ABSTRACT
Introduction
Onset time of rocuronium is prolonged in elderly patients compared to younger patients. Ephedrine reduces onset time of rocuronium in younger adults, but in elderly patients, the effect of ephedrine on onset time of rocuronium has not been investigated. The aim of this study was to determine the onset time of rocuronium 0.6 mg kg−1 after administration of ephedrine 0.15 mg kg−1 in patients aged 80 years or above. The hypothesis was that ephedrine reduces onset time compared to placebo (saline).
Methods
We included patients aged ≥ 80 years with American Society of Anesthesiologists physical health Classes I–III scheduled for surgery under total intravenous anaesthesia with rocuronium. Patients were randomised to administration of ephedrine 0.15 mg kg−1 or saline (placebo) before administration of rocuronium 0.6 mg kg−1. Primary outcome was time to Train‐of‐Four (TOF) count 0 measured from the end of administration of rocuronium. Secondary outcomes included intubating conditions, occurrence of new cardiac arrhythmia, change in mean arterial blood pressure (MAP) and occurrence of hoarseness and sore throat at 24 and 72 h after surgery.
Results
Forty‐four patients were allocated to receive ephedrine and 43 patients to receive saline, but the primary endpoint could only be analysed in 38 and 37, respectively. Time to TOF 0 was 134 s (IQR, 107 to 180) in the ephedrine group compared to 139 s (IQR, 121 to 185) in the placebo group (p = 0.60), difference 9 s (95% CI, −14 to 31). Change in MAP was 4 mmHg (SD 21) in the ephedrine group compared to –6 mmHg (SD 22) in the placebo group (p = 0.03), difference 10 mmHg (95% CI 1 to 20). Cardiac arrythmias occurred more often in the ephedrine group compared to the placebo group (p < 0.001). No difference was found in intubating conditions or occurrence of hoarseness or sore throat after surgery.
Conclusion
No reduction was found in onset time of rocuronium 0.6 mg kg−1 in elderly patients after administration of ephedrine 0.15 mg kg−1 compared to placebo during induction of anaesthesia. The ephedrine group had more stable blood pressure, but a larger occurrence of tachycardia compared to placebo.
Editorial Comment
Ephedrine intravenous treatment, which can be given around the time of anesthesia induction and muscle relaxant administration, is thought to shorten rocuronium effect onset time for some patients. In this study, this was tested in an elderly cohort, in a blinded trial compared to a placebo treatment. Ephedrine was noted to have predictable cardiovascular effects, but did not have an effect on rocuronium onset time in this cohort.
Trial Registration: NCT06681662
Keywords: elderly patients, ephedrine, neuromuscular blocking agents, onset time
1. Introduction
The neuromuscular blocking agent rocuronium can be administered during anaesthesia to facilitate tracheal intubation [1]. However, in elderly patients, the onset time of rocuronium 0.6 mg kg−1 is prolonged when comparing elderly with younger adults [2]. A prolonged onset time of rocuronium can prolong the time securing the patient's airway. It is therefore relevant to investigate measures to reduce the onset time of rocuronium in the elderly.
Elderly patients are characterized by increased vascular resistance and a decline in endothelium‐dependent vasodilatation which can reduce blood flow to muscle tissue [3, 4]. Also, a decreased vascular compliance is seen in elderly patients [5].
Ephedrine is an alpha and beta‐adrenergic agonist and is used to treat hypotension during anaesthesia and acts as both a direct and indirect sympathomimetic [6]. It binds directly to both alpha and beta receptors; however, its primary mode of action is indirectly by inhibiting neuronal norepinephrine reuptake and displacing more norepinephrine from storage vesicles [7]. This action allows norepinephrine to remain in the synapse longer to bind to postsynaptic alpha and beta receptors [8]. Ephedrine's indirect mechanism of action results in an increased heart rate due to norepinephrine's binding to alpha and beta receptors. Stimulation of alpha‐1‐adrenergic smooth muscle receptors within vasculature results in a rise in systemic vascular resistance and, consequently, blood pressure. Direct stimulation of beta‐1 receptors by ephedrine and norepinephrine increases heart rate and inotropy and therefore ephedrine can facilitate the distribution of drugs with a subsequent reduction of onset time of rocuronium during induction of anaesthesia [9, 10, 11]. However, in elderly patients, the effect of ephedrine on onset time of rocuronium has not been investigated.
It is possible to detect the neuromuscular blocking effect of rocuronium with objective neuromuscular monitoring perioperatively by train‐of‐four (TOF) stimulation at the ulnar nerve where time from administration of rocuronium till TOF count 0 defines the onset time [12].
The aim of this study was to determine the onset time of rocuronium after administration of ephedrine 0.15 mg kg−1 in patients aged 80 years or above. The hypothesis was that ephedrine reduces onset time compared to placebo (saline).
2. Methods
This study was approved by Clinical Trials Information System (CTIS) number 2024‐517933‐42‐00 (November 13, 2024) and The Danish Data Protection Agency (Privacy, November 7, 2024, P‐2024‐17740), and written informed consent was obtained from all patients. The study was conducted in accordance with the Declaration of Helsinki and registered at Clinicaltrials.gov (NCT06681662 Date of registration May 11, 2024) prior to the start of the trial and enrolment of patients. Data were managed using the web‐based data capture tool REDCap with data stored and hosted by the Capital Region of Denmark [13, 14]. The reporting adheres to the CONSORT guideline [15]. Patients were included from Department of Anaesthesia, Centre of Head and Orthopedics, Rigshospitalet, and Department of Anaesthesiology, Pain and Respiratory Support, Rigshospitalet Glostrup and conducted in accordance with the International Conference on Harmonization (ICH)/good clinical practice (GCP) guidelines [16] supervised by an independent inspector from the GCP unit of Copenhagen University Hospitals, Denmark.
Inclusion criteria were age 80 years or above, scheduled for elective surgery under total intravenous anaesthesia with intubation, American Society of Anesthesiologists (ASA) physical status of Classes I to III, informed consent, and able to read and understand Danish. Exclusion criteria were neuromuscular disease interfering with neuromuscular monitoring, known allergy to rocuronium or ephedrine, indication for rapid sequence induction, daily use of beta‐blocking agents, and known cardiac arrhythmia (defined as atrial fibrillation, supraventricular or ventricular).
Randomisation was done on the day of surgery after written informed consent was obtained. An independent investigator allocated patients to either the ephedrine group or the placebo group using a computerised random number generator in REDCap. Only individuals involved in the study were granted access to the REDCap database.
2.1. Anaesthesia
The patients were monitored with non‐invasive blood pressure measurement, pulse oximetry, and electrocardiogram. Central and peripheral temperature was kept above 35°C and 32°C, respectively, according to guidelines, with a forced air warming system. The temperature was monitored with sensors in either the nasal cavity, oesophagus, rectum or bladder and also on the thenar eminence with TOF Watch SX monitor. General anaesthesia was induced with fentanyl 1–3 μg kg−1 and propofol 1–2 mg kg−1 as needed to obtain loss of eyelash reflex. Tracheal intubation was performed after administration of rocuronium 0.6 mg kg−1 when TOF count was 0. Recommended sizes of tracheal tubes were size 7.0 for women and 8.0 for men.
The study drug (ephedrine/placebo) was administered 2 min before administration of rocuronium. The dose of rocuronium was based on ideal body weight, calculated as height (cm) minus 105 for women and height (cm) minus 100 for men or actual body weight, whichever was lower. Total intravenous anaesthesia was maintained after tracheal intubation with propofol and remifentanil according to local guidelines.
Neuromuscular monitoring was performed with TOF‐Watch SX monitor connected to a computer for collection of neuromuscular data (Version 2.5 INT 2007, Organon, The Netherlands) according to international guidelines [12]. TOF‐Watch SX was placed on the arm, where there was the least monitoring equipment. The skin was cleansed and rubbed with an abrasive. Small electrodes were placed on the wrist over the ulnar nerve and the acceleration transducer was placed on the thumb and attached to the associated hand adaptor. When the patient was adequately anaesthetised, two TOF nerve stimulations were performed followed by a tetanic stimulation at 50 Hz for 5 s. After calibration the study drug was injected (ephedrine 0.15 mg kg−1 or saline) and TOF was determined (2 Hz for 1.5 s) every 15 s. After securing a stable signal with less than 5% deviation for 2 min rocuronium 0.6 mg kg−1 was administered and tracheal intubation was performed when TOF was 0. The intubating conditions were assessed with the Fuchs‐Buder scale and Intubation Difficulty Scale (IDS) [12, 17]. With the Fuchs‐Buder scale tracheal intubating conditions were classified as excellent if all qualities were excellent, good if all qualities were either excellent or good and poor if the presence of a single quality was listed as poor. In case of TOF < 0.90 at the end of surgery the NMB was reversed with neostigmine or sugammadex at the discretion of the attending anaesthesiologist. Neuromuscular monitoring continued until TOF was ≥ 0.90 for a period of 2 min after which tracheal extubation was performed and the patient was taken to the recovery room. All patients were contacted 24 and 72 h postoperatively to identify possible adverse and serious adverse events.
2.2. Blinding
The study drug was prepared in a secured medicine storage room before surgery after double control by the study investigator who also performed the randomisation. The study drug, either ephedrine 0.15 mg kg−1 or saline, was prepared in a 1 mL syringe mixed with saline to a total volume of 1 mL to secure blinding. Only study investigators had access to allocation. The syringe was handed to the attending anaesthetist, who administered the study drug blinded to allocation. The patient, anaesthesia and surgical personnel were blinded throughout the patient's stay at the hospital and at the 24 and 72 h follow up. The study investigator controlling the neuromuscular monitoring was not blinded. The secondary outcomes were assessed by a blinded study investigator without access to treatment group allocation.
2.3. Outcomes
The primary outcome was the onset time of rocuronium 0.6 mg kg−1 defined as the time from end of administration of rocuronium until TOF count of 0.
Secondary outcomes were intubating conditions assessed by the Fuchs‐Buder scale and IDS, occurrence of new cardiac arrythmia during induction of anaesthesia (< 15 min after administration of ephedrine or saline), change in mean arterial blood pressure (MAP) from before induction to immediately after intubation, and time to TOF 0.9. Other outcomes were the occurrence of hoarseness and sore throat 24 and 72 h postoperatively assessed using a numeric ranking scale 0–10 where 10 was worst. After 24 h, patients were asked about hoarseness and sore throat. Patients who experienced either or both were contacted again at postoperative day three.
2.4. Statistics
We used SAS Studio 3.8 software. Data were reported as mean with standard deviation (SD), median with interquartile ranges (IQR), or count with frequencies. Parametric data were compared with a t‐test, and Chi Square or Fisher's exact test was used for comparison of proportions. Nonparametric data were compared with Mann–Whitney U test. Differences were reported with 95% confidence interval, using Hodges‐Lehmann Estimate for non‐parametric data. A p value < 0.05 was considered statistically significant.
The sample size calculation was based on our primary outcome. We considered a 30‐s difference in onset time between ephedrine and placebo to be clinically relevant. From previously conducted studies we estimated a standard deviation of 50 s for onset time of rocuronium 0.6 mg kg−1 [2]. A sample of 80 patients (40 patients in each group) would allow us to detect a 30‐s difference with a power of 80% at a 5% significance level.
3. Results
Between January 13, 2025 and October 5, 2025 a total of 92 patients were eligible of which four were excluded due to logistic reasons, and one patient had a change in plan for airway management (Figure 1). A total of 87 patients were randomised. Forty‐four patients were allocated to the ephedrine group of which three patients did not receive the intervention (one patient withdrew consent, one patient due to logistic reasons, and one patient had a change in the airway management plan). Forty‐three patients were allocated to the placebo group of which four patients did not receive the intervention (one patient withdrew consent, one patient had a change in the airway management plan, and two patients due to logistic reasons) (Figure 1). Thus, 41 patients received ephedrine, and 39 patients received placebo (Table 1). A TOF count of 0 was not reached in three patients in the ephedrine group and in two patients in the placebo group. Hence, data regarding onset time were analysed in 38 patients in the ephedrine group and in 37 patients in the placebo group (Figure 1).
FIGURE 1.
Flow diagram.
TABLE 1.
Characteristics and intraoperative data for patients 80 years or above randomised to either ephedrine 0.15 mg kg−1 or placebo before administration of rocuronium.
| Ephedrine | Placebo (saline) | |
|---|---|---|
| n | 44 | 43 |
| Age, years | 83 (3) [80–93] | 83 (3) [80–90] |
| Sex, M/F | 19/25 | 15/28 |
| BMI, kg.m−2 | 25 (4) | 27 (5) |
| ASA I/II/III | 1/27/16 | 0/33/10 |
| Received intervention, n | 41 | 39 |
| Type of surgery | ||
| Orthopaedic | 15 | 7 |
| Plastic | 5 | 11 |
| Spine | 16 | 17 |
| Ear nose throat | 4 | 3 |
| Eye | 1 | 1 |
| Duration of anaesthesia, min | 171 (74) | 154 (69) |
| Duration of surgery, min | 102 (58) | 95 (57) |
| Comorbidity | ||
| Diabetes | 5 (12%) | 6 (15%) |
| Kidney disease | 4 (9%) | 1 (2%) |
| Hypertension | 29 (67%) | 29 (71%) |
| Heart disease | 2 (5%) | 1 (2%) |
| Medicine | ||
| Diuretics | 16 (37%) | 6 (15%) |
| Magnesium | 3 (7%) | 0 |
| Antihypertensive | 26 (60%) | 29 (71%) |
Time to TOF 0 was 134 s (IQR, 107 to 180) in the ephedrine group compared to 139 s (IQR, 121 to 185) in the placebo group (p = 0.60), difference 9 s (95% CI, −14 to 31) (Table 2).
TABLE 2.
Outcomes in patients 80 years or above randomised to either ephedrine 0.15 mg kg−1 or placebo (saline) before administration of rocuronium.
| Ephedrine | Placebo | p | Difference with 95% CI | |
|---|---|---|---|---|
| n | 41 | 39 | ||
| Time to TOF 0 (s) |
134 (IQR, 107 to 180) |
139 (IQR, 121 to 185) |
0.60*** | 9 (−14 to 31) |
| Time to TOF 90 (min) |
87 (35) n = 6 |
83 (32) n = 8 |
0.8** | 4 (−34 to 44) |
| MAP before induction (mmHg) | 99 (12) | 98 (12) | ||
| MAP after intubation (mmHg) | 103 (25) | 92 (20) | ||
| Change in MAP (mmHg) | 4 (21) | −6 (22) | 0.03** | 10 (1 to 20) |
| Cardiac arrythmia | < 0.001* | |||
| Sinus bradycardia (SB) | 0 | 7 (18%) | ||
| Sinus tachycardia (ST) | 16 (39%) | 1 (3%) | ||
| Sinus tachycardia and bradycardia | 0 | 1 (3%) | ||
| Occurrence of hoarseness 24 h postoperatively | ||||
| 9 (22%) | 11 (28%) | 0.73* | ||
| 72 h postoperatively | ||||
| 3 (33%) | 4 (40%) | 0.55* | ||
| Occurrence of sore throat 24 h postoperatively | ||||
| 7 (17%) | 5 (13%) | 0.73* | ||
| Missing | n = 2 (5%) | n = 1 (2%) | ||
| 72 h postoperatively | ||||
| 4 (57%) | 0 | 0.06* | ||
| Intubation difficulty scale | ||||
| Not excellent | 16 (39%) | 16 (42%) | 0.78* | |
| Excellent | 25 (61%) | 22 (58%) | ||
| Fuchs‐Buder | ||||
| Not excellent | 12 (29%) | 18 (47%) | 0.10* | |
| Excellent | 29 (71%) | 20 (53%) | ||
Note: DI Confidence Interva (%) or mean and standard deviation (SD).
Mann–Whitney U test.
t‐test.
Chi square test, CI Confidence Interval.
Change in MAP was 4 mmHg (SD 21) in the ephedrine group compared to −6 mmHg (SD 22) in the placebo group (p = 0.03), difference 10 mmHg (95% CI, 1 to 20) (Table 2).
Administration of ephedrine outside the protocol at the discretion of the anaesthetist during induction occurred in one patient in the ephedrine group and in five patients in the placebo group (p = 0.09). In a per protocol analysis after exclusion of the five patients administered ephedrine, the difference in time to TOF 0 was 6 s (p = 0.73) (95% CI, −31 to 43) (Table 2).
Cardiac arrythmias within 15 min after administration of the study drug occurred more often in the ephedrine group compared to the placebo group (p < 0.001) (Table 2).
No difference was found in the occurrence of hoarseness or sore throat neither at 24 nor at 72 h postoperatively (Table 2). No difference was found in intubating conditions assessed with the IDS or the Fuchs‐Buder scale (Tables 2 and 3). Assessment of time to TOF 0.9 was possible in six patients in the ephedrine group and eight patients in the placebo group and no difference was found (Table 2).
TABLE 3.
Tracheal intubating conditions (Fuchs‐Buder) for patients 80 years or above administered either ephedrine 0.15 mg kg−1 or placebo before administration of rocuronium.
| Ephedrine | Placebo | p * | |
|---|---|---|---|
| N | 41 | 38 | |
| Vocal cords position | 0.22 | ||
| 1. Abducted | 35 (86%) | 34 (89%) | |
| 2. Intermediate | 3 (7%) | 4 (11%) | |
| 3. Closed | 3 (7%) | 0 | |
| Vocal cords movement | 0.75 | ||
| 1. None | 37 (90%) | 36 (94%) | |
| 2. Moving | 2 (5%) | 1 (3%) | |
| 3. Closing | 2 (5%) | 1 (3%) | |
| Reaction to intubation: movement | 0.58 | ||
| 1. None | 39 (95%) | 35 (92%) | |
| 2. Slight | 2 (5%) | 3 (8%) | |
| 3. Vigorous | 0 | 0 | |
| Reaction to intubation: coughing | 0.08 | ||
| 1. None | 38 (93%) | 30 (80%) | |
| 2. Slight | 3 (7%) | 8 (21%) | |
| 3. Sustained | 0 | 0 | |
| Laryngoscopy: jaw relaxation | 0.26 | ||
| 1. Relaxed | 37 (90%) | 34 (89%) | |
| 2. Not fully | 2 (5%) | 4 (11%) | |
| 3. Poor | 2 (5%) | 0 | |
| Laryngoscopy: resistance to laryngoscope | 0.68 | ||
| 1. None | 38 (93%) | 33 (87%) | |
| 2. Slight | 2 (5%) | 3 (8%) | |
| 3. Reactive | 1 (2%) | 2 (5%) | |
Note: Data presented as count and frequencies (%).
Chi‐square.
Five patients had a serious adverse event (SAE), two in the placebo group (one patient had exacerbation in chronic obstructive pulmonary disease and one patient had oozing from the wound) and three in the ephedrine group (one patient had postoperative bleeding, one patient had infection, and one patient was not able to mobilise due to muscle weakness). None of the SAEs were deemed related to the study drug.
4. Discussion
We were unable to detect a reduction in onset time of rocuronium 0.6 mg kg−1 in elderly patients after administration of ephedrine 0.15 mg kg−1 compared to placebo. Ephedrine prevented a decrease in blood pressure, but tachycardia was seen in a larger proportion of patients administered ephedrine.
The strengths of this study include the randomised blinded design with objective neuromuscular monitoring according to research guidelines performed by few trained study investigators and blinded assessment of both primary and secondary outcomes ensuring collection of precise data [12]. In addition, patients underwent standardised total intravenous anaesthesia for various surgical procedures increasing the external validity. Also, patients receiving beta blocking agents were excluded as this could counteract the possible effect of ephedrine and possibly prevent detection of a difference between the treatment groups. However, we did not determine hemodynamic status preoperatively, for example, the ejection fraction by echocardiography and this was a limitation. Also, we did not monitor cardiac output perioperatively and therefore we were not able to conclude on a possible association between cardiac output and onset time of rocuronium. At our institution it was not clinical routine to monitor cardiac output in this patient population undergoing these types of surgery neither invasively nor minimally invasively, for example, by pulse contour analysis. It should however be emphasized that few studies support that accurate measurements of cardiac output can be determined with pulse contour analysis [18]. Finally, we did not employ normalized TOF ratios or registered time to TOF 1.0. However, duration of action was only detected in a small number of patients where spontaneous recovery occurred before emergence of anaesthesia.
In younger adults (mean age approximately 40 years) a reduction in onset time of rocuronium 0.6 mg kg−1 of approximately 15–30 s has been found after administration of ephedrine 70 μg kg−1 during induction with thiopental, propofol, and fentanyl [9, 10, 19], whereas administration of ephedrine 150 μg kg−1 reduced onset time by approximately 80 s during rapid sequence induction compared to placebo [20]. However, no difference in onset time of vecuronium was detected comparing ephedrine 210 μg kg−1 with placebo [21]. In younger adults, administration of ephedrine before rocuronium resulted in an increase in cardiac output determined with a non‐invasive cardiac output monitor [22].
We hypothesized that in the elderly administration of ephedrine would decrease onset time of rocuronium. In patients administered ephedrine we did find an increased heart rate and less decrease in MAP. However, this offered no advantage in decreasing onset time compared to saline even when excluding patients taking daily beta blocking agents in this population of elderly patients [10]. A possible explanation of our findings could be that elderly patients have decreased responsiveness to beta‐adrenergic receptor stimulation in cardiomyocytes, and a decreased reactivity to baroreceptor and chemoreceptor output resulting in decreased cardiac output [23]. In addition, ageing is associated with increased vascular resistance and a decline in endothelium‐dependent vasodilatation which can reduce blood flow to muscle tissues in the pharynx which also could have influenced our findings [3, 4]. Finally, timing of the administration of ephedrine before rocuronium could have influenced the results as administration 4 min before provided a faster onset time as compared to 30 s in one study. However, the reported difference of approximately 8 s is possibly of minor clinical relevance [19]. Regardless, in our study it must be acknowledged that there is a small risk of a Type 2 error as there is a rather wide confidence interval for the difference in onset time but we can almost exclude that ephedrine provided a 30‐s faster onset. Based on the findings in our study we suggest that ephedrine should not be used to shorten onset time of rocuronium in elderly patients.
An alternative strategy to reduce onset time in elderly patients could be to increase the dose of rocuronium; however, this is at the cost of a prolonged duration of action [24]. Also, it is possible that administration of other vasopressors such as the alpha 1 agonist metaoxedrine could decrease onset time since ephedrine produces vasoconstriction of blood vessels supplying muscles at the hand [20] and future studies could address this. Finally, administration of a bolus of saline immediately after administration of rocuronium has reduced onset time, though the effect was minor and only investigated in younger adults [25]. Regardless, it is recommended to objectively monitor the neuromuscular blockade both to preclude residual effect [26] and to identify onset time since both are prolonged in elderly patients [2, 24].
In conclusion, we were unable to detect a shorter onset time of rocuronium in elderly patients after administration of ephedrine 0.15 mg kg−1 during induction of anaesthesia. Administration of ephedrine resulted in higher blood pressure but a larger occurrence of tachycardia.
Author Contributions
Study design: M.V., L.S.R., T.N. Patient recruitment: M.V., M.F.H., T.N., S.S.W., M.H.J., A.R.S., K.P.D.M., K.S., F.R., C.A. Data collection: M.V., M.F.H., T.N., S.S.W, M.H.J., A.R.S., K.P.D.M., K.S., F.R., C.A. Data analysis: M.V., L.S.R. Manuscript writing: M.V., L.S.R. Critical revision and approval of manuscript: M.V., M.F.H., T.N., S.S.W., M.H.J., A.R.S., K.P.D.M., K.S., F.R., C.A., L.S.R.
Funding
This study was funded by departmental sources.
Conflicts of Interest
The authors declare no conflicts of interest.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.