I think some EDs still have an overcautious ‘ASA 1 or 2 only’ criterion for procedural sedation, which makes no sense whatsoever when one considers the spectrum of cases in which emergent procedural sedation may be required.
Fortunately, the assumption that a higher ASA grade would be associated with increased complications has now been debunked by Edinburgh’s Emergency Medicine Research Group.
Dawson, N., Dewar, A., Gray, A., Leal, A., on behalf of the Emergency Medicine Research Group, Edinburgh. (2014). Association between ASA grade and complication rate in patients receiving procedural sedation for relocation of dislocated hip prostheses in a UK emergency department. Emergency Medicine Journal 31(3), 207–209
OBJECTIVE: To determine the association between the American Society of Anesthiologists (ASA) grade and the complication rate of patients receiving procedural sedation for relocation of hip prosthesis in an adult emergency department (ED) in the UK.
DESIGN: Retrospective study of registry data from a large UK teaching hospital ED. Consecutive adult patients (aged 16 years and over) in whom ASA grade could be calculated, with an isolated dislocation of a hip prosthesis between 8 September 2006 and 16 April 2010 were included for analyses (n=303). The primary outcome measure was association between ASA and complication rate (any of desaturation <90%; apnoea; vomiting; aspiration; hypotension <90 mm Hg; cardiac arrest). Secondary outcome measures were relationship between ASA grade and procedural success, choice of sedative agent and sedation depth, and complications and choice of sedative agent, arrival time and sedation depth.
RESULTS: There was no significant difference between ASA grade and the risk of complication (p=0.800). Moreover, there was no significant difference between ASA grade and procedural success (p=0.284), ASA and choice of sedative agent (p=0.243), or ASA and sedation depth (p=0.48). There was no association between complications and sedative agent (p=0.18), or complications and arrival time (p=0.12). There was a significant difference between sedative depth and complications (p<0.001).
CONCLUSIONS: There is no clear association between a patient’s physical status (ASA grade) and the risk of complications, chance of procedural success or choice of sedative agent in relocation of hip prostheses. There is a higher rate of complications with higher levels of sedation (p<0.001).
A multicentre European trial on intensive care units showed dexmedetomidine was non-inferior to midazolam or propofol in achieving target sedation levels, but patients were better able to communicate pain compared with midazolam and propofol. Dexmedetomidine reduced duration of mechanical ventilation compared with midazolam, but not compared with propofol.
Context Long-term sedation with midazolam or propofol in intensive care units (ICUs) has serious adverse effects. Dexmedetomidine, an α2-agonist available for ICU sedation, may reduce the duration of mechanical ventilation and enhance patient comfort.
Objective To determine the efficacy of dexmedetomidine vs midazolam or propofol (preferred usual care) in maintaining sedation; reducing duration of mechanical ventilation; and improving patients’ interaction with nursing care.
Design, Setting, and Patients Two phase 3 multicenter, randomized, double-blind trials carried out from 2007 to 2010. The MIDEX trial compared midazolam with dexmedetomidine in ICUs of 44 centers in 9 European countries; the PRODEX trial compared propofol with dexmedetomidine in 31 centers in 6 European countries and 2 centers in Russia. Included were adult ICU patients receiving mechanical ventilation who needed light to moderate sedation for more than 24 hours (midazolam, n = 251, vs dexmedetomidine, n = 249; propofol, n = 247, vs dexmedetomidine, n = 251).
Interventions Sedation with dexmedetomidine, midazolam, or propofol; daily sedation stops; and spontaneous breathing trials.
Main Outcome Measures For each trial, we tested whether dexmedetomidine was noninferior to control with respect to proportion of time at target sedation level (measured by Richmond Agitation-Sedation Scale) and superior to control with respect to duration of mechanical ventilation. Secondary end points were patients’ ability to communicate pain (measured using a visual analogue scale [VAS]) and length of ICU stay. Time at target sedation was analyzed in per-protocol population (midazolam, n = 233, vs dexmedetomidine, n = 227; propofol, n = 214, vs dexmedetomidine, n = 223).
Results Dexmedetomidine/midazolam ratio in time at target sedation was 1.07 (95% CI, 0.97-1.18) and dexmedetomidine/propofol, 1.00 (95% CI, 0.92-1.08). Median duration of mechanical ventilation appeared shorter with dexmedetomidine (123 hours [IQR, 67-337]) vs midazolam (164 hours [IQR, 92-380]; P = .03) but not with dexmedetomidine (97 hours [IQR, 45-257]) vs propofol (118 hours [IQR, 48-327]; P = .24). Patients’ interaction (measured using VAS) was improved with dexmedetomidine (estimated score difference vs midazolam, 19.7 [95% CI, 15.2-24.2]; P < .001; and vs propofol, 11.2 [95% CI, 6.4-15.9]; P < .001). Length of ICU and hospital stay and mortality were similar. Dexmedetomidine vs midazolam patients had more hypotension (51/247 [20.6%] vs 29/250 [11.6%]; P = .007) and bradycardia (35/247 [14.2%] vs 13/250 [5.2%]; P < .001).
Conclusions Among ICU patients receiving prolonged mechanical ventilation, dexmedetomidine was not inferior to midazolam and propofol in maintaining light to moderate sedation. Dexmedetomidine reduced duration of mechanical ventilation compared with midazolam and improved patients’ ability to communicate pain compared with midazolam and propofol. More adverse effects were associated with dexmedetomidine.
What are the best sedatives for patients with traumatic brain injury? A systematic review found no evidence that one sedative agent is better than another for improvement of neurologic outcome or mortality in critically ill adults with severe TBI. Thirteen randomised trials including around 380 patients were reviewed.
reduce metabolic requirements of the injured brain to avoid ischemic progression of the traumatic lesion in presence of increased ICP
facilitate mechanical ventilation to control PaCo2
avoid ICP rises due to airway instrumentation such as those induced by coughing
Sedation generally improved intracranial pressure (ICP) and cerebral perfusion pressure (CPP) vs. baseline in most trials.
Interestingly boluses or short infusions of opioids resulted in (often transient) increases in ICP and decreases in MAP and CPP in three RCTs. An accompanying editorial suggests this may be due to large opioid doses (up to 3 μg/kg of fentanyl) and consequent hypotension; hypotension itself may trigger autoregulatory cerebral vasodilatation and increase ICP and decrease CPP. Although opioids have been linked with increased ICP through decreased cerebrovascular resistance, increased cerebral blood flow or Paco2, and disturbed cerebral autoregulation, they state that in studies in which hypotension after opioid administration was prevented, an ICP increasing effect was not seen. It is important to note the small sample sizes studied and the long time period of studies included, dating back some decades.
Importantly, ketamine did not result in the increase in ICP purported by older literature.
OBJECTIVES: To summarize randomized controlled trials on the effects of sedative agents on neurologic outcome, mortality, intracranial pressure, cerebral perfusion pressure, and adverse drug events in critically ill adults with severe traumatic brain injury.
DATA SOURCES: PubMed, MEDLINE, EMBASE, the Cochrane Database, Google Scholar, two clinical trials registries, personal files, and reference lists of included articles.
STUDY SELECTION: Randomized controlled trials of propofol, ketamine, etomidate, and agents from the opioid, benzodiazepine, α-2 agonist, and antipsychotic drug classes for management of adult intensive care unit patients with severe traumatic brain injury.
DATA EXTRACTION: In duplicate and independently, two investigators extracted data and evaluated methodologic quality and results.
DATA SYNTHESIS: Among 1,892 citations, 13 randomized controlled trials enrolling 380 patients met inclusion criteria. Long-term sedation (≥24 hrs) was addressed in six studies, whereas a bolus dose, short infusion, or doubling of plasma drug concentration was investigated in remaining trials. Most trials did not describe baseline traumatic brain injury prognostic factors or important cointerventions. Eight trials possibly or definitely concealed allocation and six were blinded. Insufficient data exist regarding the effects of sedative agents on neurologic outcome or mortality. Although their effects are likely transient, bolus doses of opioids may increase intracranial pressure and decrease cerebral perfusion pressure. In one study, a long-term infusion of propofol vs. morphine was associated with a reduced requirement for intracranial pressure-lowering cointerventions and a lower intracranial pressure on the third day. Trials of propofol vs. midazolam and ketamine vs. sufentanil found no difference between agents in intracranial pressure and cerebral perfusion pressure.
CONCLUSIONS: This systematic review found no convincing evidence that one sedative agent is more efficacious than another for improvement of patient-centered outcomes, intracranial pressure, or cerebral perfusion pressure in critically ill adults with severe traumatic brain injury. High bolus doses of opioids, however, have potentially deleterious effects on intracranial pressure and cerebral perfusion pressure. Adequately powered, high-quality, randomized controlled trials are urgently warranted.
Why wouldn’t you give oxygen prophylactically to someone undergoing procedural sedation? One argument is that this will delay the detection of respiratory depression since a pre-oxygenated patient can be hyponoeic/apnoeic for longer prior to desaturation. This is not an issue for those of us who use non-invasive capnography during sedation.
In this randomized trial of oxygen vs air during ED propofol procedural sedation there was less hypoxia when high-flow supplemental oxygen was added. The authors made the following observations:
There was no difference between groups in the incidence of respiratory depression, confirming previous research that supplemental oxygen does not exacerbate respiratory depression
5 patients in the compressed air group developed hypoxia without preceding respiratory depression, so capnography cannot be completely relied on in this setting.
“…assuming that capnography is in place to monitor ventilatory function, our results strongly support the routine use of high-flow oxygen during ED propofol sedation”
STUDY OBJECTIVE: We determine whether high-flow oxygen reduces the incidence of hypoxia by 20% in adults receiving propofol for emergency department (ED) sedation compared with room air.
METHODS: We randomized adults to receive 100% oxygen or compressed air at 15 L/minute by nonrebreather mask for 5 minutes before and during propofol procedural sedation. We administered 1.0 mg/kg of propofol, followed by 0.5 mg/kg boluses until the patient was adequately sedated. Physicians and patients were blinded to the gas used. Hypoxia was defined a priori as an oxygen saturation less than 93%; respiratory depression was defined as an end tidal CO(2) greater than 50 mm Hg, a 10% absolute change from baseline, or loss of waveform.
RESULTS: We noted significantly less hypoxia in the 59 patients receiving high-flow oxygen compared with the 58 receiving compressed air (19% versus 41%; P=.007; difference 23%; 95% confidence interval 6% to 38%). Respiratory depression was similar between groups (51% versus 48%; difference 2%; 95% confidence interval -15% to 22%). We observed 2 adverse events in the high-flow group (1 hypotension, 1 bradycardia) and 2 in the compressed air group (1 assisted ventilation, 1 hypotension).
CONCLUSION: High-flow oxygen reduces the frequency of hypoxia during ED propofol sedation in adults.
As well as the benefits of cardiovascular stability, maintenance of cerebral perfusion pressure, possibly lowering ICP and providing other neuroprotective benefits, ketamine may have other advantages. These are reviewed in a British Journal of Anaesthesia article from which I’ve selected those benefits of interest to practitioners of emergency medicine and critical care.
Additional Beneficial Effects of Ketamine
the dysphoric, or ’emergence’ reactions associated with ketamine may be reduced by pre-administration or co-administration of sedatives, such as benzodiazepines, propofol, dexmedetomidine, or droperidol.
ketamine potentiates opioid analgesia in multiple settings, reducing opioid total dose and in some groups of patients reducing postoperative desaturation
ketamine has possible anti-inflammatory effects demonstrated in some types of surgical patients
ketamine may prevent awareness, recall, or both during general anaesthesia
An evaluation of single-agent alfentanil for procedural sedation in the ED has been published by the team at Hennepin County Medical Centre. A short-acting opioid, alfentanil induces 7 to 9 minutes of pain relief after a single bolus of 10 mcg/kg, a duration of action similar to that of propofol. It produces analgesia and sedation but not amnesia. In this study of 148 adult patients, alfentanil doses and the use of supplemental oxygen were at treating physician discretion. it appeared to be effective for ED procedural sedation but displayed a rate of airway or respiratory events leading to an intervention similar to that of previous reports of deeper sedation with propofol. The authors state ‘Despite very high rates of procedural pain and recall, subjects remained highly satisfied.’
STUDY OBJECTIVE: We administer alfentanil sedation for minor procedures in the emergency department (ED), and our primary objective is to assess the incidence of airway and respiratory adverse events leading to an intervention. Our secondary goals are to assess for other adverse events, the depth and duration of sedation, the incidence of subclinical respiratory depression, and patient perceptions of the quality of the sedation.
METHODS: In this observational study of adults receiving alfentanil for ED procedures, we recorded the incidence of airway or respiratory adverse events leading to an intervention (increase/addition of supplemental oxygen, bag-valve-mask ventilation, airway repositioning, or stimulation to induce breathing). Secondary goals were assessed with monitoring (including capnography), the Observer’s Assessment of Alertness/Sedation (OAA/S) scale, and postprocedure patient visual analog scale ratings of pain, recall, and satisfaction.
RESULTS: Airway or respiratory events leading to intervention were observed in 39% of the 148 subjects (supplemental oxygen 18%, bag-valve mask 3%, airway repositioning 2%, stimulation 18%); none were clinically significant. The median OAA/S nadir was 4 (interquartile range 3 to 5). Median patient ratings were positive (pain 26 mm, recall 98, satisfaction 100 mm).
CONCLUSION: Alfentanil appears effective for ED procedural sedation but displays a rate of airway or respiratory events leading to an intervention similar to that of previous reports of deeper sedation with propofol.
In adults undergoing procedural sedation with ketamine, 0.03 mg/kg IV midazolam reduced recovery agitation compared with placebo.
STUDY OBJECTIVE: We assess whether midazolam reduces recovery agitation after ketamine administration in adult emergency department (ED) patients and also compared the incidence of adverse events (recovery agitation, respiratory, and nausea/vomiting) by the intravenous (IV) versus intramuscular (IM) route.
METHODS: This prospective, double-blind, placebo-controlled, 2×2 factorial trial randomized consecutive ED patients aged 18 to 50 years to 4 groups: receiving either 0.03 mg/kg IV midazolam or placebo, and with ketamine administered either 1.5 mg/kg IV or 4 mg/kg IM. Adverse events and sedation characteristics were recorded.
RESULTS: Of the 182 subjects, recovery agitation was less common in the midazolam cohorts (8% versus 25%; difference 17%; 95% confidence interval [CI] 6% to 28%; number needed to treat 6). When IV versus IM routes were compared, the incidences of adverse events were similar (recovery agitation 13% versus 17%, difference 4%, 95% CI -8% to 16%; respiratory events 0% versus 0%, difference 0%, 95% CI -2% to 2%; nausea/vomiting 28% versus 34%, difference 6%, 95% CI -8% to 20%).
CONCLUSION: Coadministered midazolam significantly reduces the incidence of recovery agitation after ketamine procedural sedation and analgesia in ED adults (number needed to treat 6). Adverse events occur at similar frequency by the IV or IM routes.
What are the factors associated with laryngospasm in ketamine sedation? A large study was unable to identify specific predictors:
Objective: The objective of this study was to assess predictors of emergency department (ED) ketamine-associated laryngospasm using case-control techniques.
Methods: We performed a matched case-control analysis of a sample of 8282 ED ketamine sedations (including 22 occurrences of laryngospasm) assembled from 32 prior published series. We sequentially studied the association of each of 7 clinical variables with laryngospasm by assigning 4 controls to each case while matching for the remaining 6 variables. We then used univariate statistics and conditional logistic regression to analyze the matched sets.
Results: We found no statistical association of age, dose, oropharyngeal procedure, underlying physical illness, route, or coadministered anticholinergics with laryngospasm. Coadministered benzodiazepines showed a borderline association in the multivariate but not univariate analysis that was considered anomalous.
Conclusions: This case-control analysis of the largest available sample of ED ketamine-associated laryngospasm did not demonstrate evidence of association with age, dose, or other clinical factors. Such laryngospasm seems to be idiosyncratic, and accordingly, clinicians administering ketamine must be prepared for its rapid identification and management. Given no evidence that they decrease the risk of laryngospasm, coadministered anticholinergics seem unnecessary.
Despite the huge number of articles in the literature on paediatric sedation, one still encounters acrimonious debates about the appropriateness of non-anaesthetists doing it. How refreshing then, to see that the UK’s National Institute for Health & Clinical Excellence (“NICE”) has tackled this subject and come up with some reasonable recommendations. I’ve as yet only read the summary, but some of the good things are:
No unachievable ‘two doctors present’ rule: ‘Two trained healthcare professionals should be available during sedation‘
Differentiating painless imaging from painful procedures
Monitoring standards that are appropriate for the age of child and depth of sedation (no mandatory blood pressure or ECG monitoring unless deep sedation; end-tidal capnography in deep sedation).
Acknowledgement of the special features of ketamine: ‘Ketamine is a dissociative agent: the state of dissociative sedation cannot be readily categorised as either moderate or deep sedation; the drug is considered to have a wide margin of safety.’
Recognition that specialists other than anaesthetists may have specialist sedation and airway skills
There are some rather conservative recommendations on fasting, although the wording of the guideline in my interpretation allows some flexibility if ketamine is used for an emergency procedure.
Anaesthetist Dr Jan Persson from Stockholm has published an updated review of recent ketamine literature. The following interesting facts about our favourite drug are extracted from Dr Persson’s paper:
Action on multiple receptors earns it the nickname: ‘the nightmare of the pharmacologist’
Recently ketamine has also been shown to inhibit tumor necrosis factor-alpha (TNF- alpha) and interleukin 6 (IL-6) gene expressions in lipopolysaccharide (LPS)-activated macrophages. It has been speculated that these antiproinflammatory effects may be responsible for antihyperalgesic effects of ketamine
Ketamine can exist in two forms, or enantiomers; S-ketamine and R-ketamine. The physical properties of the enantiomers are identical, but their interactions with complex molecules, underlying PK/PD parameters, might differ. It has been well established that the elimination clearance of S-ketamine is larger than that of R-ketamine. The S-form has been commercially available for several years, probably based on the perception that it would have a better effect to side-effect ratio. The recent literature calls into question the proposed advantages of the S-enantiomer.
Ketamine has been shown to induce neuroapoptosis, or neuronal cell death, in newborn animals. This is obviously a concern in paediatrics, where ketamine plays an important role, both in anaesthesia and for sedation/analgesia during painful procedures. The relevance in humans of these effects, however, is unclear, and as pointed out by Green and Cote it does seem unlikely, for various reasons, that such an effect would be of major importance. It does not seem likely, though possible, that a clinically relevant effect would have passed unnoticed.
Another, somewhat unexpected, side effect that has emerged in recent years is bladder dysfunction. In some cases the bladder effects progress to ulcerative cystitis. Although the reported cases have mainly concerned recreational drug users, they are relevant for long-term analgesic use as well. The mechanisms involved are unknown. This side effect might turn out to be the most serious limitation to long-term analgesic treatment with ketamine.