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. 2023 Feb 19;38(7):657–667. doi: 10.1177/08850666231156782

Influence of Deep Sedation in Intensive Care Medicine Memories of Critical COVID-19 Survivors

A Braga 1,✉, S Martins 2,3, A R Ferreira 2,3, J Fernandes 1, T Vieira 1, L Fontes 1, I Coimbra 1, L Fernandes 2,3,4, J A Paiva 1,5
PMCID: PMC9941006  PMID: 36803155

Abstract

Introduction: Critical care survivors sustain a variety of sequelae after intensive care medicine (ICM) admission, and the Coronavirus Disease 2019 (COVID-19) pandemic has added further challenges. Specifically, ICM memories play a significant role, and delusional memories are associated with poor outcomes post-discharge including a delayed return to work and sleep problems. Deep sedation has been associated with a greater risk of perceiving delusional memories, bringing a move toward lighter sedation. However, there are limited reports on post-ICM memories in COVID-19, and influence of deep sedation has not been fully defined. Therefore, we aimed to evaluate ICM-memory recall in COVID-19 survivors and their relation with deep sedation. Materials/Methods: Adult COVID-19 ICM survivors admitted to a Portuguese University Hospital between October 2020 and April 2021 (second/third “waves”) were evaluated 1 to 2 months post-discharge using “ICU Memory Tool,” to assess real, emotional, and delusional memories. Results: The study included 132 patients (67% male; median age = 62 years, Acute Physiology and Chronic Health Evaluation [APACHE]-II = 15, Simplified Acute Physiology Score [SAPS]-II = 35, ICM stay = 9 days). Approximately 42% received deep sedation (median duration = 19 days). Most participants reported real (87%) and emotional (77%) recalls, with lesser delusional memories (36.4%). Deeply sedated patients reported significantly fewer real memories (78.6% vs 93.4%, P = .012) and increased delusional memories (60.7% vs 18.4%, P < .001), with no difference in emotional memories (75% vs 80.4%, P = .468). In multivariate analysis, deep sedation had a significant, independent association with delusional memories, increasing their likelihood by a factor of approximately 6 (OR = 6.274; 95% confidence interval = 1.165-33.773, P = .032), without influencing real (P = .545) or emotional (P = .133) memories. Conclusions: This study contributes to a better understanding of the potential adverse effects of deep sedation on ICM memories in critical COVID-19 survivors, indicating a significant, independent association with the incidence of delusional recalls. Although further studies are needed to support these findings, they suggest that strategies targeted to minimize sedation should be favored, aiming to improve long-term recovery.

Keywords: COVID-19, critical care, memories, sedation, follow-up studies

Introduction

Survivors of critical illness are known to sustain a variety of sequelae following intensive care medicine (ICM) admission, which may significantly hinder everyday activities, self-care, and well-being, potentially impacting post-ICM quality of life (QoL) and long-term outcomes.1–3 These sequelae, which may be related to acute illness or critical care treatments, can range from physical to emotional impairments, including weakness, pain, delirium, sleep, and memory disturbance. 1 Notably, increased awareness of the potential impacts of critical illness and care has emerged with the Coronavirus Disease 2019 (COVID-19) pandemic.4,5 COVID-19 mainly affects the respiratory system and, although it is generally a mild-to-moderate illness, approximately 5% to 15% of patients may develop severe disease, having prompted a sudden rise in ICM admissions.6–8 In particular, the COVID-19 pandemic has added further challenges to care by augmenting the number of patients requiring prolonged ICM stays with exposure to mechanical ventilation, sedation, and reduced mobility, contributing to an increase in the burden of risk factors for post-intensive care syndrome (PICS).9,10 PICS is increasingly recognized and encompasses physical, psychological, or cognitive constraints persisting following an ICM stay.11–14 Although its exact prevalence is unknown, reports have previously described an increased frequency of PICS in critical COVID-19 survivors in comparison to non-COVID-19 patients.10,15 Furthermore, a number of critical COVID-19 survivors demonstrate persisting adverse lung abnormalities at post-discharge follow-up,16–20 and the newly described “long COVID” syndrome may clinically overlap and compound such manifestations, further precluding patient recovery.21,22

In this regard, impairment in a mental domain has been increasingly acknowledged as an underrecognized, yet prevalent problem, potentially influencing patient recovery.23,24 Remarkably, with advances in critical care, a growing number of ICM survivors has emerged demonstrating greater psychological morbidity and utilization of healthcare resources compared with matched controls, which needs to be addressed with priority. 1 In this regard, ICM memories play a significant role, and their routine assessment during follow-up consultations is paramount to appraise ICM sequelae. Patients often sustain unpleasant, fearful experiences during ICM stay, some of which unrealistic or distorted, and recollection of events and emotions, such as being connected to tubes, an unfamiliar environment, and inability to communicate, can be stressful and durable following discharge.25–30 Conversely, lack of any memory of ICM events has also been reported to be detrimental to optimal post-discharge outcomes.31,32 Three distinct categories of ICM memories are commonly described, namely factual, delusional, and emotional memories.24,31 Factual memories are the recall of real events that occurred during the ICM stay, while emotional memories consist of recalling patient's feelings (eg, fear, anxiety). The proportion of ICM survivors reporting these 2 types varies considerably among studies, ranging between 9% and 88%. 26 Several studies suggest a protective effect of factual ICM memories on the development of chronic stress disorders including post-traumatic stress disorder (PTSD)-related symptoms.26,32 On the other hand, delusional memories comprise the recall of unreal events such as nightmares, hallucinations, or persecutory delusions, and their frequency is also highly variable in the literature, with estimates ranging between 20% and 48% of patients involved.25–27 Delusional memories represent a source of discomfort and anxiety and have been associated with poor outcomes, such as delayed return to work, sleep problems, and PTSD-related symptoms.24–27,31,33

Exposure to deep sedation is a well-described risk factor for PICS,9,14 and its maintenance tends to parallel requirements for ongoing critical care supports. Accordingly, deep sedation has been associated with a greater risk of perceiving delusional memories,25,27,29,31 bringing a move toward lighter sedation in recent years. Memory impairment in the context of the COVID-19 pandemic is becoming an increasing concern, considering that COVID-19 is a multiorgan disease with a range of neuropsychiatric manifestations, with previous estimates suggesting that 34% of patients may present persistent neurological or psychiatric symptoms in the following 6 months, and as much as 46% in post-ICM patients. 34 Such psychological impact is particularly significant since the COVID-19 pandemic carried a number of important emotional difficulties, namely isolation from families and constraints in communication due to personal protective equipment.

There are limited reports on post-ICM memories in COVID-19 survivors in the literature, with conflicting results. Specifically, in the context of COVID-19, a large cohort study examining self-reported memory problems at 8 months post-infection in patients experiencing mild disease indicated a higher prevalence of memory problems in this group than in control group of non-COVID patients. 35 Conversely, another cohort study evaluating post-discharge outcomes at 8 weeks after non-severe COVID-19 hospitalization reported some evidence of memory impairment in only 33% patients. 36 On the other hand, in the context of severe disease, 2 additional small-sized observational studies assessing ICM memory subtypes at 3 months post-infection suggested an elevated frequency of recall of delusional memories in this population of nearly 50% to 57%, which could influence long-term recovery.37,38 Another recent study that included critical COVID-19 survivors indicated an association between the presence of depressive/anxiety symptoms and the recall of emotional and delusional memory categories. 39 Nevertheless, there is still a paucity of data on the full range of long-term post-ICM memories in critical COVID-19 survivors, and influence of deep sedation has not been fully defined. Therefore, we aimed to evaluate ICM-memory recall in critical COVID-19 survivors at follow-up ICM consultation as well as their main determinants, with an emphasis on their relation with exposure to deep sedation.

Materials and Methods

Study Design and Participants

This study consisted of a single-center, prospective observational analysis with the aim to evaluate ICM memories in critical COVID-19 survivors, as well as to examine their relation with different clinical variables as potential predictors including exposure to deep sedation. Adult COVID-19 ICM survivors (≥18 years old) admitted to the Intensive Care Medicine Department of a Portuguese University Hospital [Centro Hospitalar Universitário São João (CHUSJ) in Porto, Portugal] from October 2020 to April 2021 (corresponding to the duration of the second and third COVID-19 “waves”) entered the study. Exclusion criteria were an ICM length of stay (LoS) ≤ 24 h, terminal illness, major auditory loss, or inability to communicate at the time of follow-up assessment. The present study was conducted as part of an ongoing larger multidisciplinary prospective COVID-19 research project (MAPA: “Mental Health in Critically ill patients with COVID-19: Implementation of an active monitoring program and post-discharge support”). As this was an observational study exploring outcomes related to a novel pandemic disease, no specific sample size was predefined, and all eligible patients were recruited. This study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for reporting observational studies. 40

Data Collection

Patients were evaluated by telephone appointment, 1 to 2 months after home discharge, in a scheduled ICM consultation, which includes a multidisiciplinary staff with intensivists, a specialized follow-up ICM nurse, and a clinical psychologist.

Baseline sociodemographic and clinical characteristics of critically ill COVID-19 survivors were obtained from electronic clinical records and semistructured clinical interviews and included age, sex, past medical history (Charlson Comorbidity Index) and psychotropic medication. In-hospital data were also collected, including acute illness severity scores [Acute Physiology and Chronic Health Evaluation II (APACHE-II) and Simplified Acute Physiology Score (SAPS-II)], ICM and hospital LoS, analgo-sedative medication, respiratory supports required, and major ICM complications (including delirium, nosocomial infection and difficult weaning from mechanical ventilation). All patients had laboratory confirmation of SARS-CoV-2 infection by real-time PCR methods.

Regarding sedative medication, deep sedation was defined as the use of continuous infusion of propofol and/or midazolam resulting in a sedation level corresponding to a Richmond Agitation-Sedation Scale (RASS) score of −4 or −5 as reviewed in daily clinical records, whereas light sedation consisted of the use of continuous infusion of dexmedetomidine and/or remifentanil resulting in a RASS score of −1 to −3.

ICM Memory Assessment

In order to assess the participants’ ICM memories, the “ICU Memory Tool” was used, which is a validated instrument that is available for intensive care clinicians and nurses to be used during follow-up ICM consultation. 41 It has a checklist design and categorizes ICM memories into factual, emotional, and delusional subtypes. Factual memories consist of recollections of real events that occurred during ICM stay, either related to treatment (eg, nasal and oral tubes, aspiration) or the environment (eg, visits from relatives, noise). Emotional memories consist of recollections related to feelings (eg, anxiety, pain, confusion). Delusional memories are the recall of unreal events (eg, nightmares, hallucinations). During post-ICM follow-up consultation, participants were comprehensively evaluated by a multidisciplinary staff regarding their overall health condition, and recollections relative to their stay in the ICM were appraised using the “ICU Memory Tool.”

Statistical Analysis

Descriptive statistics are expressed in tables as raw frequencies and percentages for categorical variables and as median and interquartile range (IQR) values for continuous variables. Missing data for individual clinical variables were imputed using clinical imputation rules when appropriate.

Participants were divided into 2 groups according to their exposure to deep sedation during their ICM stay (deeply sedated vs non-deeply sedated). For analysis of the statistical difference between groups, nonparametric tests were used because sample normality could not be assumed. The Mann-Whitney test was used to compare differences between 2 independent groups when the dependent variable was continuous, while the Chi-square and the Fisher exact tests were used for paired categorical variables, at a significance level of <.05. All tests were 2 sided.

Variables with a statistically significant association with each ICM memory recall category were identified in bivariate analysis and were entered in multivariate analysis. Multiple logistic regression models were tested for the identification of clinical variables independently associated with ICM memory recall. All statistical analyses were performed using the Statistical Package for the Social Sciences Version 24.0 for Windows software (SPSS, Inc.).

Ethical Considerations

This study was approved by the Ethics Committee for Health of Centro Hospitalar Universitário São João and Faculty of Medicine of Porto—CHUSJ/FMUP (authorization number 218/2020, date: 06/05/2020). This project was conducted in accordance with the ethical principles of the Declaration of Helsinki. Given the contingencies and procedures adopted due to the pandemic, informed consent was obtained verbally and registered in the clinical record. Confidentiality issues were observed with regard to data collection, storage, and analysis.

Results

The present study included 132 survivors of critical COVID-19 admitted to the ICM of CHUSJ, and their baseline demographic and clinical characteristics are detailed in Table 1.

Table 1.

Baseline Sociodemographic and Clinical Characteristics of Critically Ill COVID-19 Survivors (n = 132).

Total (n = 132) Deep Sedation (n = 56, 42.4%) Non-deep Sedation (n = 76, 57.6%) P Value
Male gender, n (%) 88 (66.7%) 37 (66.1%) 51 (67.1%) .901a
Age (years, median [IQR]) 62 (53.3-70.8) 59.5 (52-70) 63.5 (55.3-72.5) .141b
Charlson Comorbidity Index, median (IQR) 3 (1-4) 2.5 (1-4) 3 (2-4) .200b
Previous psychotropic medications, n (%) 43 (32.6%) 22 (40%) 21 (28.8%) .183a
APACHE-II, median (IQR) 15 (12-20) 17 (13-23) 14 (11.3-17) .002b
SAPS-II, median (IQR) 35 (27-43) 37 (29-54) 33 (26-38) .003b
ICM LoS (days, median [IQR]) 9 (4-25) 31.5 (14-51.5) 5 (3.3-8.8) <.001b
Hospital LoS (days, median [IQR]) 22.5 (12-44) 49.5 (26.3-111.3) 15 (11-24.5) <.001b
IMV, n (%) 57 (43.2%) 56 (100%) 1 (1.3%) <.001a

  • - Duration of IMV (days, median [IQR])

 27.5 (13.3-47.5) 19 (10-38.3) - -
ECMO, n (%) 20 (15.2%) 19 (33.9%) 1 (1.3%) <.001a

  • - Duration of ECMO (days, median [IQR])

 19.5 (8.5-47) 22 (8-47) 10 .600b
Deep sedation, n (%) 56 (42.4%) - - -

  • - Duration of deep sedation (days, median [IQR])

 19 (10-38.3) - - -
Sedation with benzodiazepines, n (%) 42 (31.8%) - - -

  • - Duration of benzodiazepine exposure (days, median [IQR])

 11 (4.5-28.5) - - -
Light sedation, n (%) 79 (59.8%) - - -

  • - Duration of light sedation (days, median [IQR])

 7 (4-12.5) - - -
Delirium, n (%) 27 (20.5%) 24 (42.9%) 3 (3.9%) <.001a
Nosocomial infection, n (%) 55 (41.7%) 46 (82.1%) 9 (11.8%) <.001a

  • - Ventilator-associated pneumonia

 45 (34.1%) 45 (80.4%) 0 <.001a

  • - Urinary tract infection

 21 (15.9%) 16 (28.6%) 5 (6.6%) .001a

  • - Bacteremia

 21 (15.9%) 17 (30.4%) 4 (5.3%) <.001a
Tracheostomy, n (%) 32 (24.2%) 32 (57.1%) 0 <.001a
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Abbreviations: APACHE-II, Acute Physiology and Chronic Health Evaluation II; COVID-19, Coronavirus Disease 2019; ECMO, extracorporeal membrane oxygenation; ICM, intensive care medicine; IMV, invasive mechanical ventilation; IQR, interquartile range; LoS, length of stay; SAPS-II, Simplified Acute Physiology Score II.

a

Chi-Square independent test.

b

Mann-Whitney test.

For the overall sample, 67% of patients were male, with a median age of 62 years (IQR 53.3-70.8). Concerning past medical conditions, participants had a median Charlson Comorbidity Index of 3, and 33% of patients were under psychotropic medications before admission.

Regarding ICM severity scores, the median APACHE II score was 15 (IQR 12-20), and the median SAPS II score was 35 (IQR 27-43). The median ICM and hospital LoS were 9 and 22.5 days, respectively.

Approximately 43% of patients required invasive mechanical ventilation (IMV), with a median duration of 27.5 days (IQR 13.3-47.5), while 15% needed salvage therapy with extracorporeal membrane oxygenation (ECMO), with a median duration of 19.5 days.

About 42% of patients had exposure to deep sedation, with a median duration of 19 days (IQR 10-38.3), including nearly 32% of patients who received sedation with continuous infusion of benzodiazepines. Conversely, almost 60% of patients received light sedation as part of their sedation strategy, with a median duration of 7 days (IQR 4-12.5).

In terms of ICM complications, the frequency of delirium in the present sample was 20.5%. Nearly 42% of patients sustained a nosocomial infection during the course of their ICM stay, the most common being ventilator-associated pneumonia (34.1%). Additionally, 24% of patients required tracheostomy as part of the weaning strategy.

Baseline demographic and clinical characteristics of critical COVID-19 survivors were evenly distributed among study sample, and no substantial differences between patients exposed and not exposed to deep sedation emerged, apart from the expected greater frequency of increased ICM scores and extended LoS as well as IMV and ECMO use in those exposed to deep sedation (P < .05) (Table 1).

Table 2 describes the recall of ICM memory types in critically ill COVID-19 survivors according to the “ICU Memory Tool,” as well as the differences among ICM memory recall between patients exposed or not exposed to deep sedation.

Table 2.

Influence of Deep Sedation in ICM Memory Recall in Critically Ill COVID-19 Survivors (n = 132).

Total (n = 132) Deep Sedation (n = 56, 42.4%) Non-deep Sedation (n = 76, 57.6%) P Valuea
Recall of ICM memories, n (%) 116 (87.9%) 45 (80.4%) 71 (93.4%) .023
Recall of Real Memories, n (%) 115 (87.1%) 44 (78.6%) 71 (93.4%) .012

  • - Family visiting

 41 (31.1%) 29 (51.8%) 12 (15.8%) <.001

  • - Alarms

 98 (74.2%) 35 (62.5%) 63 (82.9%) .008

  • - Voices

 113 (85.6%) 42 (75%) 71 (93.4%) .003

  • - Lights

 101 (76.5%) 34 (60.7%) 67 (88.2%) <.001

  • - Faces

 113 (85.6%) 42 (75%) 71 (93.4%) .003

  • - Breathing tube

 30 (22.7%) 24 (42.9%) 6 (7.9%) <.001

  • - Suctioning

 12 (9.1%) 12 (21.4%) 0 <.001

  • - Darkness

 89 (67.4%) 29 (51.8%) 60 (78.9%) .001

  • - Clock

 25 (18.9%) 12 (21.4%) 13 (17.1%) .531

  • - Tube in your nose

 78 (59.1%) 30 (53.6%) 48 (63.2%) .268

  • - Ward round

 113 (85.6%) 42 (75%) 71 (93.4%) .003
Recall of Emotional Memories, n (%) 102 (77.3%) 45 (80.4%) 57 (75%) .468

  • - Being uncomfortable

 58 (43.9%) 30 (53.6%) 28 (36.8%) .056

  • - Feeling confused

 48 (36.4%) 33 (58.9%) 15 (19.7%) <.001

  • - Feeling down

 65 (49.2%) 32 (57.1%) 33 (43.4%) .119

  • - Feeling anxious/frightened

 80 (60.6%) 38 (67.9%) 42 (55.3%) .143

  • - Panic

 11 (8.3%) 7 (12.5%) 4 (5.3%) .202

  • - Pain

 31 (23.5%) 14 (25%) 17 (22.4%) .724
Recall of Delusional Memories, n (%) 48 (36.4%) 34 (60.7%) 14 (18.4%) <.001

  • - Feeling that people were trying to hurt you

 14 (10.6%) 13 (23.2%) 1 (1.3%) <.001

  • - Hallucinations

 20 (15.2%) 16 (28.6%) 4 (5.3%) <.001

  • - Nightmares

 30 (22.7%) 22 (39.3%) 8 (10.5%) <.001

  • - Dreams

 25 (18.9%) 18 (32.1%) 7 (9.2%) .001
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Abbreviations: COVID-19, Coronavirus Disease 2019; ICM, intensive care medicine.

a

Chi-square independent test.

Most participants (approximately 88%) have reported at least one memory category, mostly for real events (87%) and emotional recalls (77%), with a lower frequency of delusional memories (36.4%). ICM memory recall was significantly higher in nondeeply sedated patients (93.4% vs 80.4%, P = .023). Additionally, deeply sedated patients reported significantly fewer real memories (78.6% vs 93.4%, P = .012) and more delusional memories (60.7% vs 18.4%, P < .001). Specifically, a variety of real memory subtypes were significantly more frequent in nondeeply sedated patients, including recall for alarms, voices, lights, faces, darkness, and ward round (all P < .05). Recollection of receiving family visiting occurred significantly more frequently in the deeply sedated group (P < .05), in comparison to nondeeply sedated patients. All delusional memory subtypes were significantly more frequent in patients exposed to deep sedation (P ≤ .001). No difference was encountered for recall of emotional memories (75% vs 80.4%, P = .468), although the confusion was more prevalent in the deeply sedated group (P < .001).

In order to investigate the influence of deep sedation in the recall of ICM memories in critical COVID-19 survivors, we attempted to control for other associated factors (apart from deep sedation) that could influence the incidence of ICM memories. Table 3 depicts individual variables that demonstrated significant association with ICM memory recall in bivariate analysis.

Table 3.

Individual Variables Demonstrating Association With ICM Memory Recall in Bivariate Analysis.

Recall of Real Memories Recall of Emotional Memories Recall of Delusional Memories
Yes (n = 115) No (n = 17) P Value Yes (n = 102) No (n = 30) P Value Yes (n = 48) No (n = 84) P Value
Male gender, n (%) 75 (65.2%) 13 (76.5%) .358a 65 (63.7%) 23 (76.7%) .186a 28 (58.3%) 60 (71.4%) .125a
Age [years, median (IQR)] 61 (53-68) 73 (55.5-76.5) .014b 60 (53-67.3) 69,5 (59.8-76.3) .004b 58.5 (51.5-67.8) 63.5 (54.3-73) .059b
Charlson Comorbidity Index, median (IQR) 3 (1-4) 4 (2.5-5) .072b 3 (1-4) 3 (2-5) .060b 2.5 (1-4.8) 3 (2-4) .512b
Previous psychotropic medications, n (%) 36 (32.1%) 7 (43.8%) .358a 33 (33.3%) 10 (34.5%) .908a 20 (42.6%) 23 (28.4%) .102a
APACHE-II, median (IQR) 15 (12-20) 16 (11.5-21.5) .943b 15 (12-20) 15 (11-19.3) .752b 15 (12-22) 15 (12-18.8) .327b
SAPS-II, median (IQR) 35 (26-41.5) 39 (32-46.5) .137b 35 (26-40.5) 35 (32.5-43) .186b 36 (28-41) 34 (26.3-43) .354b
ICM LoS [days, median (IQR)] 8 (4-17) 38 (11.5-56) <.001b 9 (5-20.5) 7 (4-45.5) .794b 15 (6.5-37) 7 (4-11.8) <.001b
Hospital LoS [days, median (IQR)] 21 (12-40) 56 (28-158) <.001b 23 (12-43) 22 (12-124.3) .767b 40 (21.3-59.8) 16.5 (11-31.5) <.001b
IMV, n (%) 45 (39.1%) 12 (70.6%) .015a 45 (44.1%) 12 (40%) .689a 34 (70.8%) 23 (27.4%) <.001a

  • - Duration [days, median (IQR)]

 20 (10.3-44) 43.5 (29.3-55.3) .013b 23 (10.5-44) 46 (30-57) .011b 24 (12.8-45.3) 32.5 (12.3-48.5) .687b
Deep sedation 44 (38.3%) 12 (70.6%) .012a 45 (44.1%) 11 (36.7%) .468a 34 (70.8%) 22 (26.2%) <.001a

  • - Duration [days, median (IQR)]

 15 (8.3-26.8) 33 (21.5-48.5) .009b 15 (8.5-26.5) 36 (23-49) .004b 17.5 (9.8-28.3) 22 (10.3-43.3) .551b
Sedation with Benzodiazepines 31 (27%) 11 (64.7%) .002a 32 (31.4%) 10 (33.3%) .839a 27 (56.3%) 15 (17.9%) <.001a

  • - Duration [days, median (IQR)]

 8 (4-29) 25.5 (8.5-35) .244b 9 (4.3-27.8) 26 (8-42) .202b 8.5 (3.3-22) 26 (7-39.5) .094b
Light sedation 65 (57%) 14 (82.4%) .046a 61 (60.4%) 18 (60%) .969a 39 (81.3%) 40 (48.2%) <.001a

  • - Duration [days, median (IQR)]

 6 (3-11) 8 (4-26) .248b 7 (3.3-11) 6 (4-14.5) 1b 9.5 (4-20.8) 5.5 (3-9) .023b
Delirium, n (%) 20 (17.4%) 7 (41.2%) .023c 19 (18.6%) 8 (26.7%) .337a 15 (31.3%) 12 (14.3%) .020a
Nosocomial Infection, n (%) 45 (39.1%) 10 (58.8%) .124a 45 (44.1%) 10 (33.3%) .292a 30 (62.5%) 25 (29.8%) <.001a
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Abbreviations: APACHE-II, Acute Physiology and Chronic Health Evaluation II; ICM, intensive care medicine; IMV, invasive mechanical ventilation; IQR, interquartile range; LoS, length of stay; SAPS-II, Simplified Acute Physiology Score II.

a

Chi-square independent test.

b

Mann-Whitney test.

c

Fisher exact test.

As illustrated in Table 3, the frequency of recall of real memories was significantly reduced in elderly patients (P = .014), patients with exposure to any sedation (deep sedation P = .012, including benzodiazepine use P = .002, and light sedation P = .046) or IMV (P = .015), as well as patients with prolonged ICM/hospital LoS (P < .001 and P < .001, respectively) and duration of deep sedation (P = .009) and IMV (P = .013), and patients with delirium during ICM stay (P = .023). Moreover, the frequency of recall of emotional memories was significantly increased in patients with younger age (P = .004), as well as the reduced duration of deep sedation (P = .011) and IMV (P = .004). Conversely, the frequency of recall of delusional memories was significantly increased in patients with exposure to any sedation (deep sedation P < .001, including benzodiazepine use P < .001, and light sedation P < .001) or IMV (P < .001), as well as patients with prolonged ICM/hospital LoS (P < .001 and P < .001, respectively) and duration of light sedation (P = .023), and patients with delirium (P = .020) or nosocomial infection (P < .001) during ICM stay.

Table 4 indicates variables that were entered in multivariate analysis, which included variables demonstrating an association with each ICM memory category in bivariate analysis, along with variables related to deep sedation (namely, “Deep Sedation” or “Duration of Deep Sedation”), in order to evaluate the presence of a significant, independent contribution of deep sedation to the incidence of ICM memories (Table 4).

Table 4.

Multiple Logistic Regression Models for Identification of Clinical Variables Independently Associated With ICM Memory Recall in Critically Ill COVID-19 Survivors.

OR 95% CI P Value
Recall of real memories
Deep sedation 1.675 0.315-8.915 .545
Age (years) 0.934 0.884-0.986 .014
ICM LoS (days) 0.982 0.961-1.003 .095
Delirium 2.968 0.756-11.658 .119
Recall of emotional Memories
Duration of deep sedation (days) 0.983 0.962-1.005 .133
Age (years) 0.938 0.877-1.003 .062
Recall of delusional memories
Deep sedation 6.274 1.165-33.773 .032
ICM LoS (days) 0.963 0.927-1.001 .054
Sedation with benzodiazepines 4.171 0.758-22.95 .101
Light sedation 1.056 1.000-1.116 .050
Delirium 1.166 0.365-3.732 .795
Nosocomial infection 0.399 0.072-2.225 .295
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Abbreviations: CI, confidence interval; COVID-19, coronavirus disease 2019; ICM, intensive care medicine; LoS, length of stay; OR, odds ratio.

After controlling for other potentially associated confounding factors using the logistic regression model, deep sedation or its duration did not independently influence the likelihood of recall of real or emotional memories (P = .545 and P = .133, respectively), whereas the odds of recalling delusional memories were significantly increased for those who were deeply sedated (OR = 6.274; 95% confidence interval (CI) = 1.165-33.773, P = .032).

Discussion

In a sample of 132 critical COVID-19 survivors admitted to an ICM Department of a Portuguese University Hospital, most participants describe at least one memory category 1 to 2 months post-hospital discharge. This is an important finding because the lack of any memory of ICM events has previously been reported to be detrimental to long-term post-discharge outcomes. 31 Memory types most commonly described included memories of real events and emotions, with fewer reports of delusional memories. These results are consistent with the recent data thus far available from critical COVID-19 survivors37–39 and are also in agreement with previous studies assessing the prevalence of post-discharge ICM memory types in non-COVID critically ill populations, although their frequency varies considerably in the literature.25–27,31

The results from this study indicate that exposure to deep sedation had an impact on the incidence of ICM memories in critical COVID-19 survivors. In this regard, deeply sedated patients reported significantly less often real memories (P = .012) and more frequently delusional memories (P < .001). Delusional memories constitute the recall of unpleasant, fearful unreal experiences during ICM stay, such as nightmares and hallucinations, that have previously been associated with suboptimal long-term patient outcomes.26,27,33,42,43 Prominently, the results from this study indicate that deep sedation had a significant, independent association with the incidence of delusional ICM memories, increasing their likelihood by more than 6 times (OR = 6.274; 95% CI = 1.165-33.773, P = .032). This was the most distinct finding arising from this study and is in line with earlier non-COVID ICM-memory studies27,31 as well as recent available data from critical COVID-19 survivors, which have described a significant rate of recall of delusional memories in this population, with reported estimates ranging from 50% to 57%.37,38

Accumulating evidence also points to a possible contribution of the presence of real memories for preventing the development of chronic stress-related symptoms.26,32 In this study, deep sedation did not independently influence the recall of real or emotional memories. Still, recollection of real memories was less frequent in patients exposed to any level of sedation in bivariate analysis (deep sedation P = .012, including benzodiazepine use P = .002, and light sedation P = .046). However, these results failed to detect an independent, significant association for this memory category, which has formerly been proposed as a protective role against poor long-term post-ICM outcomes,26,32 suggesting that these memories may not be primarily dependent on exposure to deep sedation. Rather, in our multivariate analysis, younger age has been noted as an independent contributor to the recall of factual memories.

To our knowledge, the present study was the first to evaluate post-discharge ICM memories in critical COVID-19 survivors and to investigate clinical predictors of an increased risk of different memory categories, with an emphasis on the role of deep sedation. Previous studies analyzing post-discharge memories in COVID-19 survivors have primarily focused on describing the prevalence of memory impairments in this group.35–38 Yet, whether sedation was an independent predictor of detrimental ICM memory categories linked to unfavorable outcomes had not been previously ascertained, and our study provides novel insights for a better understanding of the potential adverse effects stemming from exposure to sedation during ICM admission. This suggests that strategies targeted to minimize sedation during ICM stay should be favored. In fact, this evolving principle is reflected in the broader concept of the ICU liberation bundle [Awakening, Breathing trials, Coordination with daily sedation interruption and ventilator liberation practices, Delirium monitoring and management, Early Mobility, and Family empowerment and engagement (ABCDEF)], which has been associated with improved results in critically ill patients, including shorter lengths of ICM stay and IMV, as well as lower risk of PICS.44,45 In particular with regards to ICM memories, healthcare providers should not only advocate deep sedation interruption and awakening practices that are currently recommended44,45 but also adhere to strategies aimed at reinforcing factual memories, including elucidation of procedures, patient reassurance, promotion of a peaceful, noncrowded environment with the presence of relatives, and avoidance of physical restraints and sleep deprivation, the latter of which may further impair memory consolidation and contribute to delusional recalls. Indeed, our ICM Department has a formal sedation and analgesia protocol aiming to improve daily assessment and management. However, challenges have emerged with the COVID-19 pandemic, and a variety of routine measures may be unfeasible in this population, uniquely exposed to isolation resulting from restricted visiting as well as difficulties in communication due to the use of protective equipment, which still needs to be further addressed.

In this study, we assessed ICM memories of critical COVID-19 survivors and their main determinants, with an emphasis on exposure to sedation. Furthermore, the results from this study also indicated an influence from other clinical variables in the recall of ICM memories in these patients. These variables were, then, entered into multiple logistic regression model to evaluate for a significant, independent association with each ICM memory category, and a number of predictors could be highlighted from this analysis. In particular, the frequency of recall of real memories was significantly reduced in elderly patients (P = .014), as well as in patients with prolonged ICM LoS (P < .001), with the former relation reaching an independent association in multivariate analysis (P = .014) and the latter revealing a comparable trend (P = .095). Conversely, the recall of emotional memories was significantly increased in patients with younger age (P = .004), nearing independency of the association in our multiple logistic regression analysis (P = .062). Moreover, the frequency of recall of delusional memories was significantly increased in patients with prolonged ICM LoS (P < .001), and the association again approximated independency in multivariate analysis (P = .062). The remaining associations tested in the multivariate analysis did not approach significantly in this study. Together, these results are in line with the available data thus far from non-COVID critically ill patients indicating a tendency toward a reduction in potentially protective recalls and increase in detrimental ICM-memory subtypes with increasing age, as well as after a prolonged ICM stay.26,27,31

In addition, to our knowledge, this study was the first to comprehensively assess post-discharge ICM memories in critical COVID-19 survivors using a robust, reproducible, and validated scale, the ICU Memory Tool, to appraise ICM memories during the recovery period. This instrument was administered as part of a multidisciplinary post-ICM follow-up evaluation that includes a battery of different health-related questionnaires, and its consistent use has been increasingly reported in the literature concerning post-ICM sequelae. 41

An additional strength of this study is that key baseline demographic and clinical characteristics from the sample were evenly distributed among patients exposed and not exposed to deep sedation, thereby reducing the potential for selection bias. The exception to this was the expected greater frequency of increased ICM scores and ICM LoS, as well as the use of critical care respiratory support in patients exposed to deep sedation, which are known features of severe disease.

In addition, our sample included a total of 132 critical COVID-19 survivors, which corresponds to the entire critical COVID-19 population admitted to our ICM Department during the study time frame. Despite this consecutive recruitment of patients, the sample size did not allow for further analysis of the distribution of specific memory subtypes in each of the 3 memory categories, and additional investigation involving larger sample sizes should be a future research venue.

An added value from the methodological design of this study was the generation of multivariate models during statistical analysis, which allowed for the identification of clinical variables that were independently associated with ICM memory recall. Importantly, for consistency in determining clinical variables entering multivariate analysis, individual factors demonstrating an association with each ICM memory category in bivariate analysis were enrolled, and different compositions were tested to derive the logistic regression models.

Our study has several limitations that warrant consideration. First, the single-center design of the study limits the extent to which data can be extrapolated from these results. Nevertheless, it is worth noting that our ICM Department constitutes the regional referral center for higher-complexity, tertiary care in the Northern region of Portugal, which widens the clinical spectrum of patients included in the sample. Second, data on ICM memory recall in this study were collected at 1 to 2 months post-discharge, and it will be useful in the future to address ICM experience by critical COVID survivors at long-term follow-up. Finally, future analyses of this study population may benefit from the inclusion of a control group of non-COVID age-matched patients. In fact, in comparison to the general non-COVID population, SARS-CoV-2 infection itself has previously been hypothesized to directly account for a range of neuropsychiatric manifestations,46–49 and future efforts may be directed to address a specific role in ICM memory impairment in the context of critical COVID-19.

Important implications for clinical practice may be derived from the present findings. This study contributed to identifying post-discharge ICM memories in critical COVID-19 survivors and raises awareness of the role of deep sedation, which increased the likelihood of developing delusional memories by a factor of approximately 6, independent of other relevant clinical variables also known to impact these memories. Therefore, one of the key messages of this study is the urgent need to adhere to strategies aimed at minimizing deep sedation and promoting the use of light sedation during ICM stay, under the framework of the ABCDEF liberation bundle.44,45

Conclusion

In a sample of 132 critical COVID-19 survivors, memory types mostly described included memories for real events and emoticons, with fewer reports of delusional memories. Deep sedation has a significant and independent association with the incidence of delusional ICM memories, increasing the likelihood of developing delusional memories by a factor of approximately 6, which is consistent with previous evidence derived primarily from earlier non-COVID ICU-memory studies.

Our study provides new data for a better understanding of the potential adverse effects of exposure to sedation during ICM admission, suggesting that strategies targeted to minimize sedation during ICM stay and adoption of the concept of ABCDEF liberation bundle should be favored. The post-ICM COVID-19 population is remarkably complex, bearing a need for extended support from professionals, and such findings provide a unique opportunity to encourage the design and implementation of follow-up interventions for the management of critical care sequelae, in order to support long-term recovery. Further studies are also needed to confirm these results in the population of critical COVID-19 survivors, particularly at longer-term follow-up durations, and to investigate the impact of ICM memories and exposure to deep sedation on related long-term complications of critical illness and health-related QoL, in order to help recognize patients at increased risk and provide a basis for targeted interventions.

Footnotes

Authors’ Note: António José Falcão Peres Braga: Data curation; Formal analysis; Investigation; Resources; Writing—original draft; Sónia Patrícia Vilar Martins: Investigation; Methodology; Resources; Software; Writing—review & editing; Ana Rita Leal Ferreira: Investigation; Methodology; Resources; Software; Writing—review & editing; Joana Carolina João Fernandes: Data curation; Investigation; Resources; Writing—review & editing; Tatiana dos Santos Vieira: Data curation; Investigation; Resources; Writing—review & editing; Liliana Cristina da Silva Ferreira Fontes: Investigation; Methodology; Resources; Software; Writing—review & editing; Isabel Maria Metelo Coimbra: Conceptualization; Investigation; Methodology; Project administration; Supervision; Validation; Visualization; Writing—review & editing; Lia Paula Nogueira Sousa Fernandes: Conceptualization; Investigation; Methodology; Project administration; Supervision; Validation; Visualization; Writing—review & editing; José Artur Osório Carvalho Paiva: Conceptualization; Investigation; Methodology; Project administration; Supervision; Validation; Visualization; Writing—review & editing.

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.

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