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Title page

Manuscript number: EJA-D-19-00574.

Title: Effects of sedatives, neuromuscular blocking agents and opioids on ventilator-

associated events. An Editorial Comment for the European Journal of Anesthesiology

Running title: Sedatives on ventilator-associated events

Sergio Ramirez-Estrada (1,2); Yolanda Peña-López (3) ; Jordi Rello (4)

1- Critical Care Department, Clínica Corachan, Barcelona, Spain

2- Department of Medicine, Universitat Autónoma de Barcelona, Barcelona, Spain.
3- Vall d'Hebron Institut of Research (VHIR), Barcelona, Spain.
4- Centro de Investigación Biomédica en Red (CIBERES), Instituto de Salud Carlos III,
Barcelona, Spain.

Key words: Asynchronies, ventilator-associated pneumonia, length of stay, mechanical

ventilation, ARDS.

Word count: 842 /1500

Authors:
Corresponding author:
Sergio Ramirez-Estrada
Address: Intensive Care Department, Clínica Corachan. Carrer Buïgas 19, Barcelona,
Spain.
E mail: sergioramirezestrada@hotmail.com
Phone and fax: 34- 93 254 58 00.
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Yolanda Peña-López
Address: Valld'Hebron Institut of Research (VHIR). Paseo de la Vall d'Hebron 119,
Barcelona, Spain.
E mail: yolanhcp@yahoo.es
Phone and fax: 34 -932744998
Jordi Rello Condomines
Address: Clinical Research/epidemiology In Pneumonia & Sepsis (CRIPS). Paseo de la
Valld'Hebron 119, Barcelona, Spain.
E mail: jrello@crips.es
Phone and fax: 34 -932744998
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Text
In recent years, the use of specific care bundles in the intensive care unit (ICU) has
been postulated as a pragmatic strategy of management expanding its use to different
areas such as hemodynamic management, delirium, or infection prevention. For
instance, the ABCDEF bundle was created,1 focusing on the adverse effects of critical
illness related to acute and chronic brain dysfunction. This bundle includes Assess,
Prevent, and Manage Pain, Both Spontaneous Awakening Trials and Spontaneous
Breathing Trials, Choice of analgesia and sedations, Delirium: Assess, Prevent, and
Manage, Early mobility and Exercise, and Family engagement and empowerment. A
critical issue is what interventions should be enclosed in the bundles, with sedation
strategies being a core element. Until recently, most ventilatory bundles have been
focusing more on pathophysiological measures rather than decreasing ventilator-days,
when sedation strategies should become the cornerstone. Indeed, the difficulty on the
classification of ventilator-associated respiratory infections, represented by ventilator-
associated tracheobronchitis and ventilator-associated pneumonia2 and their impact
on outcomes leave the Centers for Disease Control and Prevention to replace
surveillance definitions from ventilator-associated pneumonia to preventable
conditions related to mechanical ventilation, defined as ventilator-associated events
(VAE). This shift tries to improve outcomes prediction, focusing on hypoxemia3
affecting both respiratory infections and acute respiratory distress syndrome (ARDS).
Therefore, standardizing a ventilator-bundle focusing on VAE would really impact on
patient outcomes.
Recently, the ROSE trial4 reported that cisatracurium infusion plus deep sedation
resulted in similar outcomes than light sedation in ARDS, being in contrast with a policy
of deep sedation in the ACURASYS trial,5 suggesting that light sedation should be
preferred in management. Both studies have similar design: patients with moderate-
to-severe ARDS were randomly assigned to receive a 48-hour continuous infusion of
cisatracurium (Initial bolus of 15 mg followed by infusion of 37.5 mg/hour) or not, a
lung protective ventilation strategy was used and there were not significant
differences in the baseline characteristics of the patients included; interestingly, while
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in the ACURASYS trial the intervention group presented a 10% decrease in 28-day
mortality (cisatracurium vs Placebo: 23.7% vs 33.3%, p: 0.05) and a lower incidence of
barotraumas (5.1% vs 11.7%, p: 0.03) and pneumothorax (4.7% vs 11.7%, p: 0.01). No
statistical differences were reported in the ROSE trial for the same group of events.
Compared with the ROSE trial, patients in the ACURASYS study had higher driving
pressure levels and few of them were excluded due to neuromuscular blockade use at
enrollment (1.3% vs 13.4%). Unfortunately, neither compliance nor prone position use
were reported in the ROSE trial. Therefore, although positive end-expiratory pressure
(PEEP) levels were higher in the ROSE study (due to updated guidelines on ventilatory
management), it is possible that the population from both trails were not comparable.
These findings agree with a recent article6 reporting that long-acting sedation
(midazolam, fentanyl or morphine) was the variable most important (HR 8.69 in adults
ventilated longer than 7 days) to be independently associated with development of
VAE (Figure 1). Interestingly, neuromuscular blocking agents did not exert any
significant effect (HR 0.81, p value 0.83) in the development of VAE.

The length of mechanical ventilation is conditioned by the choice, depth, and duration
of sedation. Less ventilator days are associated with lower rates of infection, fluid
overload, atelectasis and ARDS7 whereas a large meta-analysis found that targeting
light sedation levels is safe and improve outcomes for ventilated patients in the
intensive care unit.8 Short acting sedatives as propofol, are associated with less time to
extubation compared with benzodiazepines8 and multiple studies support a decrease
in the incidence of ventilator-associated respiratory infections when protocols aiming
at sedation restriction, early ventilator weaning and early mobility are implemented.9
Additionally, keeping patients in a collaborative state allows starting early
rehabilitation therapy and spontaneous breathing trials.10
There is still a lack of clarity regarding how the use of sedatives and opioids affects the
patient-ventilator interaction, light sedation with propofol does not affect the rate of
asynchronies but deep sedation with propofol increased it,11 indeed, deep sedation
with benzodiazepines increased mortality whereas dexmedetomidine had fewer
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asynchronies compared with propofol.12 Lastly, a recent study13 reported that the
overall rate of asynchronies did not show differences between sedatives-plus-opioids,
sedatives only or opioids alone, patients receiving sedatives have a lower level of
consciousness compared to those who received opioids alone. The sedatives-plus-
opioids protocol decreased the level of consciousness but did not decrease
asynchronies, whereas the sedative dose was directly associated with asynchronies
rate and resulted in a lower level of consciousness.
In summary, minimizing the use of sedation and the employment of short-acting
sedatives is associated with less ventilation days and lower pneumonia and mortality
rates in ventilated patients in the ICU. In ARDS, paralytic agents can sometimes be
used, when physiologically and clinically indicated14 and further studies should
determine which ARDS phenotypes can beneficiate with the use of neuromuscular
blocking agents. Adequate opioids prescription with minimal doses of sedatives might
improve patient-ventilator interaction and enable more spontaneous breathing.
Optimal titration of opioids might avoid deleterious effect of sedatives.
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Acknowledgements :

Sources of funding: none.

Conflicts of interest: none.

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References:
1. Marra A, Ely EW, Pandharipande PP, Patel MB. The ABCDEF Bundle in CriticalCare.
Crit Care Clin. 2017; 33:225-243.
2. Rello J, Lisboa T, Koulenti D. Respiratory infections in patients undergoing
mechanical ventilation. LancetRespirMed. 2014; 2:764-74.

3. Rello J, Peña-López Y, Solé-Violan J. Implications of oxygenation variations in

ventilated patients with respiratory infections. Minerva Anestesiol. 2018; 84:423-425.

4. Moss M, Huang DT, Brower RG, et al. Early neruromuscular blockade in the acute
respiratory distress syndrome. N Engl JMed. 2019; 380: 1997-2008.
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associated events: an international multicenter prospective cohort study. Eur J Clin
Microbiol Infect Dis. 2019. In press. DOI: 10.1007/s10096-019-03596-x.
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11.Vaschetto R, Cammarota G, Colombo D, et al. Effects of Propofol on patient-
ventilator synchrony and interaction during pressure support ventilation and neutrally
adjusted ventilatory assist. Crit Care Med. 2014; 42:74-82.
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12. Conti G, Ranieri VM, Costa R, et al. Effects of dexmedetomidine and Propofol on
patient-ventilator interaction in difficult-to-wean, mechanically ventilatedpatients: a
prospective, open-label, randomised, multicentre study. Crit Care. 2016; 20:206.
13. De Haro C, Magrans R, Lopez-Aguilar J, et al. Effects of sedation and opioids on
trigger and cycling asynchronies throughout mechanical ventilation: an observational
study in a large dataset from critically ill patients. Crit Care. 2019; 43:245.
14. Slutsky AS, Villar J. Early paralytic agents for ARDS? Yes, No, and sometimes. N Engl
J Med. 2019; 380:2016-2063.
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Figure 1. Factors associated with ventilator-associated events in a multivariate cox

proportional hazard model.6