The Surgical Stress Response, Preemptive Analgesia, and Procedural Sedation in the Emergency Department

In this month’s issue of AEM, Messenger et al.1 report an advance in the approach to safety in emergency department (ED) procedural sedation using propofol. This study has demonstrated that the rate of hypoxia associated with the coadministration of fentanyl with propofol for added analgesia over that used for pain control prior to the procedure is higher than the rate associated with using ketamine for the same purpose. This novel approach to supplemental analgesia suggests an approach that should improve patient safety when clinicians chose to add supplemental analgesia to propofol. The question of whether or not additional analgesics over those used for pain control prior to the procedure should be titrated concurrently with propofol has been debated, but clinical studies have been lacking. The negative effects of surgical pain and stress are well known. In addition, pain may sensitize the nervous system and lead to increased postoperative pain and hyperalgesia.2 Most of what is known, however, is based on studies of surgical stress of longer duration and much less nociceptive stimulus that those typical of procedures for ED procedural sedation and analgesia (PSA). Although serious adverse outcomes with ED PSA are rare, patient safety during sedation remains the primary concern, both in terms of respiratory depression and associated aspiration risk and in terms of the negative consequences of undertreated pain. The concurrent administration of propofol with an opioid is known to result in an increased risk of respiratory depression,3 and the benefits of adding such a dose of opioid over and above what has been used for pain control before the procedure are not clear. Attempts have been made to extrapolate what is known about the surgical stress response and preemptive analgesia to ED PSA, but very little specific information regarding its risks and benefits are available. To assess the utility of the protocols, the information available concerning surgical stress and preemptive analgesia must be considered. The inflammatory, metabolic, and endocrine changes in response to surgical injury is termed the surgical stress response.4 This response has been associated with a variety of undesirable effects on patients, including vegetative symptoms, immunosuppression, decreased vital capacity, increased energy expenditure for a given workload, and gastrointestinal dysfunction.5 It is related primarily to somatic and autonomic nerve impulses from the site of injury activating the hypothalamus to increase the production of releasing hormones, which subsequently increase the production of hormones from both the anterior and the posterior pituitary. Furthermore, autonomic stimulation, mostly sympathetic, activates the production of catecholamines. In addition, local cytokines are produced at the site of injury, dependent on both nociceptive stimulation and other factors such as anxiety, fear, and the degree of tissue damage. These changes result in an increase in serum cortisol, insulin, glucagon, and acute-phase reactants (principally cytokines), all of which have acute effects and modulate gene expression causing long term effects resulting in the surgical stress response. The surgical stress response has been shown to be decreased with the use of etomidate and benzodiazepines.6,7 Opioids have been shown to do this even more effectively, alone and in combination with benzodiazepines, but very large doses (∼5 μg/kg fentanyl) are needed to achieve this.8 Opioids decrease the stress response by decreasing nociceptive impulses and by direct action on central nervous system centers. Clonidine has been shown to blunt this effect as well, likely through an increase in norepinephrine, activating descending spinal pathways and directly blocking ACTH secretion.9 General anesthetics, without opioids or benzodiazepines, have not been found to be effective at blunting the surgical stress response.10,11 These findings have led to the routine use of opioids with general anesthesia and the frequent use of local and epidural anesthesia. In the ED, these findings have helped provide evidence to support the thorough treatment of pain in the setting of acute injury. The surgical stress response, however, is unlikely to be related to single painful events, but rather the total quantity of pain and tissue damage induced over the course of an injury. The effect of a momentary increase in pain on the stress response and its subsequent negative consequences is not known, but is likely only a small portion of the overall surgical stress response. The timely and consistent titration of opioids to patients in pain throughout their treatment is likely to decrease this response in ED patients. Preemptive analgesia is the idea that pain perceived after a tissue injury can be modified by an analgesic administered before the precipitating noxious stimulus and that a given dose of analgesic administered before the stimulus will be more effective than the same dose given after. After tissue injury and the resulting inflammatory response, a patient’s threshold to and perception of pain is altered. Stimuli that would not normally be painful can become painful (allodynia), and pain is exaggerated in the area of the injury (primary hyperalgesia) and in surrounding areas (secondary hyperalgesia). Primary hyperalgesia has been associated with both thermal and mechanical stimuli, and secondary hyperalgesia has only been associated with mechanical stimuli.12 It has long been thought that primary hyperalgesia represents sensitization of peripheral receptors by various inflammatory factors and that secondary hyperalgesia represents central sensitization.13 Central changes have been shown to occur with painful stimulation at the level of the dorsal horn, where an increase in the receptive fields of dorsal horn neurons have been shown to outlast the stimulus.14 As a stimulus is repeated, there is a temporal summation of the increases, with each successive stimulus causing a progressively larger response. As an electrical event, this effect lasts for only a short time, but the increasing effect causes changes in local gene expression and second messenger concentration that eventually results in an effect that persists for much longer. The N-methyl d-aspartate (NMDA) receptor likely plays an important role in this effect.15 The prevention of central sensitization is the basis for the use of preemptive analgesia. If the analgesia is given before the noxious stimuli, then the nociceptive stimuli would not be transmitted to the dorsal horn neurons, and the central changes could be prevented, resulting in less pain and a shorter duration of symptoms. This was first demonstrated in animal models using formalin-injected rats.16 In these studies, two phases of acute pain were found: Phase 1, which lasts for approximately the first 10 minutes, and Phase 2, which extends from 15 to 90 minutes. In an early study, pretreatment was found to suppress both phases of acute pain; treatment 2 minutes after the start of the noxious stimulus did not suppress Phase 2 pain, indicating that for Phase 2 pain to occur, Phase 1 must have been present.17 The dose of analgesic in this study was sufficient to block 95% of pain fiber transmission to the spinal cord. This effect was demonstrated with morphine and an NMDA receptor antagonist. Since NMDA receptors have no role in peripheral pain fiber transmission, it was assumed that this was due to a central role of NMDA receptors in establishing this response.18 No such response was found for halothane or isoflurane; however, Phase 2 suppression was found with nitrous oxide.19,20 A number of clinical studies have been performed to confirm this as well.21 This has principally been described with the use of high-dose opioids and spinal and nerve blocks. Low-dose opioids have not shown this effect and are unlikely to provide preemptive analgesia. Collis et al.22 studied the effects of using 10 and 20 mg of morphine premedication in patients undergoing abdominal hysterectomy and found no difference between the two groups in terms of reported pain or postoperative morphine requirements, suggesting either a ceiling effect for preemptive analgesia for low-dose opioids or no effect at all. However, studies using much larger doses of opioids (e.g., 5 μg/kg fentanyl or 2 μg/kg ketamine23) have found a preemptive analgesic effect.24 A similar effect has also been shown for nonsteroidal anti-inflammatory drugs.25 Studies using local nerve blocks have shown decreased pain after the procedure when local anesthetics are used but have not shown an effect related to the timing of the block, indicating that their analgesic effect is not due to preemptive analgesia.26,27 Because the NMDA receptor plays a role in central sensitization, it seems likely that using an NMDA receptor antagonist would produce a preemptive analgesic effect. Ketamine has documented analgesic effects.28 In clinical studies of preemptive analgesia,29,30 however, analgesic effects were detected but the findings concerning preemptive analgesic effects were mixed. The animal data for preemptive analgesia is compelling, and while the clinical findings have been less clear, they indicate a role for preemptive analgesia. The problem for emergency medicine, however, is extrapolating the animal findings that use a model of constant prolonged pain and the human clinical studies that mostly consist of prolonged and severe stimulus to the brief procedural increase in pain typical of ED PSA. It is likely that the total amount of pain, in terms of duration and magnitude, rather than a peak impulse, increases the summation of signals at the dorsal horn and effects the development of central sensitization. A large part of the summation of pain signals in the dorsal horn likely occurs before the procedure has started or in the postprocedure period. Due to this, the pain that a patient experiences before or after the procedure likely plays a much larger role in the development of central sensitization than a brief procedural increase. Based on what is known, it is clear that it is important to control a patient’s pain. When a patient presents with a painful injury, there is ample evidence to support rapid and thorough treatment with analgesics. If that patient subsequently requires a painful procedure, the evidence for preemptive analgesia is less clear. The quantity of opioids needed to make a patient comfortable before a procedure may differ drastically after the procedure than before. For procedures such as the reduction of severely angulated fractures, a patient’s pain can improve drastically as a result of the reduction. For patients who undergo incision and drainage of an abscess, the pain after the procedure may be much greater than that from before. Frequent reassessment and treatment, especially immediately after PSA, to adequately treat pain and detect changes in the response to analgesics, in addition to improving patient comfort and safety, may improve the patient’s outcome in terms of his or her stress response and the future pain medication requirements. The best approach to procedural sedation remains beyond our current knowledge. It is generally accepted that propofol has sedative and amnestic properties and lacks any specific analgesic effect. The clinical significance of procedural pain that a patient experiences, but cannot later recall, remains unclear. Amnesia from propofol lasts an average of 15.7 minutes in adults who have received 1 mg/kg propofol followed by 0.5 mg/kg until sedated.31 Patients receiving these doses or propofol often demonstrate a response to noxious stimuli during the procedure (such a response is the defining characteristic of deep sedation relative to general anesthesia). Propofol and remifentanil have been shown to have a synergistic effect in terms of controlling this response to noxious stimuli, better than either alone.32 Previous work, however, has demonstrated that administering combinations of propofol concurrently with analgesics may increase the likelihood of adverse outcomes33,34 and Messenger et al.1 have demonstrated this effect for fentanyl more specifically than previous works concerning ED PSA. There is evidence to support preprocedural pain management with both weight-based protocols35,36 and nonstandardized dosing based on the patients level of complaint.37 It is likely that these methods result in different degrees of preprocedural pain relief that influence the level of sedation needed and the amount of sedative used in the subsequent procedure. It is also likely that patients who receive more preprocedural analgesia are more prone to respiratory depression during the sedation.38 Furthermore, it is known that adding an opioid to propofol, specifically adding fentanyl, synergistically increases the rate of respiratory depression relative to either agent alone. The best approach to balancing the risk of increased respiratory depression with the risk of increased future pain is not known.39 The dose of fentanyl given with propofol in the study by Messenger et al.1 causes a high rate of hypoxia and, in the absence of more clear data indicating an effect on surgical stress or the induction of preemptive analgesia, does not appear to be a useful addition to adequate pain treatment prior to the start of the procedure and propofol titrated alone. Given the brief nature of procedures for ED PSA, and the fact that the doses of supplemental analgesics associated with increased risk are several times smaller than those associated with decreased surgical stress and preemptive analgesia, the available evidence does not support this practice. Messenger et al.1 have demonstrated an alternative approach using ketamine, providing added analgesic effect during the procedure that could possibly decrease future pain, while minimizing the addition of increased risk to the procedure. Although the dose of ketamine used in this study has not been shown to induce preemptive analgesia, it is a dose associated with analgesia, similar to opioids at the dose used in this study. Given the superior safety associated with the ketamine group in this study, it appears that if a clinician chooses to titrate additional analgesic with propofol, ketamine is a better choice than fentanyl. Important questions that we still face on this subject include whether or not this dose of ketamine is sufficient to decrease the surgical stress response or to induce preemptive analgesia and to determine the optimal timing of the medication relative to the procedure. These are obviously tough questions to answer and are unlikely to be tackled in a single study, but progressive works such as the outstanding study by Messenger et al. will continue to improve the practice of ED PSA.