NICO Trial – Intubation in Acute Drug Overdose – Does Intubation Matter?

Blog Written by Dr Jose Chacko 

Effect of Noninvasive Airway Management of Comatose Patients with Acute Poisoning: A Randomized Clinical Trial

(Freund et al. JAMA. 2023;330(23):2267-2274. doi:10.1001/jama.2023.24391)

Clinical question

Assessment of the neurological status using the Glasgow coma scale (GCS) was introduced by Jennett and Teasdale to guide the early management of patients with acute brain injury. However, it is widely employed to decide upon the necessity for airway protection by endotracheal intubation in various clinical situations. The NICO randomized controlled addressed the question of whether a conservative strategy of withholding intubation among patients with acute poisoning and a GCS of 8 or less would improve clinical outcomes compared to routine practice.

Population and design

The NICO randomized controlled trial was conducted in 21 centres in France between May 16, 2021, and April 12, 2023. Adult patients ≥18 years with a reduced level of consciousness (GCS 8 or less) following acute poisoning were eligible.

Excluded

• Patients who required urgent intubation (acute respiratory distress, suspicion of brain injury, seizures, shock)
• Pregnant patients
• Intoxication with drugs leading to cardiac toxicity – including calcium channel blockers ACE inhibitors; intoxication with a single, reversible agent (opioids and benzodiazepines)

Patients were randomized to withholding of immediate intubation (intervention) or routine care (control group). Randomization was stratified by center.

Intervention group

Intubation was withheld unless there was an emergency indication – including oxygen saturation <90% with supplemental oxygen through nasal prongs, vomiting, and systolic blood pressure <90 mm Hg after 1L of fluid resuscitation.

Control group

The decision to intubate was left to the judgment of the treating clinician.

Patients were closely monitored, with oxygen saturation levels, heart rate, respiratory rate, and the GCS score for the next 4 hours or until the level of consciousness improved to 9 or more. After 4 hours, the intervention period was considered complete; further management was carried out according to routine practice, based on clinician discretion. Intubation was carried out based on standard guidelines for rapid sequence intubation. The intubation protocol included the administration of a sedative – etomidate or ketamine – followed by succinylcholine or rocuronium. Non-invasive ventilation was allowed in patients with hypoxia.

Sample size

The composite primary outcome was a hierarchy of endpoints in the order of their clinical importance (death first, ICU length of stay second, and hospital length of stay third in importance) truncated at 28 days. The authors calculated a sample size of 100 patients in each group, giving the study 98% power to detect a difference in the primary outcome at a two-sided % significance level of 5%. Allowing for loss to follow-up and lack of consent, 120 patients were planned to be included in each group.

Results

A total of 237 patients were randomized; 225 were included in the primary analysis; 116 patients were in the intervention group and 109 in the control group. The median age was 33 years, 62% were male patients. The median GCS at randomization was 6 (3–7) in both groups; alcohol was the toxin in 67% of patients. The intubation rate was lower in the intervention group [19 (16.4%) vs. 63 (57.8%)]. Among the 19 patients intubated in the intervention group, 16 had at least one criterion for emergency intubation.

The primary outcome

The composite primary endpoint was significantly more favorable in the intervention group with a win ratio of 1.85 (95% CI, 1.33–2.58; P < 0.001). The results were

similar after stratification by study center.

The win ratio favored the intervention group on pre-specified subgroup analysis among patients with a GCS of <7. There was no significant difference between groups in patients intoxicated with alcohol, benzodiazepines, γ-hydroxybutyric acid, or γ-butyrolactone.

Among the individual components of the primary outcome, no patients died in either group. The median ICU length of stay was shorter in the intervention group (0 hours [IQR, 0–18.5] vs 24.0 hours [IQR, 0–57.0]; rate ratio [RR] = 0.39 (0.24 to 0.66). The median duration of hospital stay was also shorter in the intervention group 21.5 hours (IQR, 10.5–44.5) vs. 37.0 hours (IQR, 16.0–79.0); RR, 0.74; 95% CI, 0.53–1.03).

On exploratory analysis, a clinical benefit was observed in the primary composite endpoint among patients who were not intubated compared to those who were.

Secondary outcomes

Fewer patients were admitted to the ICU in the intervention group [39.7% vs. 66.1%, OR = 0.23 (0.12–0.44)]. Mechanical ventilation was carried out less often in the intervention group (18.1% vs 59.6%; OR = 0.12 (0.06–0.24). Adverse events during intubation were also less common in the intervention group (6.0% vs 14.7%).

Among patients who were intubated (n = 86), the median length of stay in the ICU and the hospital were not significantly different; the risk of adverse events due to intubation was also similar.

Conclusion

Among comatose patients with acute poisoning and a GCS of 8 or less, a strategy of withholding intubation resulted in a lower incidence of the composite endpoint on in-hospital mortality, ICU, and hospital length of stay.

Strengths

• It is probably the first RCT that compared intubation strategies based on GCS among patients with poisoning
• Robust findings of reduced intubation rates, lower adverse events, and improved outcomes with a withholding of intubation strategy
• The study suggested that intubation for presumed airway protection may, paradoxically, increase the risk of pneumonia.
• First pass failure rate was lower in the intervention group
• The study busted the “less than 8, intubate” dogma

Limitations

• Unblinded trial – clinicians were aware of group assignment, which could have led to bias, particularly regarding the duration of stay in the ICU and hospital.
• Composite primary outcome – there was no mortality in either group. The favourable benefit of withholding the intubation strategy was almost entirely driven by the duration of ICU stay (which could have been subject to bias, given clinicians were aware of the assignment)
• Patients were included solely based on the suspicion of poisoning
• The toxins involved in the study (alcohol, benzodiazepines, γ-hydroxybutyric acid, and γ-butyrolactone) were short-lasting and may have facilitated a withholding of intubation strategy. The withholding of intubation strategy may not be appropriate in toxins with a more prolonged effect
• Would monitoring unintubated patients with a low level of sensorium be more labour-intensive?
• Would the results apply to emergency settings in other countries?