Impact of HUA on complications of sedation and clinical outcome was analyzed only for patients who required MV beyond 24h. Descriptive results were calculated based on the total number of valid cases and are presented for continuous variables as mean (SD) and median and interquartile range (IR P25–P75) in case of non-normal distribution and as frequencies for categorical variables. Categorical variables underwent univariate analysis using Pearson's Chi-squared test and Fisher's test in case of lower frequencies than expected. Continuous variables were compared with the Student t test (normal distribution) and U-Mann–Whitney test, considering a p<0.05 value as statistically significant. For the multivariate analysis, a multinomial (categorical dependent factors) and linear regression models (continuous factors) were used to determine the effect of each factor on the sedation complications and risk probabilities. Variables identified as significantly different between HUA and no HUA groups were included in the multivariate analysis to determine their impact on the prevalence of SF and WS. DS was not included in the analysis since SF and WS are part of this clinical entity. Results are presented as odds ratios (OR) along with 95% confidence intervals (95% CI) thus considering as possible risk factor those with an OR>1 and a protective factor those with an OR<1. All statistical analysis was performed with SPSS 13.0® for Windows.

A total of 509 patients were admitted to the 8 participating ICUs during study period and 38 of them were excluded (Fig. 1). Total study sample (n=471) was 58.9 (17.2) years old, mostly male (66.9%), with a medical cause for admission (52.2%) and a mean APACHE II of 13.2 (8.3).

Figure 1.

Process of patients’ inclusion.

(0.2MB).

A 16.7% of cases were considered as HUA and 20% of all patients were smokers. PPM and IP were reported in 19.3% and 4.4% of patients, respectively. A total of 244 (51.8%) patients received MV and 119 (23.4%) did so for ≥24h constituting the study group.

Demographic characteristics and consumption habits of the study group are presented in Table 2. Most patients were male (68.9%) and had a medical cause of admission (53.9); mean age was 57.0 (17.9) years old and APACHEII was 18.8 (7.2); half (50.5%) of the patients referred consumption of at least one psychotropic, being tobacco (27.7%) and HUA (25.2%) the most frequently reported. PPM were reported in 15.1% of patients and hypno-sedatives (9.2%) where the most commonly prescribed, being benzodiazepines (7.5%) the more frequent type. Of the IP users, 75% were also, with cocaine (4.2%) and cannabis (3.3%) as the preferred drugs. A 75% of IP users were also tobacco or alcohol consumers. Use of PPM was reported in 15.1% of patients being hypno-sedatives (benzodiazepines 81.5%) and antidepressants (SSRI 50%) the most commonly prescribed.

One-third of the study population required of the simultaneous administration of ≥2 sedatives in order to achieve adequate sedation. Similarly, SF was reported in 14.2% of the cases. The incidence of SF shows important variations across the evidence, (i.e. midazolam SF 25–33%23 or propofol 3–34%24), due to the lack of a clear consensus on the definition of the maximal dose for some of the most used sedatives in ICU. Doses ranging between 4 and 5mg/kg/h have been recommended by several scientific societies as the maximal safe dose for propofol since higher infusions have been associated with direct toxicity defined as propofol infusion syndrome.25 This demarcation is less clear for midazolam thus the maximum dose reported in the available evidence ranges from 0.2 to 0.5mg/kg/h. In absence of a clear definition of a toxicity syndrome directly associated with midazolam,26 the ranges considered to define sedative failure in this study were those recommended by the SEMICYUC.23

Sedative withdrawal rate observed in our study (20.1%) was lower than the reported by other authors (20–80% in critically ill patients undergoing sedation and analgesia beyond a week,27 but again, differences in SW definition and case-mix28 may account for conflicting results. Diagnosis of SW was established by study investigators whenever the presence of specific and easily recognizable clinical signs and symptoms such as insomnia, anxiety, agitation, nausea, delirium and seizures were observed at the time of sedatives’ reduction or discontinuation (in the absence of pain or other organic causes). The use of standard definitions such as DSM-IV29 or several questionnaires/interviews designed to identify SW might be limited in the ICU setting since their implementation requires an adequate level of patients’ consciousness and/or preserved verbal, motor, hearing and visual abilities.30

Sequential sedation, a strategy aimed to avoid the adverse effects of accumulation of sedatives, was implemented in 1 of every 4 patients. Authors did not find relevant evidence in literature to compare with.

HUA patients were sedated for longer periods, required more frequently the simultaneous use of ≥2 sedatives and presented higher rates of sedation complications than No-HUA patients. Moreover, HUA was identified as an independent risk factor for the development of SF and SW. Similar results were reported in the study of De Wit et al.11 where critical patients with psychotropic consumption history needed 2.5 times more sedatives and 5 times more analgesics to obtain similar sedation level as well longer infusion periods than patients without history of consumption. The need for higher doses of sedatives and analgesics observed in HUA patients might be explained by a possible cross-tolerance mechanism between sedatives and alcohol, as well as to an increased metabolism of these substances through the action of p450 enzyme.31 The same underlying mechanisms could also explain the higher incidence of SW.32 Although alcohol has no specific receptors as benzodiazepines or barbiturates do, all three substances exert their action through the stimulation of GABA A receptors (reduce brain excitability33 while inhibiting glutamate's N-methyl-d-aspartate (NMDA) receptors34 (excitatory). Chronic exposure to any of these agents may induce to a series of compensatory mechanisms at the cellular receptor level producing a gradual decrease in GABA receptors (down-regulation) and increasing NMDA ones (up-regulation) in such a way that balance is only restored in the presence of such psychotropic agents.35 Prolonged use of benzodiazepines enhances the GABA/NMDA unbalance, making necessary to increase sedative agents’ dose to reach/maintain the adequate levels of sedation. Similarly, reduction or discontinuation of these agents may disrupt the balance, increasing brain excitability which together with the interruption of the inhibitory effect, is manifested as the known symptoms and signs of withdrawal.32

In the present study, HUA patients required longer periods of MV. This finding was not found by De Wit et al.11 who described that despite the increased risk for need of MV, alcoholic patients did no required prolonged times of MV, except for those presenting with withdrawal syndrome.36 Similarly to data reported by Suchyta et al.,10 in our series, HUA patients presented longer ICU LOS. These findings have not been replied in other retrospective investigations with different case mixes.11 PS and the need for higher number and/or doses of sedatives consistently found in patients with chronic use of psychotropics may play a role in the prolongation of MV and ICU stay times. Oversedation has been associated with prolonged time on MV and complications such as pneumonia, barotrauma, upper digestive haemorrhage, bacteraemia, or venous thrombosis among others.37 On the other hand, and similarly to other reports,10,11,36 HUA was not associated with higher rates of mortality in ICU patients.

One of the main limitations of the present study is that, in order to attain an easy and rapid detection in the ICU setting, criteria used for classification of “psychotropic consumption” were less strict than those used in other studies, which may contribute to a possible overestimation of psychotropic use rates. However, several studies in the hospital and out-of-hospital setting have shown that detection of drug dependence is frequently under-diagnosed with rates ranging from 10 to 86%.38 This may be particularly true in the context of critically ill patients, where the implementation of standard criteria for disease classifications39 and screening tools may be hampered by factors such as the lack of critical care physicians specific training in drug dependencies, the need for urgent care, and the frequently imprecise sources of information available in this setting (subjective information from relatives or incomplete medical records).40

The study was conducted in 2007. Sedation and analgesia practices may have changed since then hampering the validity of data presented in this manuscript with today's practice.

The implementation of sedation and analgesia protocols were responsibility of each of the participating centres as well as for the diagnosis of SW or SF that was performed according to the clinical criteria of investigators. The knowledge of history of HUA could have influenced beforehand the sedation strategy implemented and diagnosis of WS by the attending physician affecting the internal validity of the study. However it is important to recognize that all the study investigators are active members of the Spanish National Sedation and Analgesia Work Group of SEMICYUC which may influence the highly consonance of sedoanalgesia practices described in this study with the recommended by scientific societies.

We are also aware that the definition of SW used in the present study may lead to a false overrepresentation of this clinical profile due to the inclusion of misdiagnosed ICU delirium cases in mechanically ventilated patients, a syndrome that although sharing some of the clinical symptoms has different pathophysiologic mechanisms and outcomes.

Despite the multicentre design, the low number of patients and events per variable finally included advise to take cautiously results found in multivariate analysis. Similarly, although statistically significant, the impact of IPP on sedation practices and complications should be re-evaluated due to the low number of cases. The different case-mix (age, social background, etc.) of the included patients in the different participating centres may also hamper external validity of the results making them not applicable to other hospitals with different characteristics.

In conclusion, HUA patients may be at higher risk of requiring prolonged sedation and the use of higher doses of sedatives and analgesics, increasing the risk of sedation failure and withdrawal that could ultimately impact negatively on their outcome. Early identification of HUA patients might be advisable in patients admitted to ICUs since these patients are in higher risk of sedation failure and withdrawal and could benefit from strategies oriented to the prevention of these complications.