The choice of agent for RSI in the critically ill patient has been a matter of great debate for years. In general services have either adopted a fairly restricted approach with relatively standardised protocols (for example the Fentanyl:Ketamine:Rocuronium approach), or they have allowed a more individual approach at the discretion of the operator and adjusted for circumstance. It’s fair to say that I’m much more of the former type in emergency care as our patients are often quite complex, there are many other things going on, and a protocolised approach helps me and the team manage cognitive bandwidth. There are other approaches of course, some clinicians prefer to use drugs with which they are familiar, and others seek a more bespoke approach. In principle I don’t have an objection to such approaches, but in practice I have seen problems.
Many of our patients requiring RSI in the resus room (and prehospital) have some degree of cardiovascular compromise, or perhaps ‘challenge’ is a better word. This may or may not be obvious on the numbers on the monitor screen, but for a whole range of pathophysiological reasons, combined with a lack of information on underlying conditions means that our patients are significantly more likely to have adverse reactions to the drugs used as part of an RSI.
It is quite difficult to answer the question of what induction agents are best to use in RSI. There have been a number of comparison trials over the years, but these are often quite difficult to interpret due to the complexities of ensuring that baseline groups are equal in terms of pathology, physiology and polypharmacy. An alternative approach is to conduct observational trials in practice. Such trials are not as methodologically robust but they may tell us what the real world experience is.
The International Observational Study to Understand the Impact and Best Practices of Airway Management in critically ill patients (INTUBE) trial is one such study that observes outcomes in a number of hospitals across 29 countries (original study published back in 2021). They have recently published observational data factors associated with cardiac arrest from that study as Peri-intubation Cardiovascular Collapse in Patients Who Are Critically Ill: Insights from the INTUBE Study. The abstract is below.
Abstract
Rationale: Cardiovascular instability/collapse is a common peri-intubation event in patients who are critically ill. Objectives: To identify potentially modifiable variables associated with peri-intubation cardiovascular instability/collapse (i.e., systolic arterial pressure <65 mm Hg [once] or <90 mm Hg for >30 minutes; new/increased vasopressor requirement; fluid bolus >15 ml/kg, or cardiac arrest).
Methods: INTUBE (International Observational Study to Understand the Impact and Best Practices of Airway Management In Critically Ill Patients) was a multicenter prospective cohort study of patients who were critically ill and undergoing tracheal intubation in a convenience sample of 197 sites from 29 countries across five continents from October 1, 2018, to July 31, 2019.
Measurements and Main Results: A total of 2,760 patients were included in this analysis. Peri-intubation cardiovascular instability/collapse occurred in 1,199 out of 2,760 patients (43.4%). Variables associated with this event were older age (odds ratio [OR], 1.02; 95% confidence interval [CI], 1.02-1.03), higher heart rate (OR, 1.008; 95% CI, 1.004-1.012), lower systolic blood pressure (OR, 0.98; 95% CI, 0.98-0.99), lower oxygen saturation as measured by pulse oximetry/FiO2 before induction (OR, 0.998; 95% CI, 0.997-0.999), and the use of propofol as an induction agent (OR, 1.28; 95% CI, 1.05-1.57). Patients with peri-intubation cardiovascular instability/collapse were at a higher risk of ICU mortality with an adjusted OR of 2.47 (95% CI, 1.72-3.55), P < 0.001. The inverse probability of treatment weighting method identified the use of propofol as the only factor independently associated with cardiovascular instability/collapse (OR, 1.23; 95% CI, 1.02-1.49). When administered before induction, vasopressors (OR, 1.33; 95% CI, 0.84-2.11) or fluid boluses (OR, 1.17; 95% CI, 0.96-1.44) did not reduce the incidence of cardiovascular instability/collapse.
Conclusions: Peri-intubation cardiovascular instability/collapse was associated with an increased risk of both ICU and 28-day mortality. The use of propofol for induction was identified as a modifiable intervention significantly associated with cardiovascular instability/collapse.Clinical trial registered with clinicaltrials.gov (NCT03616054).
What kind of study is this?
This is a prospective observational study. This design does not dictate what happens to patients but collects data that is subsequently subject to statistical analysis. It’s better that the data is prospectively acquired as that is likely to be better than retrospective data, but this design is not as powerful as comparing interventions in a randomised controlled trial model. However, it is able to look at many factors at the same time and that can give indications of association, but it’s not the greatest of design to look at causality, and we should be cautious when intrrpreting the findings.
Tell me about the patients.
To be included patients had to require in-hospital intubation in participating hospitals across an 8-week period. Cardiac arrest patients and routine anaesthesia were not included. Data was collected at the time by an investigator who ideally was not involved in the resuscitation.
What about the aim?
The aim was to observe whether there are common factors associated with cardiovascular collapse in this challenging group of patients.
What about the outcomes.
It looks as though a number of analyses were undertaken from the original data, but in this study they were specifically looking at cardiovascular instability which was defined as SBP< 65 mmHg recorded at least once; systolic arterial pressure < 90 mmHg for > 30 minutes; new requirement for, or increase of vasopressors; fluid bolus > 15 ml/kg to maintain the target blood pressure or cardiac arrest. Life threatening collapse was defined as SBP< 65 mmHg recorded at least once or cardiac arrest within 30 minutes. That’s a reasonable set of criteria, although I’m always a bit sceptical about single blood pressure recordings, as we have seen that this can occur as a result of monitor malfunction, and we have also seen that NIBP recordings are unreliable in critically ill patients (but as it’s usually all we have, it’s OK to include here with that caveat).
How did they analyse the data?
The biggest problem with observational studies like this is that biases and irregularities can creep in without being noticed. The different centres, patients, countries and operators can all influence results. The authors approach of using a logistic regression model to try and account for known differences/confounders is reasonable (and a common one), but it won’t mitigate the issue completely.
What about the results?
3659 patients were screened and 2760 patients were recruited through to final analysis. 1199 (41%) met the criteria for cardiovascular collapse, which seems high to me. The baseline data is interesting as compared to UK practice. 2/3 of intubations took place on ICU, 62% were RSI’s, perhaps less than I would expect in the UK. There was a lot of variability in all aspects of the study, but noticeably in drug use. A large proportion (41.4%) had propofol as an induction agent, just 75% had a muscle relaxant, and drugs such as midazolam, and etomidate were used in a significant minority of patients. Ketamine was also used widely.
Patients with CVS collapse were morel ikely to die and spent longer on the ICU.
The multivariate logistic regression model is interesting. As previously described it can be difficult to pick out the impact of single interventions when you have an observational trial such as this. A multivariate model takes account of a range of factors and seeks to isolate one factor in the analysis to highlight it;s specific impact. In this cohort factors that were independently associated with cardiovascular collapse were
- Use of Propofol (OR 1.28, 95% CI 1.05 – 1.57)
- Older age (OR 1.02, 95% CI 1.02-1.03)
- Higher heart rate (OR 1.01, 95% CI 1.00-1.01)
A further analysis using inverse probability test weighting further highlighted the association of Propofol use with CVS collapse (OR 1.23, 95% CI 1.02-1.49)
The important observation here is that although there are a range of factors that can affect outcome, not all of them are modifiable. Drug choice is a modifiable aspect and therefore worthy of consideration.
So should we stop using Propofol for critically ill patients?
It’s tempting to just say yes. It fits with my practice and preconceptions, but this is critical appraisal and we should not take things at face value. This study, like all studies has limitations. Many of the patients defined as having instability were a result of starting vasoactive drugs which is somewhat subjective. It’s also notable that the propofol dose seems to have been predetermined, which may not have allowed the expert adjustment to dose practiced by those most familiar with the drug. Interestingly a recent observational study in Scandinavia found little difference between ketamine and propofol when a more tailored approach was used. I suspect that pretty much any drug can be used, but that some are more difficult to use than others, and (almost certainly) that many clinicians over-estimate their personal skills to dose adjust to a patient about whom we often know relatively little, and can control even less.
We must also be mindful that the main outcomes in this study are not directly patient related outcomes, but more about monitor readings. Ideally we would want to see better patient related outcomes such as mortality and functional outcome scores.
The bottom line.
This paper plays to my prejudices and preconceptions, but even so, the observational data here is that Propofol is associated with worse outcomes. Since it is a modifiable part of the RSI process it makes sense to reduce its use in practice. For me, that makes little or no difference as pretty much all my RSIs are done in high risk resus room/prehospital patients. My troubles may be in persuading others to consider agents other than those that are most familiar with, when dealing with unfamiliar patients.
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@EMManchester
References
- Russotto V, Tassistro E, Myatra SN, Parotto M, Antolini L, Bauer P, Lascarrou JB, Szułdrzyński K, Camporota L, Putensen C, Pelosi P, Sorbello M, Higgs A, Greif R, Pesenti A, Valsecchi MG, Fumagalli R, Foti G, Bellani G, Laffey JG. Peri-intubation Cardiovascular Collapse in Patients Who Are Critically Ill: Insights from the INTUBE Study. Am J Respir Crit Care Med. 2022 Aug 15;206(4):449-458. doi: 10.1164/rccm.202111-2575OC. PMID: 35536310.
- Russotto V, Myatra SN, Laffey JG, et al. Intubation Practices and Adverse Peri-intubation Events in Critically Ill Patients From 29 Countries. JAMA. 2021;325(12):1164–1172. doi:10.1001/jama.2021.1727
- Ketamine versus propofol for rapid sequence induction in trauma patients: a retrospective study. https://sjtrem.biomedcentral.com/articles/10.1186/s13049-021-00948-5
- Seitz KP, Gandotra S, Casey JD. Emergency Tracheal Intubation: A Procedure in Need of Better Evidence. Am J Respir Crit Care Med. 2022 Aug 15;206(4):370-371. doi: 10.1164/rccm.202204-0792ED. PMID: 35579619.
- Leisman DE, Crowley JC. Predicting Peri-intubation Cardiovascular Instability: Preintubation Vital Signs Are Vital. Am J Respir Crit Care Med. 2023 Mar 1;207(5):622-623. doi: 10.1164/rccm.202208-1526LE. PMID: 36194891; PMCID: PMC10870917.
- Simon Carley, “Non-invasive or arterial pressure monitoring in PHEM?,” in St.Emlyn’s, September 29, 2024, https://www.stemlynsblog.org/non-invasive-or-arterial-pressure-monitoring-in-phem/.
- Laamanen J, Ljungqvist H, Nurmi J. Comparison of Esketamine and Propofol for Prehospital Emergency Anaesthesia in Patients With Traumatic Brain Injury-A Retrospective Observational Study. Acta Anaesthesiol Scand. 2025 Nov;69(10):e70131. doi: 10.1111/aas.70131. PMID: 41123115; PMCID: PMC12542310.
