This prospective open-label randomized controlled study revealed that critically ill patients who received 100–200 mg of gabapentin at bedtime had significantly increased SWS, TST, RCSQ score, and IGF-1 concentrations. Clinical outcomes, such as delirium, self-extubation, mortality, ICU-free days, MV-free days, and hospital-free days, were improved in the gabapentin group. However, the differences were not statistically significant.
Sleep deprivation has many adverse cognitive, autonomic, and hormonal effects that may contribute to prolonged ICU admission and increased morbidity [26]. Pain, illness, medications, and environment, including noise and light, have been reported to disturb sleep in the ICU [27]. ICU patients may experience fragmented sleep and decreased SWS [5]. SWS is crucial as IGF-1 is released in response to GH [6], and it drives the glymphatic system and the clearance of solutes and waste products (including β-amyloid and inflammatory cytokines) from the brain [28, 29]. IGF-1 also has beneficial metabolic effects such as increased PPAR-γ transcription, stimulated glucose uptake through GULT-4, and decreased hepatic glucose production [30]. Therefore, we also measured the IGF-1 level as one of the parameters for evaluating SWS.
We performed the study using gabapentin since it has less severe adverse effects than other medications that promote SWS. The most common adverse effects of gabapentin are dizziness and somnolence, but they are dose-dependent and reversible [31]. Other medications that promote SWS have several concerning issues regarding their use, such as QTc prolongation and hypotension for trazodone, difficulty in dose titration for mirtazapine, and a long half-life for olanzapine [32, 33, 34]. From a pharmacokinetics point of view, gabapentin has a short half-life (5–7 hours) and no protein binding, is not metabolized by CYP450, and is excreted unchanged in the urine. The maximum dose of gabapentin in patients with renal insufficiency (creatinine clearance < 15 mL/min) is 300 mg. Gabapentin can also be administered via a nasogastric tube [31]; therefore, it is suitable for critically ill patients.
Several studies reported that gabapentin showed an increase in SWS and improved sleep quality in those with primary insomnia [25], alcohol dependence [35, 36, 37], and neuropathic pain [38, 39, 40, 41], but there were no data on critically ill patients. In the current study, we found that gabapentin (100–200 mg/day) promoted SWS and TST in critically ill patients compared to the control group. SWS in the gabapentin group increased to an hour on day 3 but not on day 5. This might be because only 15 patients (50% from the beginning) in the gabapentin group were in the ICU until day 5. Six were weaned from MV to BIPAP on day 4, which might have negatively affected their sleep. However, in the subgroup of patients with MV, SWS increased to an hour on days 3 and 5 in the gabapentin group. Our study revealed that SWS as a primary outcome was significantly increased in ICU patients who received gabapentin.
Concerning the mechanism of action, gabapentin was bound to both the α2δ1 and α2δ2 subunits of the voltage-gated calcium channel. The binding of gabapentin to the α2δ2 subunit in nucleus incertus, which is a center for arousal, led to increased SWS and TST [16, 17]. The binding of gabapentin to α2δ1 in the amygdala might alleviate anxiety in critically ill patients [42].
Additionally, gabapentin enhances SWS in patients receiving other sedative drugs. Our study showed an increase in SWS from baseline after patients who had taken benzodiazepines or quetiapine received gabapentin. Benzodiazepines increased TST but decreased SWS and REM; quetiapine also increased TST but did not increase SWS and REM sleep [33, 43]. Therefore, gabapentin might enhance SWS in patients who receive sedative-hypnotics but do not experience improved restorative sleep.
As mentioned earlier, IGF-1 concentrations increased during SWS. Chennaoui [44] and Rusch [45] found that improved sleep quality led to increased IGF-1 concentrations. We found that IGF-1 levels at baseline (34.21 ± 8.20 ng/mL in the control group and 41.75 ± 11.09 ng/mL in the gabapentin group) were much lower than the normal range. The normal range of IGF-1 concentration is 50–200 ng/mL in the elderly (> 60 years) [46]. In our research, IGF-1 concentrations significantly increased in critically ill patients who received gabapentin compared to the control group, in parallel to the increase in SWS. Blood samples for IGF-1 measurement cannot be drawn from all patients since ethical requirements recommend that blood be drawn only when necessary. Although we could not measure IGF-1 concentrations in all patients, our study indicates that IGF-1 concentrations were significantly higher after receiving gabapentin.
This study also reported the following clinical outcomes: delirium, self-extubation, mortality, ICU-free days, MV-free days, and hospital-free days. We found no difference between the two groups regarding these clinical outcomes. Delirium is influenced by many factors, such as sleep deprivation, ventilator setting, and immobilization [2, 47, 48, 49]. Sleep deprivation leads to inspiratory muscle fatigue, resulting in prolonged MV use [50, 51, 52]. Prolonged MV use was associated with increased ICU length of stay, hospital stay, and mortality in ICU patients [53, 54, 55], similar to delirium [56, 57, 58]. However, the gabapentin group showed a trend in the reduction in delirium (5/30 cases) compared to the control group (10/30 cases). We also found that mortality rate, 28-day ICU-free days, 28-day MV-free days, and 28-day hospital-free days tended to be better in critically ill patients who received gabapentin, but the findings were also not statistically significant. Other factors, such as nutritional status, ventilator settings, and rehabilitation, were not controlled during our study period. Further studies controlling these factors should be conducted in the future.
Concerning the adverse effects of gabapentin, we found only one case where a physician decided to discontinue gabapentin after two doses were administered because of over-sedation. The low incidence of adverse effects in our study was due to the low dose of gabapentin (100–200 mg) prescribed to the patients.
The key limitation of our study was our inability to monitor sleep outcomes by PSG, which is the gold standard for sleep assessment. This was because of limited access to the sleep laboratory and limitations regarding the number of visitors allowed at the bedside during the COVID-19 pandemic [59, 60, 61]. As mentioned in the methods section, we decided to conduct our study without PSG and assessed sleep with BIS and RCSQ. Kakar et al. [62] and Richards et al. [63] showed that BIS and RCSQ are well correlated with PSG (p < 0.001). Therefore, the data from BIS and RCSQ are considered reliable if PSG cannot be performed in ICU patients. Other factors, such as uncontrolled non-pharmacological interventions (e.g., physical restraints, noise reduction, and mobilization), might have affected the clinical outcomes [2, 64, 65]. It is challenging to control noise in the ICU because of many factors, such as new patients’ entry, monitor alarms, and healthcare personnel discussions. During the COVID-19 outbreak, the limitation on family visits might have resulted in increased delirium [59, 60, 61]. Nevertheless, although the improvement of secondary clinical outcomes in our study was not statistically significant in the gabapentin group, all clinical outcomes tended to be better in critically ill patients who received gabapentin.