Effects of sedatives and opioids on trigger and cycling asynchronies throughout mechanical ventilation: an observational study in a large dataset from critically ill patients

Patient-ventilator asynchronies are frequent during invasive mechanical ventilation (MV) [1, 2]. Poor patient-ventilator interaction could be associated with prolongation of MV, longer intensive care unit (ICU) and hospital stays [2], and increased mortality [1, 3]. Thus, optimizing patient-ventilator interaction may improve outcomes [4].

Many aspects of clinical management affect patient-ventilator interaction. Adjusting ventilator settings can decrease asynchronies and associated anxiety and dyspnea [5, 6]. Sedatives can cause ventilatory depression affecting respiratory drive and timing, worsening patient-ventilator interaction in proportion to decreasing level of consciousness [7, 8]; these effects appear to differ with different drugs [9, 10]. Sedation is associated with deleterious side effects. Deep sedation is associated with worse short- and long-term outcomes [11‐14]. Forgoing or minimizing sedatives during MV is increasingly recommended [15‐17].

The relationship between asynchronies, level of consciousness (sedation level), and sedatives and opioids is poorly understood. Increasing sedatives in ICU patients with double cycling (DC) not only failed to correct this asynchrony [6], but also prolonged MV and ICU and hospital stays. The rate of ineffective inspiratory efforts increases proportionately with the depth of sedation [8]. Different studies have reported disparate effects of sedative dosage on the overall rate of asynchronies. Whereas one study found that light sedation with propofol did not affect the rate of asynchronies but deep sedation with propofol increased it [10], another found that deep sedation reduced but did not eliminate asynchronies [18]. A recent study showed that deep sedation, benzodiazepines, and cumulative doses of benzodiazepines were associated with higher mortality [19]. In another trial, patients on dexmedetomidine had slightly fewer asynchronies than those on propofol [20]. However, these studies did not take opioid administration into account.

Opioids are commonly used in ICU patients. In a study comparing midazolam vs. fentanyl plus midazolam, patients receiving fentanyl had fewer asynchronies than those receiving only midazolam [21]. Thus, the effects of opioids alone or together with sedatives on asynchronies warrant investigation. Adequate opioid treatment with minimal doses of sedatives might enable more spontaneous breathing and improve patient-ventilator interaction; however, the relationships between opioids, level of consciousness, and asynchronies remain to be elucidated. We hypothesized that opioids alone would improve trigger and cycling asynchronies and result in more wakeful patients than sedatives alone or sedatives-plus-opioids.

Table 1 reports on the demographic, clinical, and outcome data for the 79 patients. We analyzed 579 days on invasive MV, comprising 14,166,469 breaths.

This is the first study to present data relating asynchronies and treatment with sedatives and opioids throughout the complete MV period. The overall rate of asynchronies did not differ between days classified as opioids-only, sedatives-only, and sedatives-plus-opioids. Patients receiving sedatives had a lower level of consciousness than those receiving opioids-only; sedatives-plus-opioids decreased the level of consciousness, but did not result in fewer asynchronies than the other treatments. Interestingly, in sedatives-plus-opioids days, the sedative dose was directly associated with the rate of asynchronies and with a lower level of consciousness, whereas higher opioid doses were associated with a lower AI without worsening level of consciousness. Thus, opioid administration seems a clinically sound approach to improve patient-ventilator synchrony while preserving consciousness.

Patients with shock or severe respiratory failure often require sedatives. Moreover, sedatives are sometimes administered in attempts to improve patient-ventilator interaction. However, deep sedation has been associated with worse outcomes [13]. Lighter or no-sedation is favored in partial ventilatory support modes, where patient-ventilator synchrony is crucial. Physiological studies show that sedatives have varying effects on asynchronies. Increasing sedatives/analgesia is relatively ineffective in abolishing severe breath-stacking [6]. Deep sedation with propofol increases asynchronies during pressure support ventilation, whereas light sedation does not [10]; deeper sedation is associated with increased ineffective triggering events [8] and with increased mortality [26]. Thus, sedative management in MV is a modifiable variable that could improve outcomes [26].

Associations between sedatives and asynchronies are probably confounded by many factors, especially by clinicians’ ventilator adjustments. In our study, the incidence of asynchronies was associated with the drugs used (sedatives and opioids), irrespective of the ventilatory mode. However, sedatives lowered patients’ level of consciousness without decreasing asynchronies beyond opioids alone. Inadequate pain control worsens patient-ventilator synchrony [21] and is associated with agitation, which negatively affects outcomes [27]. Richman et al. [21] found that patients receiving midazolam-plus-opioids had fewer asynchronies/day over a 3-day period than those receiving midazolam alone. Our results support these findings, showing that opioids could help improve asynchronies beyond sedatives, although prospective trials are necessary to determine whether appropriate opioids favor better synchrony by ensuring adequate analgesia without depressing consciousness and without affecting respiratory drive or minute ventilation [28‐30].

Increasing sedative doses prolongs MV and ICU and hospital stays [12, 14]. Paired with pain management protocols [17], sedation protocols including light sedation or daily interruptions of sedation [13, 15, 16] improve ICU patients’ outcomes. Our results suggest that, compared with treatments including sedatives, treatment with opioids-only enables patients to be more awake without increasing asynchronies. Opioids-only treatment resulted in a higher level of consciousness than treatment with sedatives-plus-opioids. Our findings on the effects of sedatives and opioids throughout MV are in line with those of a randomized clinical trial where MV patients receiving morphine had more ventilator-free days and shorter ICU stays than those receiving sedatives-plus-morphine, without increases in accidental extubation or ventilator-associated pneumonia [16]. Moreover, we found that in assist-control modes, compared with no-drugs, treatment with sedatives-plus-opioids and opioids-only favored better patient-ventilation interaction (lower AI), suggesting that opioids might improve patient comfort. Thus, it might be beneficial to maintain opioid treatment until liberation from MV.

We also found significantly lower AI, IEE, and DC in sedatives-plus-opioids than in no-drugs days. However, asynchronies in MV patients who do not require sedatives or opioids probably are intrinsically different from those that occur in patients who require these treatments, and therefore, they probably require a different clinical approach. Rue et al. [31, 32] recently used a Bayesian joint model incorporating longitudinal ICU stay markers to evaluate outcome determinants. Finding that overall AI was not associated with severity of illness or vital status, they postulated that some asynchronies could be a marker of life. In our study, we considered the effect of severity of illness to better understand this possible confounding factor. We found no associations between severity and AI or IEE (Table 2), so patients with more asynchronies were not necessarily more severely ill. The lower severity and higher rates of asynchronies in no-drugs days compared with sedatives-only, opioids-only, and sedatives-plus-opioids days are likely due to differences in the origin and behavior of the asynchronies that occur in the different groups. Therefore, from a clinical perspective, it makes no sense to compare asynchronies and their management in no-drugs versus in treatment days [3, 33].

Finally, our analysis of the relationship between asynchronies and drug dosage found that, unlike sedatives, increasing doses of opioids were associated with decreasing rates of asynchronies, without significantly affecting the level of consciousness, independently of the level of severity. This finding highlights the importance of titrating opioids for comfort, and possibly asynchronies, in addition to pain control.

Unlike some physiological studies, we found that sedatives, alone or together with opioids, did not decrease asynchronies more than opioids-only. On the other hand, our findings of increased rates of asynchronies, especially IEE, with an increased daily dose of sedatives are in line with physiological studies [8, 10]. Whereas physiological studies analyze only short time periods, our study considered the entire period of MV, making it closer to clinical practice. One strength of our study is that it is based on prospectively accrued physiological data with enough breadth and depth to characterize a patient’s condition throughout MV. Observational trials like this are increasingly being used because conclusions drawn from data collected in real-world situations can be more generalizable than the more restricted, if more vigorous, conclusions of randomized clinical trials [34‐36]. Our findings add to the growing body of evidence pointing to the inability of sedatives to prevent and/or correct asynchronies in daily practice and the association of opioids with improved asynchrony rates, thus supporting the strategy of managing pain while maintaining the lightest sedation possible [17, 37].

Our study has several limitations. First, patients were not randomized to each drug regimen. Furthermore, patients received opioids, sedatives, or no-drugs in any sequence or combination as deemed clinically necessary. Granular data for sedative or opioid doses over smaller time intervals were unavailable, thus precluding analyses of temporal associations between sedatives/opioids and asynchronies that might have enabled causal inferences and greater insight. Moreover, we did not consider factors that influenced clinicians to modify sedative or opioid dosing. Patients often receive more drugs early in MV and less when approaching weaning; however, to counterbalance this bias, we explored the relationship between severity and drugs and asynchronies, but found no relevant associations. Additionally, we did not analyze other painkillers such as acetaminophen and nonsteroidal anti-inflammatory drugs, which may influence patient-ventilator interaction differently, so our findings cannot be extrapolated to other non-opioid drugs. We used no objective measures of pain levels, precluding the analysis of associations between pain and asynchronies. Likewise, we did not measure surrogates of respiratory center activity, so we cannot evaluate associations between respiratory drive and different asynchronies. As individual patients could be considered in more than one group because management strategies evolved from day-to-day, our analysis of drug doses could not take into account the prolonged half-life and accumulation of some sedatives [38]. Nevertheless, we found a good relationship between SAS score and the sedative treatment group. We analyzed only IEE and DC because they are the most relevant asynchronies; we did not analyze flow asynchronies because they cannot be established from ventilator airway pressure and flow scalars alone. Thus, our findings cannot be extrapolated to these asynchronies. Additionally, because the measure unit was days rather than patients, it was difficult to analyze the effect of the underlying disease on the results. In an attempt to overcome this difficulty, we adjusted the results by including SOFA score as a marker of severity, but we found no effect of severity in the incidence of asynchronies per group. Finally, clinically detected asynchronies were treated according to each ICU’s protocols; thus, differences between centers might have affected the results. We performed an analysis to evaluate the influence of each center and we did not find significant differences between centers.

Our findings suggest that sedatives, alone or together with opioids, do not decrease asynchronies beyond what can be achieved with opioids alone, independently of MV mode. Optimal titration of opioids might improve patient-ventilator interaction while avoiding the deleterious effects of sedatives.