post-intubation sedative use in the emergency department. Emerg Med J. 2013; 30: 893-895Crossref PubMed Scopus (22) Google Scholar Awareness during paralysis has been associated with an increased risk of psychological sequelae such as posttraumatic stress disorder. 7Ballard N. Robley L. Barrett D. Fraser D. Mendoza I. Patients' recollections of therapeutic paralysis in the intensive care unit. Am J Crit Care. 2006; 15: 86-95Crossref PubMed Google Scholar, 8Fuller B. M. Pappal R. D. Mohr N. M. et al. Awareness with paralysis among critically ill emergency department patients: a prospective cohort study. Crit Care Med. 2022; 50: 1449-1460Crossref PubMed Scopus (10) Google Scholar, 9Schwender D. Kunze-Kronawitter H. Dietrich P. Klasing S. Forst H. Madler C. Conscious awareness during general anaesthesia: patients' perceptions, emotions, cognition and reactions. Br J Anaesth. 1998; 80: 133-139Abstract Full Text PDF PubMed Google Scholar Notably, a shift in practice to using rocuronium has occurred because of perceived advantages in side effect profile. 10Brown CA 3rd Bair A. E. Pallin D. J. Walls R. M. NEAR III InvestigatorsTechniques, success, and adverse events of emergency department adult intubations. Ann Emerg Med. 2015; 65 (published correction appears in Ann Emerg Med. 2017;69 (5): 540): 363-370. e1Abstract Full Text Full Text PDF PubMed Google Scholar The expected duration of paralysis from rocuronium exceeds that of commonly administered induction sedatives (eg, etomidate, midazolam, and ketamine). 11Almaject, Inc. Rocuronium package insert. Published March 2020. Almaject, Inc. , website. Accessed December 20, 2023. https: //www. fffenterprises. com/assets/downloads/product-information/almaject/pi-ROCURONIUM-BROMIDE. pdfGoogle Scholar, 12Hospiral, Inc. Etomidate package insert. Hospiral, Inc. , website. Published April 2017. 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Based on population pharmacokinetic studies, the average duration of action of rocuronium (0. 6-1. 2 mg/kg) is 60 min, but highly variable (ie, 15-160 min). 11Almaject, Inc. Rocuronium package insert. Published March 2020. Almaject, Inc. , website. Accessed December 20, 2023. https: //www. fffenterprises. com/assets/downloads/product-information/almaject/pi-ROCURONIUM-BROMIDE. pdfGoogle Scholar, 16Magorian T. Flannery K. B. Miller R. D. Comparison of rocuronium, succinylcholine, and vecuronium for rapid-sequence induction of anesthesia in adult patients. Anesthesiology. 1993; 79: 913-918Crossref PubMed Google Scholar Critically ill patients experience many of the possible risk factors for prolonged durations, including older age, higher doses, hypothermia, liver disease, renal failure, electrolyte disturbances, and concurrent administration of certain medications. 17Lee L. A. Athanassoglou V. Pandit J. J. Neuromuscular blockade in the elderly patient. 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Am J Emerg Med. 2023; 71: 99-103Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Some of these studies also describe a tendency toward lower doses of postintubation sedatives at certain time points after rocuronium as compared with succinylcholine. 28Korinek J. D. Thomas R. M. Goddard L. A. St John A. E. Sakles J. C. Patanwala A. E. Comparison of rocuronium and succinylcholine on postintubation sedative and analgesic dosing in the emergency department. Eur J Emerg Med. 2014; 21: 206-211Crossref PubMed Google Scholar, 29Carlson R. T. Shah S. Wells E. Fertel B. S. Campbell M. J. Post-intubation analgesia and sedation following succinylcholine vs. rocuronium in the emergency department. Am J Emerg Med. 2023; 71: 99-103Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar However, studies are lacking that consider critically ill patients outside of the emergency room, the possibility of prolonged paralysis, dosing of induction agents, and administration and dosing of subsequent sedatives for the full duration of neuromuscular blockade. This study aimed to elucidate the prevalence and duration of sedation gaps in critically ill patients experiencing bedside procedural paralysis. This was a retrospective cross-sectional study conducted at a large academic medical center with five adult ICUs (February 2023-April 2023). The study protocol was approved by the institutional review board (identifier: 2030129-1 April 7, 2023). Hospitalized adult patients who received rocuronium for a bedside procedure were screened for inclusion. Patients were excluded if they were receiving continuous sedation before the procedure, received additional NMBAs after the procedure, or were undergoing cardiac arrest around the time of the procedure. Patients who received multiple doses of rocuronium during a single admission were eligible for inclusion if clear recovery was documented (eg, extubation, charted movement or arousal) between administrations. Patients were identified from a list of rocuronium administrations outside the operating room using the electronic medical record (EMR). The list was sorted by date of rocuronium administration, and consecutive patients were reviewed for study inclusion to minimize potential selection bias. Patient screening and clinical data collection were performed via manual review. Baseline demographics, patient location, bedside procedure performed, and indication for mechanical ventilation were collected. Indication for mechanical ventilation was determined by procedure note review; some patients had more than one indication identified. Doses and administration dates and times were collected for rocuronium, induction agents (etomidate, ketamine, midazolam, and propofol), and sedatives (dexmedetomidine, ketamine, midazolam, and propofol) given during the presumed paralysis period. The durations of action of induction agents were defined as 5 min (etomidate and propofol), 10 min (ketamine), and 15 min (midazolam) based on population pharmacokinetic studies. 11Almaject, Inc. Rocuronium package insert. Published March 2020. Almaject, Inc. , website. Accessed December 20, 2023. https: //www. fffenterprises. com/assets/downloads/product-information/almaject/pi-ROCURONIUM-BROMIDE. pdfGoogle Scholar, 12Hospiral, Inc. Etomidate package insert. Hospiral, Inc. , website. Published April 2017. Accessed December 20, 2023. https: //www. accessdata. fda. gov/drugsatfdadocs/label/2017/018227s032lbl. pdfGoogle Scholar, 13Par Pharmaceutical. Ketamine package insert. Revised August 2020. Par Pharmaceutical website. Accessed December 20, 2023. https: //www. accessdata. fda. gov/drugsatfdadocs/label/2020/016812s046lbl. pdfGoogle Scholar, 14Olkkola K. T. Ahonen J. Midazolam and other benzodiazepines. in: Modern Anesthetics (Handbook of Experimental Pharmacology). 182. Springer, 2008: 335-355Google Scholar If more than one induction agent was administered, the medication dosed closest to recommended weight-based dosing per respective package insert was considered the primary agent. The weight used for all medication calculations was actual body weight. Adequate postinduction sedation was defined as intermittent midazolam IV boluses ≥ 2 mg every 15 min, propofol continuous infusion ≥ 20 μg/kg/min, or ketamine continuous infusion > 10 μg/kg/min. A conservative threshold for continuous ketamine infusion rate was chosen because it was used as an adjunct therapy at the study institution. Dexmedetomidine was not considered adequate sedation. In patients whose recorded administration times for rocuronium and induction agent differed by > 2 min, review of procedure notes, nursing notes, and medication dispensing dates and times was completed to determine accuracy of charted administration time. If accuracy of charted administration times remained unclear, the patient was censured from review. The primary outcome was the cumulative time of inadequate sedation during presumed paralysis. This sedation gap was calculated by subtracting the cumulative time of adequate sedation from the total duration of presumed paralysis, which was defined as 60 min after rocuronium administration. The duration of action for each sedative agent was used to determine the period of sedation. For example, if a patient received etomidate and rocuronium simultaneously, the upper limit of inadequate sedation would be 55 min, given that the presumed etomidate duration was 5 min. Additionally, if propofol was administered at adequate doses for the first 25 min, but then turned off, the remaining 35 min were accounted for as part of the sedation gap. Secondary outcomes included time to initiation of adequate sedation and the sedation gap when assuming a prolonged duration of paralysis, which was defined as 120 min. 30de Boer H. D. Driessen J. J. Marcus M. A. Kerkkamp H. Heeringa M. Klimek M. Reversal of rocuronium-induced (1. 2 mg/kg) profound neuromuscular block by sugammadex: a multicenter, dose-finding and safety study. Anesthesiology. 2007; 107: 239-244Crossref PubMed Scopus (0) Google Scholar, 31Pühringer F. K. Rex C. Sielenkämper A. W. et al. Reversal of profound, high-dose rocuronium-induced neuromuscular blockade by sugammadex at two different time points: an international, multicenter, randomized, dose-finding, safety assessor-blinded, phase II trial. Anesthesiology. 2008; 109: 188-197Crossref PubMed Scopus (0) Google Scholar, 32Arain S. R. Kern S. Ficke D. J. Ebert T. J. Variability of duration of action of neuromuscular-blocking drugs in elderly patients. Acta Anaesthesiol Scand. 2005; 49: 312-315Crossref PubMed Scopus (0) Google Scholar, 33Debaene B. Plaud B. Dilly M. P. Donati F. Residual paralysis in the PACU after a single intubating dose of nondepolarizing muscle relaxant with an intermediate duration of action. Anesthesiology. 2003; 98: 1042-1048Crossref PubMed Scopus (412) Google Scholar A nested cohort compared outcomes between groups with and without a pharmacist present to facilitate delivery and preparation of medications during the bedside procedure. Pharmacists at the study center had a high participation rate in ICU procedures between 6: 30 am and 3: 30 pm, variable participation between 3: 30 pm and 10: 00 pm, and 24-h participation in the ED. A pharmacist was considered present at bedside if he or she removed any procedural rocuronium, induction, or sedative agent from an automated dispensing cabinet or documented procedural involvement in the EMR. Baseline characteristics and medication doses were assessed using descriptive statistics. Sedation gap comparisons were assessed using the Mann-Whitney U test and the log-rank test. Bootstrapping with replacement was performed subsequently for 10, 000 iterations of the original data set to mitigate the effects of stochastic events in each group: pharmacist present vs pharmacist not present. P values of 1 mg/kg. Table 1Baseline CharacteristicsCharacteristicData (n = 80) Male sex46 (57. 50) Age, y60 ± 17. 72Weight, kg84 ± 22. 71BMI, kg/m229 ± 6. 93Location ED44 (55. 00) Medical ICU25 (31. 25) Cardiothoracic ICU5 (6. 25) Surgical ICU1 (1. 25) Neurosurgical ICU4 (5. 00) Non-ICU floor1 (1. 25) Burn ICU0 (0. 00) Procedure RSI79 (98. 75) Tracheostomy1 (1. 25) Indication for mechanical ventilationaMultiple indications for intubation existed. Altered mental status57 (71. 3) Hypercapnia36 (45. 0) Hypoxiac51 (63. 8) Data are presented as No. (%) or mean ± SD. RSI = rapid sequence intubation. a Multiple indications for intubation existed. Open table in a new tab Table 2Pharmacologic Agents AdministeredPharmacologic Agents AdministeredData (n = 80) Primary induction agentaTwo patients were intubated without receiving an induction agent. Etomidate72 (90. 0) Dose 143 (53. 8) Postprocedural sedation within 2 h after NMBAbPostintubation sedation percentages do not add up to 100% because patients could receive multiple sedative agents. Propofol68 (85. 0) Initial dose ≥ 20 μm/kg/min48 (70. 6) Initial dose 11 μm/kg/min0 (0. 00) Initial dose ≤ 11 μm/kg/min1 (1. 25) Dexmedetomidine7 (8. 75) Adjunctive6 (7. 50) Primary sedative1 (1. 25) Data are presented as No. (%) or mean ± SD. Dosing weight used was actual body weight. NMBA = neuromuscular blocking agent. a Two patients were intubated without receiving an induction agent. b Postintubation sedation percentages do not add up to 100% because patients could receive multiple sedative agents. Open table in a new tab Data are presented as No. (%) or mean ± SD. RSI = rapid sequence intubation. Data are presented as No. (%) or mean ± SD. Dosing weight used was actual body weight. NMBA = neuromuscular blocking agent. Overall, 68 patients (85. 0%; 95% CI, 80. 7%-89. 3%) experienced a sedation gap of any duration during presumed paralysis (Table 3). For the primary outcome, the median sedation gap during a 60-min period of presumed paralysis after rocuronium administration was 19 min (interquartile range IQR, 4. 0-47. 5 min) (Fig 2, Table 3). The median sedation gap during a 120-min period of presumed paralysis was 39 min (IQR, 5. 3-101. 0 min) (Fig 2, Table 3). The probability of initiating adequate sedation was higher when a pharmacist was present at the bedside (hazard ratio, 1. 49 95% CI, 1. 42-1. 55; P <. 0001, bootstrapping log-rank test) (Fig 3). The median sedation gap with a pharmacist at the bedside was significantly lower than without one (11 min IQR, 3-27. 5 min vs 40 min IQR, 17-55 min; P =. 012, Mann-Whitney U test) (Table 3). Bootstrapping resulted in a median sedation gap of 11 min (IQR, 3-25 min) vs 40 min (IQR, 17-25 min) for pharmacists present vs not present, respectively. The resulting difference of medians was 29 min (95% CI, 11-37 min; P =. 0143, bootstrapping Mann-Whitney U test). Table 3OutcomesOutcomeOverall (n = 80) Pharmacist Present (n = 49) Pharmacist Not Present (n = 31) P ValueSedation gap 1 h after NMBA - no. (%) 68 (85. 0) 42 (85. 7) 26 (83. 9). 822aFisher exact test. Sedation gap 1 h after NMBA, min18. 5 (4-47. 5) 11 (3-27. 5) 40 (17-55). 012bMann-Whitney U test. Sedation gap 2 h after NMBA, min38. 5 (5. 8-101. 0) 29 (4-84) 85 (18-115). 031bMann-Whitney U test. No adequate postintubation sedation within 1 h after NMBA18 (22. 5) 9 (18. 4) 9 (29. 3). 269aFisher exact test. Data are presented as No. (%) or median (interquartile range). NMBA = neuromuscular blocking agent. a Fisher exact test. b Mann-Whitney U test. Open table in a new tab Figure 3Kaplan-Meier curve showing the probability of initiating adequate sedation. If a patient received no postintubation sedation, they were assigned the maximum possible time. If a patient received no induction agent, the initial gap was from rocuronium administration to initial sedative administration. View Large Image Figure ViewerDownload Hi-res image Download (PPT) Data are presented as No. (%) or median (interquartile range). NMBA = neuromuscular blocking agent. The predominant postintubation sedative was propofol (85. 0%) ; a substantial proportion of these patients (29. 4%) received doses of less than the minimum rate for adequate sedation. Midazolam intermittent injections were administered to 37. 5% of patients. Dexmedetomidine was started as an adjunctive agent in six patients and as the primary sedative in one patient (Table 2). For all patients, the median time from end of induction effect to first sedative dose was 6 min (IQR, 0-31. 8 min). For the subset of patients who experienced a sedation gap, a delay in initial sedation occurred in 83. 8% (n = 57/68), with a median delay to postintubation sedation of 14 min (IQR, 25-55 min). For patients who received an adequate postintubation sedative within 60 min, 39. 7% (n = 24/63) experienced interruption (s) in adequate sedation during the expected duration of paralysis (eg, midazolam IV push administe