Introduction
Patients who attend the emergency department (ED) for any form of trauma and critically ill conditions frequently present with physical or mental pain and agitation. These stresses may be associated with tremendous neuro-humoral elevation of plasma catecholamine, cortisol, glucose, antidiuretic hormone and acute phase protein levels [
1,
2]. This elevation can cause significant tachycardia, hypertension, vasoconstriction, increase oxygen consumption, blunting of immune response, and salt and water retention. In addition, these patients are extremely anxious. During these critical situations, procedures may be indicated that require patients to be subjected to some form of chemical induction to facilitate the procedure planned either to save their lives or salvage the remaining functioning organs or limbs. A collective decision needs to be made to choose the most appropriate form of chemical induction for the purpose of analgesia or sedation; usually patients receive the latter [
3,
4]. The superiority of one of these drugs and the lack of potentially dangerous adverse reactions would determine the appropriate choice in the ED setting. The main goal of procedural sedation and analgesia (PSA) is to give patients some relief from both pain and anxiety with minimal adverse events. This technique has to be effective in reducing the stress response and improving patient compliance with a procedure [
5‐
7].
Commonly benzodiazepine, such as diazepam or midazolam, is used as an agent for the PSA. Pharmacologically, it takes up to 45 min for the patients to recover fully and be discharged, and adverse events such as respiratory depression are a known occurrence [
8,
9]. This study examined an alternative agent to PSA, namely propofol. We already know that propofol has a similar mode of action to benzodiazepine, but with a much shorter duration of action [
10]. The use of an effective short-acting drug in PSA relieves patients from numerous unpleasant side effects that are commonly seen with the use of conventional long-acting diazepam. We conducted a randomized controlled trial to compare the adverse events between propofol and midazolam during PSA in adult patients who attended the emergency department. The study was approved by the University Hospital Ethics and Research Committee.
Results
Comparison of demographic and other initial parameters for both groups is shown in Table
2. The senior resident (final year residents) in the Emergency Medicine Department and the specialist emergency physicians performed 75% (n = 30) and 25% (n = 10) of the procedures, respectively. None of the patients in either group developed any adverse events during and after the procedures. No significant drops in blood pressure, heart rate, respiratory rate, end tidal CO
2 and pulse oximetry were observed during and after the procedures. Even though a few parameters, such as MAP, SBP and DBP, dropped intra-procedure, these values normalized post-procedure, and the changes were statistically insignificant within and between the groups (Tables
3 and
4).
Table 2
Demographic data and vital sign parameters for both treatment groups
Number of patients | 20 | 20 | >0.05 |
Age (years) | 40.6 (95% CI 38.2, 43.3) | 35.0 (95% CI 33.2, 37.6) | p = 0.424 |
Sex: |
Male | 15 | 16 | p = 0.705 |
Female | 5 | 4 |
Systolic BP (mmHg) | 127.50 (95% CI 120.00, 143.75) | 130.00 (95% CI 120.00, 140.00 | p = 0.241 |
Diastolic BP (mmHg) | 75.00 (95% CI 70.00, 80.00) | 70.00 (95% CI 70.00, 80.00) | p = 0.093 |
Mean arterial pressure (mmHg) | 94.50 (95% CI 87.10, 100.00) | 93.30 (95% CI 87.10, 99.17) | p = 0.541 |
Oxygen saturation (%) | 99.9 (95% CI 99.80, 100.00) | 100.00 (95% CI 100.00, 100.00) | p = 0.286 |
End tidal CO2 (mmHg) | 38.50 (95% CI 33.25, 40.00) | 36.00 (95% CI 33.25,39.00) | p = 0.662 |
Heart rate (per minute) | 80.00 (95% CI 71.00, 100.00) | 80.00 (95% CI 78.00, 96.50) | p = 0.776 |
Respiratory rate (per minute) | 19.50 (95% CI 18.00, 23.50) | 18.00 (95% CI 14.00, 22.00) | p = 0.334 |
Table 3
Comparing propofol and midazolam by SBP, DBP and MAP
Systolic blood pressure |
Pre-procedure | 134.00 (16.27) | 127.50 (120.00, 143.75) | 131.50 (15.31) | 130.00 (120.00, 140.00) | 0.679 |
Intra-procedure | 115.50 (10.50) | 120.00 (110.00, 120.00) | 121.00 (17.59) | 120.00 (110.00, 133.00) | 0.388 |
Post-procedure | 122.50 (13.43) | 120.00 (111.25, 130.00) | 120.75 (15.25) | 120.00 (110.00, 128.75) | 0.608 |
Diastolic blood pressure |
Pre-procedure | 75.30 (9.27) | 75.00 (70.00, 80.00) | 75.25 (11.53) | 70.00 (70.00, 80.00) | 0.731 |
Intra-procedure | 64.75 (8.66) | 65.00 (60.00, 70.00) | 65.75 (11.62) | 67.50 (60.00, 70.00) | 0.868 |
Post-procedure | 70.25 (6.52) | 70.00 (60.00, 78.75) | 73.00 (15.25) | 70.00 (61.25, 78.75) | 0.989 |
MAP |
Pre-procedure | 94.45 (9.88) | 94.50 (87.10, 100.00) | 94.66 (10.31) | 93.30 (87.10, 99.17) | 0.765 |
Intra-procedure | 82.00 (8.70) | 81.65 (76.70, 89.17) | 83.84 (12.27) | 85.00 (74.97, 89.17) | 0.744 |
Post-procedure | 87.76 (9.41) | 86.70 (80.00, 92.90) | 87.73 (12.44) | 86.70 (80.82, 92.25) | 0.733 |
Table 4
Comparisons of respiratory parameters for both treatment groups
Respiratory rate |
Pre-procedure | 20.30 (4.90) | 19.50 (18.00, 23.50) | 18.25 (5.00) | 18.00 (14.00, 22.00) | 0.574 |
Intra-procedure | 20.90 (5.31) | 21.50 (16.50, 25.00) | 18.40 (4.60) | 18.50 (14.50, 21.75) | 0.082 |
Post-procedure | 20.10 (5.28) | 20.00 (15.00, 24.00) | 18.20 (3.59) | 18.00 (16.00, 22.00) | 0.554 |
Oxygen saturation |
Pre-procedure | 99.90 (0.45) | 100.00 (100.00, 100.00) | 99.85 (0.49) | 100.00 (100.00, 100.00) | 0.226 |
Intra-procedure | 99.80 (0.89) | 100.00 (100.00, 100.00) | 99.05 (2.01) | 100.00 (99.25, 100.00) | 0.106 |
Post-procedure | 99.90 (0.45) | 100.00 (100.00, 100.00) | 99.80 (0.69) | 100.00 (100.00, 100.00) | 0.215 |
ETCO2 |
Pre-procedure | 36.05 (6.57) | 38.50 (33.25, 40.00) | 34.45 (7.82) | 36.00 (33.25, 39.00) | 0.558 |
Intra-procedure | 37.80 (4.96) | 38.00 (34.25, 42.25) | 35.05 (8.97) | 39.50 (25.50, 40.75) | 0.775 |
Post-procedure | 36.75 (5.46) | 38.00 (35.00, 40.00) | 36.70 (7.20) | 39.00 (33.50, 42.00) | 0.606 |
The end tidal carbon dioxide in the propofol group did not show much variation between the pre- and intra-procedural readings. The means (SD) of pre-procedural and intra-procedural end tidal carbon dioxide were 36.05 (6.57) and 37.80 (4.96), respectively. The post-procedural mean (SD) on the other hand was 36.75 (5.46) with the intra-procedural p value being 0.775. In the midazolam group, the means (SD) of end tidal carbon dioxide both pre-procedure and intra-procedure were 34.45 (7.82) and 35.05 (8.97), respectively (p = 0.775). After the procedure, the mean (SD) of end tidal carbon dioxide was 36.70 (7.20). Similarly, no statistical difference in ETCO2 was found between the two study groups.
Discussion
The main goal of PSA is to give patients some relief from both pain and anxiety. In addition, this technique has been clinically shown to be effective in reducing the stress response and improving patient compliance with undergoing a procedure. In general, procedural sedation should be accompanied by analgesia simply because analgesia is able to decrease the stressful effect. This could result in a low requirement for sedatives [
12].
The use of PSA has generated much interest and debate, although the technique has been widely practiced in many settings that previously were regarded as being in the domain of anesthesiology [
13,
14]. PSA offers many advantages. Firstly, patients are able to maintain consciousness while undergoing an unpleasant procedure. Their tolerance of such painful procedures makes them able to cooperate with the care providers, thereby increasing the compliance further. In addition, this technique does not greatly disrupt the patient’s daily activities. Upon being discharged from the hospital, the patients can resume their jobs and daily activities within a relatively short period of time with minimal discomfort. The settings found to be of benefit to patients undergoing PSA include procedures in dentistry (dental and oral surgery), radiology, medicine (bronchoscopy, endoscopy, cardiac studies, pacemaker placement) and gynecology (in vitro fertilization). This approach is also being utilized in the outpatient setting [
15‐
17]. In the ED, procedural sedation and analgesia have been widely indicated in overtly anxious patients undergoing procedures such as repair of complicated lacerations, reduction of fractures, application of plaster casts, incision and drainage of abscesses and wound care, thus making it a technique of choice.
Despite the promising outcomes and benefits, some precautions are still required. Adverse events such as cardiorespiratory compromise occurring during and after PSA are commonly reported. Reasons for the complications include inexperienced physicians administering the PSA, improper equipment for monitoring, wrong choice of drugs and presence of comorbidities that lead to the adverse events. Patients undergoing PSA must be closely and continuously monitored to avoid any progression into a deeper state of sedation [
18,
19]. Should this occur, the actual purpose of PSA would be nullified. Monitoring can be achieved effectively through visual observation coupled with the use of a pulse oxymeter and a capnograph. The procedure can be carried out safely and non-invasively with the advent of new monitoring strategies. The use of a pulse oxymeter, for example, coupled with non-invasive monitoring of blood pressure optimizes the comfort and care in patients receiving PSA [
20].
The pulse oxymeter has been used to monitor the level of oxygenation. Since sedation can result in the emergence of apnea and hypoventilation, failure to detect these conditions may eventually lead to oxygen desaturation. The pulse oxymeter has been clinically shown to be a relevant tool to monitor the existence of oxygen desaturation. The capnograph is another very useful instrument for recognizing any ventilatory and circulatory problems that occur during sedation. A capnograph has the capacity to provide early warnings of apnea and detect the occurrence of respiratory depression, obstruction or laryngopasm through the monitoring of end tidal expiratory carbon dioxide (EtCO
2), which can be accurately measured. Respiratory depression is said to take place when O2 saturation is <90 mmHg, EtCO
2 is >50 mmHg or when there is an absence of EtCO2 waveform [
21,
22].
Benzodiazepine such as midazolam has been widely used in many surgical procedures performed under local anesthesia. The use of midazolam has been well documented to enhance patient comfort, improve operating conditions and most importantly, because of its amnesic properties, prevent patients from recalling unpleasant events during the procedure. In addition, midazolam acts indirectly as a gamma amino butyric acid agonist and is relatively cardio-respiratory safe. Once administered, it is rapid in onset and has a short duration of action, which makes midazolam a very popular drug of choice for PSA [
23]. However, over the last few years, propofol has emerged quite rapidly as a good agent to be used in PSA by non-anesthesiologists especially in the ED. When given intravenously, the effect is almost immediate. Because of its short half-life, patients on propofol will recover rapidly.
Propofol has a bronchodilating effect, which makes it an appropriate drug of choice for patients with bronchial asthma. Its anti-emetic characteristic gives an added advantage to minimize post-sedation nausea [
24]. However, propofol reduces the mean arterial pressure (MAP), which makes it a rather poor choice in patients who develop hypotension, cardiorespiratory compromise or have head injuries. Apnea and painful injection are other disadvantages of this drug. It may also cause deep sedation and analgesia. Deep sedation is said to take place when a purposeful response is triggered with repeated stimuli, while moderate sedation is a purposeful response to light stimuli, e.g., verbal and tactile. Respiratory depression occurs mainly during deep sedation and not moderate sedation. In moderate sedation, the protective airway reflex is intact and thus reduces the risk of aspiration. Respiratory depression occurs in 19% of patients receiving propofol alone as compared to those who received fentanyl alone (20%), while a combination of midazolam with fentanyl causes respiratory depression in 23% of cases. Due to deep or over-sedation produced by propofol within the normal range, anesthetists object to its use in the emergency and other departments [
25]. However, Zed et al. and Sipe et al. have shown that a bolus dose of 1 mg/kg followed by 0.5 mg/kg (when it is necessary) may reduce both the hypoxia and apnea compared to the 1.5 mg/kg dose [
26,
27].
This randomized controlled trial study was initiated primarily to determine the safety of PSA delivery in the ED setting. In addition, this study also aimed to evaluate the safety profile and effectiveness of the two sedative hypnotics, namely propofol and midazolam, which have been commonly used in patients undergoing PSA. Non-parametric analysis of data was applied in this study because of the small sample size and non-Gaussian distribution in descriptive analysis. Two tests were applied throughout, namely the Mann-Whitney U test (chi-square) and Kruskal-Wallis (chi-square and P value). The data were further analyzed as non-stratified to see the effect without the confounder, for example, the sex of subjects in the study and later the stratified analysis where the confounders were controlled. In this study, age could not be stratified because the subjects recruited were adults. This trial, which took 1 year to complete, involved 40 subjects who fully consented to participate. There were no drop-outs. Clear instructions and guidelines were strictly adhered to in order to minimize bias as well as errors in evaluating the safety profile and efficacy between the two drugs used in PSA. A standard set of forms was utilized, and all relevant information required for the study has been clearly documented.
This study did not show remarkable differences between the two drugs used, namely propofol and midazolam in PSA. Both drugs have been found to be safe for use and did not cause any serious adverse side effects, such as hypoventilation, hypotension, apnea, hypoxia or allergic reactions. None of the patients involved in this study developed any complications throughout the process of procedural sedation. These findings were consistent and supported the study done by Hasen et al. on PSA using intravenous propofol for 48 patients undergoing elective orthopedic surgery under regional blockade [
28]. They firmly concluded that propofol is a safe and effective drug to be used in PSA with no respiratory or cardiovascular depression, or other undesirable adverse effects. Cheol et al., who conducted a randomized double-blind comparative study using propofol alone and combined propofol and midazolam for colonoscopy, found that both propofol alone and combined propofol and midazolam are safe and effective [
29].
However, some results found in this trial remained significant and may illustrate the relevant direction of the future use of these drugs in the emergency department setting.
Changes in blood pressure recorded during procedural sedation
There was a significant and relevant variation in blood pressure before, during and after the procedure. It was found in this study that propofol caused a marked reduction in both the systolic and diastolic blood pressures during the procedure when compared to midazolam. Systolic blood pressure dropped from a mean (SD) of 134.00 mmHg (16.27) to 115.50 mmHg (10.50), while the diastolic blood pressure dropped from a mean (SD) of 75.30 mmHg (9.27) to 65.00 mmHg (8.66) intra-procedure. After the procedure ended, the systolic and diastolic blood pressures normalized to the pre-procedural value (SD) 122.5 mmHg (13.43).
The midazolam group on the other hand showed a marked elevation in both systolic and diastolic blood pressures when the procedure was carried out. Prior to the procedure the mean systolic blood pressure was 121.00 mmHg (17.59) and increased to 131.50 mmHg (15.31) intra-procedure, then normalized with the completion of the procedure. A similar observation was seen in the diastolic blood pressure. The different blood pressure responses can be explained by the different pharmacodynamics of the two drugs. Propofol is known to affect the cardiovascular function of the body system, in particular compromising the blood pressure mainly through the vasodilation effect, whereas benzodiazepine is commonly known to depress more of the respiratory function.
Effects on mean arterial pressure
In this study both propofol and midazolam did not have a significant effect on the mean arterial pressure when a procedure was carried out to completion. Despite the changes in MAP in both drugs under study, during the procedure the p value showed non-statistical significance (p = 0.774). Both drugs did not result in changes of perfusion to various organs in the body, further confirming the safety of both drugs.
Effects on respiratory rate
Both propofol and midazolam showed no difference in respiratory rate during and after procedures (p = 0.106). This could be due to the appropriate titration dose technique used for the procedural sedation.
Effects on heart rate
There was a slight reduction of heart rate recorded in this trial during the procedure in the propofol group with a mean value of 76.40 (16.37), while the pre-procedure mean heart rate (SD) was 83.55 (16.3). The heart rate reduced slightly after the completion of the procedure, but did not reach the pre-procedural level. In the midazolam group, the heart rate was also found to be reduced during the procedure stage. The mean heart rate during the procedure was 79.65 (16.69) and the mean before the procedure (SD) was 85.45 (13.38). The p value for both groups was 0.795.
End tidal carbon dioxide level
Capnography could provide an accurate assessement of various aspects of respiratory functions, which included real-time ventilatory status, endotracheal tube placement and function, ventilatory circuit disconnection and airway leaks. This study utilized nasal prong microstream devices, which measured respiratory gas concentration remotely by aspirating a small sample of gas from the breathing circuit through tubing to a sensor located inside the monitor. The partial pressure of carbon dioxide was kept constant between the level of 35 mmHg to 45 mmHg. Any adverse changes or complications in respiratory functions that arise can be easily detected through capnography. Early detection would ensure an immediate intervention on the patient [
30].
In this study, the end tidal carbon dioxide level in the propofol group did not show much variation between the pre- and intra-procedural readings. The means (SD) of pre-procedural and intra-procedural end tidal carbon dioxide levels were 36.05 (6.57) and 37.80 (4.96), respectively. The post-procedural mean was 36.75 (5.46) with an intra-procedural p value of 0.775. In the midazolam group, the mean end tidal carbon dioxide levels both pre-procedure and intra-procedure were 34.45 (7.82) and 35.05 (8.97), respectively (p = 0.77). There were no marked differences in end tidal carbon dioxide readings between these two drugs. This was because the doses of both drugs used were adequately safe, and additional use of capnography monitoring of the end tidal carbon dioxide level could provide early warning should there be evidence of apnea or hypoventilation. Interventions including repositioning of the airway can be carried out if there is evidence of reduction of partial pressure of carbon dioxide. Jennifer et al. pointed out that capnography is capable of providing important data regarding airway permeability, cardiac and circulatory function and ventilator performance, apart from its ability to evaluate alveolar ventilation. The use of capnography could replace the need to analyze ABG in a non-invasive manner [
31]. It is important to emphasize that all subjects in both groups A and B were provided with continuous oxygen via nasal prong devices throughout the PSA. In a review done by Vargo, he has stressed the significance of unrecognized respiratory difficulty and hypoxemia as a major factor contributing to morbidity and mortality among patients with PSA in the ambulatory setting. To overcome these potential risks, he strongly recommended the use of capnography, which can monitor and detect any evidence of respiratory compromise early on with the combined use of pulse oxymetry.
In all the domains of recorded vital signs, it was found to be insignificant, as shown by the p value of >0.005 on Mann-Whitney U test. For the respiratory rate in male subjects, during the procedure a slight reduction of respiratory rate was observed in the midazolam group from a mean value of 19.37 (4.96) per minute to 19.12 (4.36) (p = 0.148). There was no similar reduction among males in the propofol group using stratified Mann-Whitney analysis.
The time interval to discharge for male subjects in the propofol group was observed to be shorter when compared to the midazolam group with a mean (SD) value of 30.33(12.46) as compared to 59.06 (22.7), respectively, with a p value of 0. 001. In female subjects, the mean (SD) values for the propofol and midazolam were 26.00 (4.18) and 122.50 (28.16), respectively (p = 0.001). There was no significant change found when the data were stratified further to look at the effect of the confounder (sex) on the differences between both propofol and midazolam. Other studies had shown similar patterns of outcome [
32,
33].
Recommendations
This study did not detect any occurrence of hypoxemia, hypoventilation or apnea in any of the participating subjects despite evidence indicating that both propofol and midazolam do cause the above complications. This is because the study used appropriate doses to commence procedural sedation in the emergency department setting. As both of these drugs are safe and effective, the main researcher would like to recommend the following doses to be administered when performing PSA in the ED setting. For propofol, the recommended dose is 1 mg/kg body weight as a bolus dose followed by 0.5 mg/kg if required in a titrating dose. For midazolam, the recommended dose is 0.1 mg/kg body weight as a bolus dose followed by 0.1 mg/kg in a titrating dose when necessary. Although these drugs are regarded as safe and effective, caution is still needed to ensure avoidance and minimization of any possible complications. Appropriate attention must be given to all patients on PSA by continuous monitoring before, during and after the procedure has been completed. Studies have indicated that the use of supplemental oxygen could significantly reduce the magnitude of oxygen desaturation in any procedure performed when a patient is undergoing procedural sedation. This fact should be considered seriously.
A capnograph is a very useful instrument to monitor the arterial partial pressure of carbon dioxide indirectly during PSA. It is a very sensitive tool for picking up these changes at very early stages of hypoventilation, and its detection accuracy is heavily supported by numerous studies worldwide. It is recommended that capnography should be used when PSA is performed in the ED setting. Early intervention could be instituted once abnormal partial pressure of carbon dioxide is detected.
Finally, all patients planned for PSA in the ED setting must be thoroughly assessed, which involves detailed medical history taking in order to prevent the possibility of developing unexpected complications and delay in recovery after the procedure has been completed.