Anesth Analg 2002;95:417-422
© 2002 International Anesthesia Research Society
CRITICAL CARE AND TRAUMA
The Effect of Midazolam on Stress Levels During Simulated Emergency Medical Service Transport: A Placebo-Controlled, Dose-Response Study
Volker Dörges, MD*,
Volker Wenzel, MD
,
Susanne Dix, BS
,
Alexander Kühl, BS,
Thomas Schumann, BS,
Michael Hüppe, PhD,
Heiko Iven, PhD
, and
Klaus Gerlach, MD
*Department of Anesthesiology and Intensive Care Medicine, University Hospital of Kiel; Departments of Anesthesiology, and Pharmacology, Medical University of Lübeck, Germany; and Department of Anesthesiology and Critical Care Medicine, Leopold-Franzens-University, Innsbruck, Austria
Address correspondence and reprint requests to Volker Dörges, MD, Department of Anesthesiology and Intensive Care Medicine, University Hospital of Kiel, 24105 Kiel, Schwanenweg 21, Germany. Address e-mail to v.doerges{at}t-online.de
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Abstract
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Patients in the emergency medical service (EMS) may have increased endogenous catecholamines because of pain or fear and may benefit from sedation similar to premedication in the hospital. During a simulated EMS scene call, 72 healthy male volunteers were either transported by paramedics from a third-floor apartment through a staircase with subsequent EMS transport with sirens (three stress groups of n = 12; total, n = 36) or asked to sit on a chair for 5 min and lie down on a stretcher for 15 min (three control groups of n = 12; total, n = 36). Catecholamine plasma samples were measured in the respective stress and control groups at baseline and after placebo IV (n = 12) or 25 (n = 12) or 50 (n = 12) µg/kg of midazolam IV throughout the experiment, respectively. Statistical analysis was performed with analysis of variance; P < 0.05 was considered significant. The Placebo Stress versus Control group, but not the 50 µg/kg Stress Midazolam group, had both significantly increased epinephrine (73 ± 5 pg/mL versus 45 ± 5 pg/mL; P < 0.001) and norepinephrine (398 ± 34 pg/mL versus 278 ± 23 pg/mL; P < 0.01) plasma levels after staircase transport. After EMS transport, the Placebo Stress versus Control group had significantly increased epinephrine (51 ± 4 pg/mL versus 37 ± 4 pg/mL; P < 0.05) but not norepinephrine (216 ± 24 pg/mL versus 237 ± 18 pg/mL) plasma levels, whereas no significant differences in catecholamine plasma levels occurred between groups after either 25 or 50 µg/kg of midazolam. In conclusion, simulated EMS patients may be subject to more stress during staircase transport than during transport in an EMS vehicle. Titrating sedation with 25 µg/kg of midazolam significantly reduced endogenous catecholamines but not heart rate.
IMPLICATIONS: Simulated emergency medical service patients were more likely to be stressed when being transported by paramedics through a staircase than in an ambulance. Accordingly, it may be beneficial to inject sedative drugs before initiating transport to ensure patient comfort and safety.
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Introduction
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Midazolam, a benzodiazepine (half-life, 
2.5 h), is a preferred drug for premedication of patients before the routine induction of anesthesia because of its amnestic, sedative, hypnotic, anxiolytic, and anticonvulsant properties (1). This approach provides patient comfort for surgical or diagnostic procedures in operating rooms, emergency departments, intensive care units, and outpatient clinics (2). Although the main purpose of midazolam in most settings may be sedation and ameliorating anxiousness, beneficial metabolism effects were observed when 2 mg IV of midazolam in 70-kg adult postoperative patients attenuated the increase in oxygen consumption during chest physical therapy (3). This indicates that midazolam may be able to protect a patient from a critical mismatch between oxygen demand and oxygen delivery, which may result in ischemia.
Whereas the need for and benefit of a sedative for premedication is fully established for patients in the hospital, most standing orders in the emergency medical service (EMS) do not call for this sedation strategy. This is actually surprising, because EMS patients may suffer from more stress than a patient being transported within the hospital to the operating room to undergo a scheduled, routine surgical procedure. For example, in a myocardial infarction patient outside the hospital, endogenous catecholamines are released because of severe ischemic pain, shortness of breath, and, possibly, fear of death. This may subsequently result in a catecholamine-induced increase in cardiac oxygen consumption, cardiac ischemia, and, possibly, infarction size. Whereas the need for potent narcotics in patients with severe pain may be obvious, a significant amount of fear may contribute to an endogenous catecholamine release as well. In a previous investigation (4), simulated EMS patients had significant increases of endogenous catecholamines, indicating that EMS patients may benefit from sedation to decrease transport-related stress.
In this report, we assessed the role of a dose-response effect of midazolam versus placebo on endogenous catecholamine release and hemodynamic variables in a previously validated model of transport-related stress in the EMS. Our hypothesis was that there would be no differences in study end points between groups.
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Methods
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After approval by the IRB, and after written informed consent was obtained, IV cannulation was performed in 72 healthy male volunteers (age range, 18–40 yr). Exclusion criteria for volunteers taking part in the study were previous experience in the EMS, diabetes mellitus, asthma, seizure disorders, cardiac pathology, hypertension, allergies, and being on any prescription drugs. Before enrollment into the study, an internist took a past medical history and performed a physical examination of all volunteers. Because sex-related differences of catecholamine responses in a former study revealed that norepinephrine and epinephrine responses were significantly higher in women than in men during incremental exercise, but not at rest (5), only male volunteers were enrolled. Also, all experiments were conducted between 11 AM and 3 PM to ensure that circadian-related differences in endogenous catecholamine levels could be excluded (6). Forty-five minutes after obtaining IV access, baseline epinephrine and norepinephrine plasma levels, as well as heart rate and blood pressure, were measured. The waiting time was incorporated to ensure that an IV cannulation-related stress response with subsequent catecholamine discharge did not alter catecholamine plasma levels and cardiocirculatory variables (7). The volunteers were then randomized into two groups, namely stress (n = 36) and control (n = 36). Subsequently, both the Stress and Control group volunteers were randomized to receive either 25 µg/kg IV of midazolam (n = 12), 50 µg/kg IV of midazolam (n = 12), or an IV saline placebo (n = 12) 5 min before the initiation of the trial (both volunteers and investigators were blinded to the drugs). Volunteers randomized into the Stress group were carried by paramedics from a third-floor apartment through a staircase of 72 steps before being loaded onto a stretcher; subsequently, they were subjected to a standardized EMS transport with sirens for 15 min. Volunteers randomized into the Control group had to sit on a chair for 5 minutes and subsequently lay on a stretcher for 15 min, which was the equivalent time of the experiment with the Stress group. Blood samples and hemodynamic variables were taken in the apartment before initiation of the investigation, 5 minutes after the drug administration before transport through the staircase, at the ground floor, and at the end of EMS transport in the Stress group and at corresponding time points in the Control group.
Blood samples for plasma catecholamine measurements were collected in lithium heparinate monovettes filled with 100 µL of an antioxidative solution containing 61 g of glutathione and 76 g of EGTA/L. Blood samples were immediately centrifuged at 3000 rpm for 10 min, and the plasma was separated from cellular blood components and subsequently stored at -76°C until analysis. Measurement of plasma catecholamine concentration was based on their selective isolation by adsorption onto surface-activated aluminum oxide at a pH value of 8.6 (2 mol/L of Tris buffer) followed by elution with a solution containing 250 mg of EDTA, 500 mg of sodium disulfide, and 12.5 mL of 0.2 mol/L of acetic acid and quantified by high performance liquid chromatography with electrochemical detection (Waters Associates, Milford, MA) (8). The level for catecholamine detection was 10 pg/mL. The coefficient of variation for epinephrine, calculated at an epinephrine concentration of 600 pg/mL, was 6.0. The coefficient of variation for norepinephrine, calculated at a norepinephrine concentration of 998 pg/mL, was 6.4.
Venous blood samples for midazolam plasma levels were also collected in 3 mL EDTA-tubes. After centrifugation at 1700g (Megafuge 1.0, Heraeus, Hamburg, Germany) for 10 min, the plasma samples were stored at -30°C until the day of analysis. A stock solution of 1 mg/mL of midazolam was prepared by appropriate dilution of the commercial Dormicum® solution (Hoffmann La Roche, Grenzach-Whylen, Germany) given to the subjects. In general, 32 plasma samples accompanied by a standard curve were extracted and analyzed in 1 day. The standard curve covered the range from 20 to 320 ng/mL and was prepared in drug-free plasma; it was found linear up to a concentration of 3000 ng/mL. To 0.5 mL of plasma, 0.2 mL of saturated carbonate buffer with a pH value of 9.8 was added, and midazolam was extracted into 5 mL of chloroform/2-propanol (v/v, 90/10). After shaking for 10 min and then centrifugation for 10 min at 4000g, 4 mL of the organic phase was transferred to another tapered bottom glass vial and evaporated to dryness with nitrogen. The residue was taken up in 100 µL of the mobile phase by heating in a water bath at 56°C for 5 min. Fifty microliters were injected onto the high-pressure liquid chromatography system (Shimadzu: Sil-10A auto injector, LC 10 AT pump, SPD 10AV UV detector, Class LC10 software). We used a reversed phase RP-select B column (LichroCart 125–4, particle size 5 µm; Merck, Darmstadt, Germany) with guard column. The mobile phase contained 0.01 mol/L of potassium dihydrogenphosphate, methanol, and tetrahydrofurane (v/v/v, 40/59/1) adjusted to a pH value of 6.8. The flow rate was 1.2 mL/min. Midazolam was detected by UV-absorption at a wavelength of 254 nm. Under these chromatographic conditions, the retention time of midazolam was approximately 5 min. Under these conditions, the lower limit of detection was 5 ng/mL, and the inter-day variability was 20.1% at 40 ng/mL and 4.1% at 160 ng/mL (n = 8). Personnel performing blood sample analysis were blinded to the study interventions.
All analyses were performed with the Statistical Package for the Social Sciences (SPSS, Chicago, IL). A Kolmogorov-Smirnov adjustment test was performed to assess the distribution of the data. Subsequently, the results were evaluated by a 2 x 3 x 4-factor analysis of variance with repeated measurements on the factor measuring time. Additionally, because of differences in epinephrine plasma levels between groups at baseline, an analysis of covariance with initial values as covariates was performed. P < 0.05 was considered significant.
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Results
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There were no significant differences in age, weight, or height between groups. No significant alterations in plasma catecholamine levels and heart rate were present in the Control groups throughout the study. Epinephrine (P < 0.001) and norepinephrine (P < 0.01) plasma levels in the Placebo-Stress group were significantly higher after transport through the staircase when compared with the Placebo-Control group but could be slightly reduced with 25 µg/kg of midazolam (epinephrine, P < 0.001 versus Stress Placebo and P < 0.05 versus Control Placebo; norepinephrine, P = 0.096 versus Stress Placebo and P = 0.30 versus Control Placebo) and fully suppressed with 50 µg/kg of midazolam (Figs. 1 and 2). After simulated EMS transport, epinephrine plasma levels decreased significantly (P < 0.01) in comparison with the staircase transport but remained significantly (P < 0.05) higher in the Placebo-Stress versus Control group, whereas no significant differences could be shown between groups after the administration of either 25 or 50 µg/kg of midazolam (Fig. 2). Also, norepinephrine plasma levels decreased significantly (P < 0.001) but did not reveal any significant differences between groups (Fig. 1). From 5 min after the drug administration until the end of EMS transport, midazolam plasma levels were significantly different in volunteers receiving 25 versus 50 µg/kg of midazolam (Fig. 3). Heart rate was significantly (P < 0.001) increased in the Placebo-Stress versus Control group during the staircase transport but was comparable between groups throughout EMS transport (Fig. 4). Even after the administration of both 25 and 50 µg/kg of midazolam, heart rate increased significantly (P < 0.01) during staircase transport compared with baseline (Fig. 4). Mean ± SEM arterial blood pressure data ranged from 87 ± 2 to 99 ± 2 mm Hg throughout the study and was comparable among all groups for the entire experiment.
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Figure 2. Norepinephrine plasma levels at baseline and 5 min after medication in the apartment (Baseline, Medication), after transport through the staircase (Ground Floor), and after high-speed ambulance transport with sirens (EMS Transport). Data are given as mean ± SEM; *P < 0.01 versus control placebo and stress 50 µg/kg of midazolam; P < 0.001 versus baseline, 5 min after medication, and after ambulance transport; P < 0.001 versus 5 min after medication and after ambulance transport. Note that the scale starts at 150, not zero. Because all control groups (Placebo, 25 µg/kg, and 50 µg/kg IV of Midazolam, respectively) were comparable, only the Control Placebo group is presented.
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Figure 3. Midazolam plasma levels at baseline and 5 min after medication in the apartment (Baseline, Medication), after transport through the staircase (Ground Floor), and after high-speed ambulance transport with sirens (EMS Transport). Data are given as mean ± SEM; *P < 0.001 versus 25 µg/kg of midazolam; P < 0.001 versus baseline and after ambulance transport; #P < 0.001 versus after staircase transport.
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Figure 4. Heart rate at baseline and 5 min after medication in the apartment (Baseline, Medication), during and after transport through the staircase (Staircase, Ground Floor), and during and after high-speed ambulance transport with sirens (EMS Transport, Minutes, After EMS Transport). Data are given as mean ± SEM; *P < 0.001 versus control placebo; P < 0.001 versus control placebo; P < 0.01 versus baseline, 5 min after medication, and during and after ambulance transport; #P < 0.05 versus baseline, 5 min after medication, and during and after ambulance transport. Note that the scale starts at 60, not zero. Because all control groups (Placebo, 25 µg/kg, and 50 µg/kg IV of Midazolam, respectively) were comparable, only the Control Placebo group is presented.
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Discussion
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The present study revealed that patients who were carried by paramedics from a third-floor apartment through a staircase to an ambulance had significantly higher endogenous catecholamine plasma levels and heart rates, but not blood pressures, than a Control group subjected to rest at corresponding time points. Increases in catecholamine plasma levels were reduced or even prevented with 25 or 50 µg/kg IV of midazolam, respectively, 5 minutes before transport initiation.
Whereas the approach to measure plasma catecholamines in the EMS is relatively novel, endogenous stress markers in EMS personnel have been measured many years ago. Urine and plasma catecholamine levels of EMS physicians were especially high when responding to scene calls with the danger of loss of limb or life. Accordingly, it was suggested that epinephrine plasma levels of EMS physicians reflected psychological stress caused by the responsibility for an entire rescue squad and for severely injured patients or patients with life-threatening illnesses in difficult situations in remote locations (9,10). The stress response in a patient with, for example, severe myocardial infarction may be fundamentally greater than in EMS personnel because of fear of life, pain, and shock. However, it is almost impossible, because of ethical and study design limitations, to evaluate in clinical practice what exact stress response is present in patients with, for example, a high injury severity score. Accordingly, a simulated EMS transport with volunteers was assumed to be an acceptable model to measure levels of stress response.
Similar to a previous study, stress responses of our volunteers were significantly larger in the staircase than during high-speed ambulance transport with sirens when placebo only was administered (4). This was reflected by a 20% increase in heart rate, which may be due to ß-receptor-mediated effects of endogenously discharged epinephrine. Although epinephrine, but not norepinephrine, plasma levels after EMS transport remained increased in the Placebo-Stress group when compared with Control volunteers, this observation is in contrast to studies revealing transport-related stress and catecholamine release in at least somewhat comparable settings, such as in drivers of subway trains or cattle, dog, and pig being trucked, and therefore undergoing stress caused by vibration, acceleration, and braking (11).
Although our paramedics were extremely careful while carrying our volunteers in the staircase, we were unable to determine if the simulated patients were afraid of being dropped and injured on the stairs. Thus, because our volunteers were not subjected to any physical pain throughout the study, psychological stress because of anxiety may have contributed to increased catecholamine levels in the staircase (12). This would be in agreement with studies revealing increasing catecholamine levels in truck drivers encountering fog on the highway (13) or air traffic controllers on duty during shifts with a peak of arriving and departing flights (14).
Ameliorating stress reaction by preventing increased endogenous catecholamine plasma levels in our young, healthy volunteers was easily achieved with either 25 or 50 µg/kg IV of midazolam; however, it is most likely that the stress response in severely sick patients would have been even greater. Whereas even fundamentally increased endogenous catecholamines because of transport-related stress may not impair cardiovascular function in healthy people, such as our volunteers, the case may be completely different in patients with unstable cardiac angina. For example, patients with diffuse coronary artery disease suffering from severe psychological stress after the 1994 Los Angeles earthquake had a significantly higher mortality rate one week after the catastrophic event compared with a reference period one year before the earthquake (15). Further, mental arithmetic work and anger recall altered ventricular tachycardia cycle length and termination without evidence of ischemia, indicating that mental stress may lead to sudden death through facilitation of lethal arrhythmias (16).
Besides increasing myocardial work, increased endogenous catecholamines may impact coagulation. For example, stress-related endogenous catechola-mine-mediated coagulation catastrophes were reported in patients with pheochromocytoma (17), endurance exercise (18), severe head trauma (19), and atherosclerosis (20). This indicates that especially patients with atherosclerosis or unstable cardiac ischemia may suffer significantly from increased catecholamine plasma levels. Many hog farmers understand these aforementioned issues very well, and although it is illegal, they frequently sedate their stress-sensitive swine or even administer ß-blockers before loading on slaughter days. A similar problem has been recognized in the EMS when managing cocaine addicts who present with combativeness despite restraints (21) thus requiring immediate generous sedation. Without doubt, sedation may have significantly different effects in EMS patients suffering from hemorrhage or myocardial infarction in comparison with patients in the hospital awaiting a routine surgical procedure. Because the underlying physiology is fundamentally different, we suggest that sedation in the EMS may be especially useful in patients who do not necessarily require an increased heart rate to maintain cardiocirculatory function, rendering patients at cardiovascular risk the most likely target of a sedation strategy.
Two questions arise: which midazolam dosage provides adequate patient comfort, and which midazolam dose is safe to administer? In our study, 50 µg/kg IV of midazolam (3.5 mg in a 70-kg patient) was required to fully prevent increased catecholamine plasma levels. This dosage is almost the same as that used in an investigation of geriatric patients with co-existing disease undergoing intraocular surgery when 3.75 mg of oral midazolam was found to reduce endogenous catecholamines and to preserve hemodynamic stability (22). Although some authors have suggested that midazolam is under-used in the EMS (23), many physicians may choose not to use sedation because of the fear that prolonged memory and motor reaction times after midazolam may complicate hospital admission. In contrast, too generous sedation may make obtaining a detailed medical history difficult; further, it may result in hypotension and the inability to maintain the airway (24). This may tip the scales towards midazolam as the preferred sedation drug versus other drugs, such as propofol, because of a larger therapeutic range (25). Extrapolating the data from our study, titrating sedation with incremental dosages of 25 µg/kg IV of midazolam may be beneficial to achieve both optimal sedation and patient safety (24). Moreover, sedation with midazolam has the advantage that titration with an antagonist, such as flumazenil, is possible.
The present study has several limitations. First, our study population consisted of healthy young males with no underlying disease. Accordingly, we are unable to state whether EMS transport of severely injured or sick patients would have resulted in ambulance transport-related stress. Second, we did not evaluate possible negative effects on respiratory mechanics and cardiocirculatory variables in severely sick patients undergoing a sedation protocol. Third, because of design limitations, it is impossible to determine the impact of evaluated catecholamine levels on physiological variables such as myocardial oxygen consumption. Fourth, arterial blood sampling possibly could have prevented the spill over of systemic norepinephrine and local epinephrine. Last, we are unable to report any information on catecholamine kinetics in the present study.
In conclusion, simulated EMS patients may be subject to more stress during staircase transport than during transport in an EMS vehicle. Titrating sedation with 25 µg/kg of midazolam significantly reduced endogenous catecholamines but not heart rate.
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Acknowledgments
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Supported, in part, by the Department of Anesthesiology, Medical University of Lübeck, Lübeck, Germany, and analyses were supported, in part, by Hoffmann La Roche, Grenzach-Whylen, Germany.
The authors wish to thank the volunteers and the staff of the St John’s Ambulance Service and the German Red Cross, Lübeck, Germany, who donated their time and effort to make this study possible. Dr Ilona Dörges and Dr Hans-Jürgen Friedrich helped with ideas, support, and encouragement.
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Footnotes
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Presented, in part, as an abstract at the American Society of Anesthesiologists Annual Meeting, Dallas, TX, October 1999.
No author has a conflict of interest in regards to drugs or devices used in this study.
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Accepted for publication April 2, 2002.
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Abstract
Introduction
