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Anesth Analg 2002;95:263-265
© 2002 International Anesthesia Research Society


EDITORIAL

Rescue Is Stressful

Gilbert Park, MD FRCA

Addenbrooke’s Hospital, Cambridge, United Kingdom

Address correspondence to Gilbert Park, MD, FRCA, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK. Address e-mail to gilbert.park{at}addenbrookes.nhs.uk

Imagine you are in a third-floor flat in a building 200 or 300-years-old. You trip and, unfortunately, break your leg. The ambulance is called. Because the building is so old, the stairs are narrow, winding, and steep; there is no lift. The injury prevents you from getting down the stairs unaided. They are so narrow that only one person can use them at a time, so a stretcher-chair is needed. You are strapped to it so that you cannot fall off it or move, and the feet-first journey downstairs starts. The ambulance men struggle and strain to get you out of the door and onto the stairs. The view is spectacular; you can see the dimly lit stairs all the way down to the basement. You hope that you will not be dropped because it is a long, long way down. As well as the pain, fear causes more adrenaline to be released. If you are young, your body will cope well with the stress, but what if you are elderly, suffering not from a broken leg, but perhaps from a myocardial infarct? Will the increased adrenaline from the fear cause more vasoconstriction and increase the work of the heart, resulting in an increased oxygen demand, more ischemia, and, perhaps, a fatal arrhythmia?

The adverse effects of pain, such as that caused by myocardial infarction, are well reported, but what about those of stress? The effect of psychological stress causing both silent and overt myocardial ischemia has been reported in patients with ischemic heart disease (1). In this issue, Dörges et al. (2) use plasma concentrations of epinephrine and norepinephrine to measure the response to fear in volunteers undergoing simulated medical evacuation.

The simulation consisted of being carried down from a third-floor flat and then driven in an ambulance for 15 min with the sirens going. Some of the volunteers experiencing this were given 25 or 50 µg/kg of midazolam IV, whereas the remainder were given placebo injections. There was also a control group, who sat in a chair for 3 min (representing the period of evacuation down the stairs) and then lay flat on a stretcher for 15 min.

The trip down the staircase resulted in larger concentrations of both catecholamines than the ambulance ride with the sirens on. Epinephrine concentrations were larger in volunteers carried down the staircase than in the control volunteers at all times. The administration of midazolam either abolished or significantly reduced these increases, probably indicating a reduction in stress. However, heart rate did increase in all the groups of volunteers who were stressed, whether they were given midazolam or not. Arterial blood pressure was not different between the groups. Unfortunately, we are not given the effect on level of consciousness, although the plasma concentrations reported would be expected to reduce this.

This study shows that simulated medical evacuation is stressful to volunteers. Unlike patients, they have no injury or life-threatening illness, nor are they leaving their homes or families for a journey to the hospital. The stress the volunteers are experiencing is presumably the fear of being dropped down the stairs. Once in the ambulance they can relax. For patients, we can only assume that the stress of going downstairs is greater and continues once they are in the ambulance. To confirm this, studies would need to be done on patients.

On the face of it, it seems like a good idea to give patients an anxiolytic when they are about to have something frightening done to them. Should the use of anxiolytics be explored more? The answer is yes. It may do patients some good. However, while the idea is attractive, we also need to be aware of the potential problems.

The trial was performed by doctors in a highly controlled situation on volunteers. The real world is not like that. Ambulance personnel or paramedics care for emergency patients in many parts of the world. The environment is often not just difficult, but at times also dangerous. The patients are not always young, but are often elderly, with chronic disease complicating their acute illness. Furthermore, the effect of analgesia on the need for sedation was not explored. The relief of pain may be sufficient for many. No one would disagree that relief of pain has a greater priority than relief of fear. Indeed, opioids will often produce a sense of euphoria, perhaps obviating the need for anxiolysis. In the critically ill, opioids alone may be sufficient in over half of patients when given in adequate amounts (3). In those who do still need anxiolysis, there is the problem of synergy between opioids and drugs such as midazolam (4,5). Although this will improve patient comfort, it will also enhance some of the side effects of both types of drugs. Similar problems may also occur when the benzodiazepines are used with alcohol, even in small doses (6,7). Since alcohol is commonly used in many societies and may contribute to accidents, this interaction is likely to be a problem.

Midazolam or similar drugs would need to be given IV to acutely ill patients, as IM and oral absorption would be too slow and unreliable, although intranasal use has been explored in children (8). All these drugs can have cardiovascular depressant effects (9) that are likely to be worse in patients who are hypovolemic or otherwise compromised (1012), although these are the patients who may benefit most from the use of anxiolysis. Similarly, respiratory depression may be slight or absent in volunteers (13,14) but may become significant in patients with respiratory disease (15).

These difficulties can cause even an experienced anesthesiologist who uses these drugs for sedation every day to get the dose wrong occasionally. In the operating room, the consequences are usually not life threatening. However, will the ambulance personnel, who may use these drugs only occasionally and in difficult circumstances, be able to retrieve such a situation?

Midazolam is also a potent amnesic drug (1618), and although the amnesia affects memory only from the time the drug was given, will this place patients at risk of forgetting important parts of their illness? In the elderly it will increase confusion and thus make history-taking more difficult. Indeed, might the depression of consciousness level also confuse clinicians? Given midazolam’s sedative properties, will consent for surgical procedures taken after it is given be viewed as valid? Certainly its administration as a premedicant before surgery may preclude consent being obtained afterward, although in an emergency situation this is less clear (19).

Flumazenil may be used to reverse most of the effects of midazolam (20), although hypotension may still persist. But even this drug has created some difficulties in emergency medicine. Its use in mixed overdoses, causing fits (21,22), increases the potential for such episodes in epileptics who might be receiving benzodiazepines to stop their fits (23). Those patients on chronic benzodiazepine treatment might also suffer an acute withdrawal syndrome if given flumazenil (23,24). These would be extremely difficult situations to control in the field.

There are still many questions that need to be answered before an antianxiolytic is given at the scene routinely. For me, though, if I break my leg in a third-floor flat, morphine followed by perhaps the odd milligram of midazolam would be very nice. I have a fear of writing editorials, but heights scare me more!

References

  1. Freeman LJ, Nixon PG, Sallabank P, Reaveley D. Psychological stress and silent myocardial ischemia. Am Heart J 1987; 114: 477–82.[Web of Science][Medline]
  2. Dörges V, Wenzel V, Dix S, et al. Effect of midazolam on stress levels during simulated emergency medical service transport: a placebo-controlled, dose-response study. Anesth Analg 2002; 95: 417–22.[Abstract/Free Full Text]
  3. Kessler P, Chinacotti T, Van den Berg P, Kirkham A. Remifentanyl versus morphine for the provision of optimal sedation in ICU patients. Intensive Care Med 2001; 27 (Suppl 2): A406.
  4. Ben-Shlomo J, Abd-El-Khalim H, Ezry J, et al. Midazolam acts synergistically with fentanyl for induction of anaesthesia. Br J Anaesth 1990; 64: 45–7.[Abstract/Free Full Text]
  5. Vinik HR, Bradley EL, Kissin I. Midazolam-alfentanil synergism for anesthesia induction in patients. Anesth Analg 1989; 69: 213–7.[Abstract/Free Full Text]
  6. Hoyo-Vadillo C, Mandema JW, Danhof M. Pharmacodynamic interaction between midazolam and a low dose of ethanol in vivo. Life Sci 1995; 57: 325–33.[Web of Science][Medline]
  7. Subhan Z, Hindmarch I. The effects of midazolam in conjunction with alcohol on iconic memory and free-recall. Neuropsychobiology 1983; 9: 230–4.[Web of Science][Medline]
  8. Yealy DM, Ellis JH, Hobbs GD, Moscati RM. Intranasal midazolam as a sedative for children during laceration repair. Am J Emerg Med 1992; 10: 584–7.[Web of Science][Medline]
  9. Whitwam J, Al-Khudhairi D, McCloy RF. Comparison of midazolam and diazepam in doses of comparable potency during gastroscopy. Br J Anaesth 1983; 55: 773–7.[Abstract/Free Full Text]
  10. Adams P, Gelman S, Reves JG, et al. Midazolam pharmacodynamics and pharmacokinetics during acute hypovolemia. Anesthesiology 1985; 63: 140–6.[Web of Science][Medline]
  11. Kawar P, Carson IW, Clarke RSJ, et al. Haemodynamic changes during induction of anaesthesia with midazolam and diazepam (Valium) in patients undergoing coronary artery bypass surgery. Anaesthesia 1985; 40: 767–71.[Web of Science][Medline]
  12. Power SJ, Morgan M, Chakrabarti MK. Carbon dioxide response curves following midazolam and diazepam. Br J Anaesth 1983; 55: 837–84.[Abstract/Free Full Text]
  13. Alexander CM, Gross JB. Sedative doses of midazolam significantly depress hypoxic ventilatory response in humans. Anesth Analg 1988; 67: 377–82.[Abstract/Free Full Text]
  14. Gross JB, Zebrowski ME, Carel WD, et al. Time course of ventilatory depression after thiopental and midazolam in normal subjects and in patients with chronic obstructive pulmonary disease. Anesthesiology 1983; 58: 540–4.[Web of Science][Medline]
  15. Polster MR, Gray PA, O’Sullivan G, et al. Comparison of the sedative and amnesic effects of midazolam and propofol. Br J Anaesth 1993; 70: 612–6.[Abstract/Free Full Text]
  16. Polster MR, McCarthy RA, O’Sullivan G, et al. Midazolam-induced amnesia: implications for the implicit/explicit memory distinction. Brain Cogn 1994; 22: 244–65.
  17. Polster MR, Gray PA, McCarthy RA, Park GR. Implicit and explicit memory after intramuscular midazolam. In: Bonke B, Fitch W, Millar K, eds. Memory and awareness in anaesthesia. Amsterdam: Swetz and Zeitlinger, 1990: 272–80.
  18. Association of Anesthetists of Great Britain and Ireland. Information and consent for anaesthesia, 2002. London: Association of Anesthetists of Great Britain and Ireland, 1999.
  19. Gross JB, Weller RS, Conard P. Flumazenil antagonism of midazolam-induced ventilatory depression. Anesthesiology 1991; 75: 179–85.[Web of Science][Medline]
  20. Burr W, Sandham P, Judd A. Death after flumazepil. BMJ 1989; 298: 1713.[Free Full Text]
  21. Marchant B, Wray R. Flumazenil causing convulsions and ventricular tachycardia. BMJ 1989; 299: 860.[Free Full Text]
  22. Spivey WH. Flumazenil and seizures: analysis of 43 cases. Clin Ther 1992; 14: 292–305.[Web of Science][Medline]
  23. Griffiths RR, Evans SM, Guarino JJ, et al. Intravenous flumazenil following acute and repeated exposure to lorazepam in healthy volunteers: antagonism and precipitated withdrawal. J Pharmacol Exp Ther 1993; 265: 1163–74.[Abstract/Free Full Text]
  24. Mintzer MZ, Stoller KB, Griffiths RR. A controlled study of flumazenil-precipitated withdrawal in chronic low-dose benzodiazepine users. Psychopharmacology Berl 1999; 147: 200–9.[Medline]
Accepted for publication April 23, 2002.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2002 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press