Vichaya Arunthari, MD

Study Overview

Objective. To assess whether procalcitonin-guided antibiotic usage results in less exposure to antibiotics than usual care, without a significantly higher rate of adverse events.

Design. Multi-center 1:1 randomized trial.

Setting and participants. This study was conducted at 14 academic hospitals in the United States between 2014 and 2017 in which procalcitonin assay was not routinely used. All adult patients in the emergency department with an initial diagnosis of acute lower respiratory tract infection without a decision to give or withhold antibiotics because of uncertainty regarding the need for antibiotics were included in the study. Patients were excluded if antibiotics were unlikely to be held in their case, such as if there was a need for mechanical ventilation or known severe immunosuppression, and if procalcitonin could be falsely elevated (chronic dialysis, metastatic cancer, surgery in the past 7 days).

Intervention. Patients were randomly assigned to receive guideline-based care using procalcitonin (procalcitonin group) or usual care (usual-care group). In the procalcitonin group, the procalcitonin assay results, and the procalcitonin treatment guidelines were provided to the treating physician. The guideline used previously established cutoffs (procalcitonin level of < 0.1 µg/L, antibiotics were strongly discouraged; 0.1 to 0.25 µg/L, antibiotics were discouraged; 0.25 to 0.5 µg/L, antibiotics were recommended; and > 0.5 µg/L, antibiotics were strongly recommended). Procalcitonin was measured initially in the emergency department. If the patient was hospitalized, procalcitonin was again measured 6 to 24 hours later, and on hospital days 3, 5, and 7. To implement this intervention, a multifaceted approach was used, which included sending letters to local primary care providers describing the trial, ensuring rapid delivery of procalcitonin results by tracking and coordinating blood samples with routine morning draws, and embedding the procalcitonin results and guidelines into the sites’ electronic health records. In the usual-care group, procalcitonin levels at enrollment were measured but not disclosed to clinicians. In both treatment groups, clinicians retained autonomy regarding care decisions.

Main outcome measures. The primary outcome was total antibiotic exposure, defined as the total number of antibiotic-days within 30 days after enrollment. The primary safety outcome was any adverse effects that could be attributable to withholding antibiotics in lower respiratory tract infections, within 30 days after enrollment. Secondary outcomes included admission to the intensive care unit (ICU), subsequent emergency department visits by day 30, and quality of life as assessed with the Airway Questionnaire 20.

Main results. 8360 patients with acute lower respiratory tract infection who presented to the emergency department were screened for eligibility; of these, 1664 patients underwent randomization. Ultimately, 1656 patients were included in the final analysis cohort (826 in the procalcitonin group and 830 in the usual-care group), because 8 patients withdrew. Of the cohort, 1345 (81.2%) patients completed the full 30-day follow up. Baseline characteristics were similar between the treatment groups. In the procalcitonin group, clinicians received the procalcitonin results for 95.9% of the patients. As a result of clinical care, 2.2% of the patients in the usual-care group also had procalcitonin testing. Clinicians adhered to the procalcitonin guideline recommendations for 64.8% of the procalcitonin group.

There was no significant difference in the intention-treat-treat analysis between the procalcitonin group and the usual-care group in antibiotic days during the first 30 days (mean antibiotic days, 4.2 and 4.3 days, respectively [95% confidence interval {CI}, –0.6 to 0.5; P = 0.87]). Within 30 days there was no significant difference in the proportion of patients with adverse outcomes in the procalcitonin group and usual-care group (11.7% and 13.1%, respectively [95% CI, –4.6 to 1.7]; P < 0.01 for noninferiority). There was no significant difference between the procalcitonin and usual-care groups for any of the secondary outcomes.

Conclusion. A procalcitonin-directed antibiotic administration guideline did not result in fewer antibiotic days than did usual-care among patients with suspected lower respiratory tract infection.

Commentary

Procalcitonin is a serum biomarker synthesized in thyroid neuroendocrine cells and is the precursor to calcitonin.¹ It is undetectable in healthy human serum, but in the setting of systemic inflammation caused by bacterial infection, procalcitonin synthesis is induced in many tissues. Since its discovery in 1970, procalcitonin’s potential utility has been sought in various settings, such as guiding the initiation and/or discontinuation of antibiotics.²

In a prospective randomized trial in patients with an acute chronic obstructive pulmonary disease (COPD) exacerbation, treatment success was not better with antibiotics than placebo in patients with a procalcitonin level < 0.1 µg/L.³ Others replicated these results in COPD patients with acute exacerbation of COPD.⁴ Another small randomized trial showed that using procalcitonin in intensive care patients reduced antibiotic duration.⁵ Another small study found similar results in their critical care setting.⁶ Procalcitonin-guided antibiotic treatment produced similar results in patients with aspiration pneumonia.⁷ In summary, previously published studies nearly uniformly report reduced antibiotic duration or initiation using procalcitonin cutoffs without increasing adverse events.

In the current study, Huang and colleagues conducted a multi-center randomized trial in 14 academic US hospitals, while simultaneously attempting quality improvement methods for implementing and maximizing compliance with procalcitonin guidelines for local physicians. This study was able to achieve approximately 65% compliance with the guideline, which is relatively lower than in previously reported studies using procalcitonin guidelines. This study was larger and involved more hospitals than the other studies. Interestingly, this study did not find statistically significant differences in antibiotic usage or duration between the procalcitonin group compared to the usual-care group. While this result can be partially explained by the low rate of compliance with the guideline, the result may actually reflect the real-life pattern of procalcitonin guideline usage in clinicians. These results suggest that procalcitonin-based guidelines attempting to reduce antibiotic usage and exposure may be of low value, contrasting with findings from previous studies.

The Huang et al study is well-designed, had a low rate of follow-up loss and withdrawal, was conducted mostly at urban academic hospitals that had a high level of adherence to Joint Commission pneumonia core measures, and had appropriate statistical analyses; however, several factors should be considered when applying the results of this study to clinical practice. First, the large majority (80.1%) of the study cohort had final diagnoses of a COPD exacerbation, asthma exacerbation, or acute bronchitis. These patients had a moderate degree of disease (required hospitalization in 59% of patients with a mean hospital length of stay of 5 days), but their symptoms were severe enough for the patients to present to the emergency department. Patients with a suspected nonrespiratory infection or a milder degree of infection, especially in the ambulatory care setting, may have different antibiotic prescribing patterns. Also, patients in the ambulatory care setting likely have different causal organisms of their diagnosis. Second, this study excluded patients with severe disease who required ICU admission with either septic shock or respiratory failure, patients with pre-existing diseases that placed them at high risk (eg, immunosuppressed patients), and/or patients who had complications of their infection with either a lung abscess or empyema. This pattern of exclusion was widely similar to the other previous procalcitonin studies, which shows that procalcitonin guidelines should not be applied blindly in critically ill patients, even those not requiring ICU admission. Third, patients were excluded from the study if they were on chronic dialysis, had metastatic cancer, or had a recent surgery because of possible elevation of procalcitonin levels without a bacterial infection.

In conclusion, the current study did not find any difference in antibiotic exposure throughout the course of care (including discharge or hospitalization) of patients with a lower respiratory tract infection who presented to the emergency department when a procalcitonin guideline was implemented. The results of the current study raise questions regarding the new trend of widely accepting procalcitonin-based antibiotic usage.

Applications for Clinical Practice

Procalcitonin is a relatively new marker that is released during a systemic bacterial infection. While prior studies have supported systematic use of procalcitonin-based guidelines to initiate and discontinue antibiotics in order to limit antibiotic exposure, clinicians should be mindful that a procalcitonin antibiotic guideline may be useful in specific patients and should only be used in combination with usual clinical judgment. Clinicians must also recognize the medical conditions that may falsely elevate the procalcitonin level. Most important, the procalcitonin level should not be used as the sole indication to withhold antibiotics in an otherwise appropriately indicated clinical scenario.

—Minkyung Kwon, MD, Scott A. Helgeson, MD, and Vichaya Arunthari, MD
Pulmonary and Critical Care Medicine, Mayo Clinic Florida, Jacksonville, FL

Study Overview

Objective. To assess whether procalcitonin-guided antibiotic usage results in less exposure to antibiotics than usual care, without a significantly higher rate of adverse events.

Design. Multi-center 1:1 randomized trial.

Setting and participants. This study was conducted at 14 academic hospitals in the United States between 2014 and 2017 in which procalcitonin assay was not routinely used. All adult patients in the emergency department with an initial diagnosis of acute lower respiratory tract infection without a decision to give or withhold antibiotics because of uncertainty regarding the need for antibiotics were included in the study. Patients were excluded if antibiotics were unlikely to be held in their case, such as if there was a need for mechanical ventilation or known severe immunosuppression, and if procalcitonin could be falsely elevated (chronic dialysis, metastatic cancer, surgery in the past 7 days).

Intervention. Patients were randomly assigned to receive guideline-based care using procalcitonin (procalcitonin group) or usual care (usual-care group). In the procalcitonin group, the procalcitonin assay results, and the procalcitonin treatment guidelines were provided to the treating physician. The guideline used previously established cutoffs (procalcitonin level of < 0.1 µg/L, antibiotics were strongly discouraged; 0.1 to 0.25 µg/L, antibiotics were discouraged; 0.25 to 0.5 µg/L, antibiotics were recommended; and > 0.5 µg/L, antibiotics were strongly recommended). Procalcitonin was measured initially in the emergency department. If the patient was hospitalized, procalcitonin was again measured 6 to 24 hours later, and on hospital days 3, 5, and 7. To implement this intervention, a multifaceted approach was used, which included sending letters to local primary care providers describing the trial, ensuring rapid delivery of procalcitonin results by tracking and coordinating blood samples with routine morning draws, and embedding the procalcitonin results and guidelines into the sites’ electronic health records. In the usual-care group, procalcitonin levels at enrollment were measured but not disclosed to clinicians. In both treatment groups, clinicians retained autonomy regarding care decisions.

Main outcome measures. The primary outcome was total antibiotic exposure, defined as the total number of antibiotic-days within 30 days after enrollment. The primary safety outcome was any adverse effects that could be attributable to withholding antibiotics in lower respiratory tract infections, within 30 days after enrollment. Secondary outcomes included admission to the intensive care unit (ICU), subsequent emergency department visits by day 30, and quality of life as assessed with the Airway Questionnaire 20.

Main results. 8360 patients with acute lower respiratory tract infection who presented to the emergency department were screened for eligibility; of these, 1664 patients underwent randomization. Ultimately, 1656 patients were included in the final analysis cohort (826 in the procalcitonin group and 830 in the usual-care group), because 8 patients withdrew. Of the cohort, 1345 (81.2%) patients completed the full 30-day follow up. Baseline characteristics were similar between the treatment groups. In the procalcitonin group, clinicians received the procalcitonin results for 95.9% of the patients. As a result of clinical care, 2.2% of the patients in the usual-care group also had procalcitonin testing. Clinicians adhered to the procalcitonin guideline recommendations for 64.8% of the procalcitonin group.

There was no significant difference in the intention-treat-treat analysis between the procalcitonin group and the usual-care group in antibiotic days during the first 30 days (mean antibiotic days, 4.2 and 4.3 days, respectively [95% confidence interval {CI}, –0.6 to 0.5; P = 0.87]). Within 30 days there was no significant difference in the proportion of patients with adverse outcomes in the procalcitonin group and usual-care group (11.7% and 13.1%, respectively [95% CI, –4.6 to 1.7]; P < 0.01 for noninferiority). There was no significant difference between the procalcitonin and usual-care groups for any of the secondary outcomes.

Conclusion. A procalcitonin-directed antibiotic administration guideline did not result in fewer antibiotic days than did usual-care among patients with suspected lower respiratory tract infection.

Commentary

Procalcitonin is a serum biomarker synthesized in thyroid neuroendocrine cells and is the precursor to calcitonin.¹ It is undetectable in healthy human serum, but in the setting of systemic inflammation caused by bacterial infection, procalcitonin synthesis is induced in many tissues. Since its discovery in 1970, procalcitonin’s potential utility has been sought in various settings, such as guiding the initiation and/or discontinuation of antibiotics.²

In a prospective randomized trial in patients with an acute chronic obstructive pulmonary disease (COPD) exacerbation, treatment success was not better with antibiotics than placebo in patients with a procalcitonin level < 0.1 µg/L.³ Others replicated these results in COPD patients with acute exacerbation of COPD.⁴ Another small randomized trial showed that using procalcitonin in intensive care patients reduced antibiotic duration.⁵ Another small study found similar results in their critical care setting.⁶ Procalcitonin-guided antibiotic treatment produced similar results in patients with aspiration pneumonia.⁷ In summary, previously published studies nearly uniformly report reduced antibiotic duration or initiation using procalcitonin cutoffs without increasing adverse events.

In the current study, Huang and colleagues conducted a multi-center randomized trial in 14 academic US hospitals, while simultaneously attempting quality improvement methods for implementing and maximizing compliance with procalcitonin guidelines for local physicians. This study was able to achieve approximately 65% compliance with the guideline, which is relatively lower than in previously reported studies using procalcitonin guidelines. This study was larger and involved more hospitals than the other studies. Interestingly, this study did not find statistically significant differences in antibiotic usage or duration between the procalcitonin group compared to the usual-care group. While this result can be partially explained by the low rate of compliance with the guideline, the result may actually reflect the real-life pattern of procalcitonin guideline usage in clinicians. These results suggest that procalcitonin-based guidelines attempting to reduce antibiotic usage and exposure may be of low value, contrasting with findings from previous studies.

The Huang et al study is well-designed, had a low rate of follow-up loss and withdrawal, was conducted mostly at urban academic hospitals that had a high level of adherence to Joint Commission pneumonia core measures, and had appropriate statistical analyses; however, several factors should be considered when applying the results of this study to clinical practice. First, the large majority (80.1%) of the study cohort had final diagnoses of a COPD exacerbation, asthma exacerbation, or acute bronchitis. These patients had a moderate degree of disease (required hospitalization in 59% of patients with a mean hospital length of stay of 5 days), but their symptoms were severe enough for the patients to present to the emergency department. Patients with a suspected nonrespiratory infection or a milder degree of infection, especially in the ambulatory care setting, may have different antibiotic prescribing patterns. Also, patients in the ambulatory care setting likely have different causal organisms of their diagnosis. Second, this study excluded patients with severe disease who required ICU admission with either septic shock or respiratory failure, patients with pre-existing diseases that placed them at high risk (eg, immunosuppressed patients), and/or patients who had complications of their infection with either a lung abscess or empyema. This pattern of exclusion was widely similar to the other previous procalcitonin studies, which shows that procalcitonin guidelines should not be applied blindly in critically ill patients, even those not requiring ICU admission. Third, patients were excluded from the study if they were on chronic dialysis, had metastatic cancer, or had a recent surgery because of possible elevation of procalcitonin levels without a bacterial infection.

In conclusion, the current study did not find any difference in antibiotic exposure throughout the course of care (including discharge or hospitalization) of patients with a lower respiratory tract infection who presented to the emergency department when a procalcitonin guideline was implemented. The results of the current study raise questions regarding the new trend of widely accepting procalcitonin-based antibiotic usage.

Applications for Clinical Practice

Procalcitonin is a relatively new marker that is released during a systemic bacterial infection. While prior studies have supported systematic use of procalcitonin-based guidelines to initiate and discontinue antibiotics in order to limit antibiotic exposure, clinicians should be mindful that a procalcitonin antibiotic guideline may be useful in specific patients and should only be used in combination with usual clinical judgment. Clinicians must also recognize the medical conditions that may falsely elevate the procalcitonin level. Most important, the procalcitonin level should not be used as the sole indication to withhold antibiotics in an otherwise appropriately indicated clinical scenario.

—Minkyung Kwon, MD, Scott A. Helgeson, MD, and Vichaya Arunthari, MD
Pulmonary and Critical Care Medicine, Mayo Clinic Florida, Jacksonville, FL

Study Overview

Objective. To assess whether procalcitonin-guided antibiotic usage results in less exposure to antibiotics than usual care, without a significantly higher rate of adverse events.

Design. Multi-center 1:1 randomized trial.

Setting and participants. This study was conducted at 14 academic hospitals in the United States between 2014 and 2017 in which procalcitonin assay was not routinely used. All adult patients in the emergency department with an initial diagnosis of acute lower respiratory tract infection without a decision to give or withhold antibiotics because of uncertainty regarding the need for antibiotics were included in the study. Patients were excluded if antibiotics were unlikely to be held in their case, such as if there was a need for mechanical ventilation or known severe immunosuppression, and if procalcitonin could be falsely elevated (chronic dialysis, metastatic cancer, surgery in the past 7 days).

Intervention. Patients were randomly assigned to receive guideline-based care using procalcitonin (procalcitonin group) or usual care (usual-care group). In the procalcitonin group, the procalcitonin assay results, and the procalcitonin treatment guidelines were provided to the treating physician. The guideline used previously established cutoffs (procalcitonin level of < 0.1 µg/L, antibiotics were strongly discouraged; 0.1 to 0.25 µg/L, antibiotics were discouraged; 0.25 to 0.5 µg/L, antibiotics were recommended; and > 0.5 µg/L, antibiotics were strongly recommended). Procalcitonin was measured initially in the emergency department. If the patient was hospitalized, procalcitonin was again measured 6 to 24 hours later, and on hospital days 3, 5, and 7. To implement this intervention, a multifaceted approach was used, which included sending letters to local primary care providers describing the trial, ensuring rapid delivery of procalcitonin results by tracking and coordinating blood samples with routine morning draws, and embedding the procalcitonin results and guidelines into the sites’ electronic health records. In the usual-care group, procalcitonin levels at enrollment were measured but not disclosed to clinicians. In both treatment groups, clinicians retained autonomy regarding care decisions.

Main outcome measures. The primary outcome was total antibiotic exposure, defined as the total number of antibiotic-days within 30 days after enrollment. The primary safety outcome was any adverse effects that could be attributable to withholding antibiotics in lower respiratory tract infections, within 30 days after enrollment. Secondary outcomes included admission to the intensive care unit (ICU), subsequent emergency department visits by day 30, and quality of life as assessed with the Airway Questionnaire 20.

Main results. 8360 patients with acute lower respiratory tract infection who presented to the emergency department were screened for eligibility; of these, 1664 patients underwent randomization. Ultimately, 1656 patients were included in the final analysis cohort (826 in the procalcitonin group and 830 in the usual-care group), because 8 patients withdrew. Of the cohort, 1345 (81.2%) patients completed the full 30-day follow up. Baseline characteristics were similar between the treatment groups. In the procalcitonin group, clinicians received the procalcitonin results for 95.9% of the patients. As a result of clinical care, 2.2% of the patients in the usual-care group also had procalcitonin testing. Clinicians adhered to the procalcitonin guideline recommendations for 64.8% of the procalcitonin group.

There was no significant difference in the intention-treat-treat analysis between the procalcitonin group and the usual-care group in antibiotic days during the first 30 days (mean antibiotic days, 4.2 and 4.3 days, respectively [95% confidence interval {CI}, –0.6 to 0.5; P = 0.87]). Within 30 days there was no significant difference in the proportion of patients with adverse outcomes in the procalcitonin group and usual-care group (11.7% and 13.1%, respectively [95% CI, –4.6 to 1.7]; P < 0.01 for noninferiority). There was no significant difference between the procalcitonin and usual-care groups for any of the secondary outcomes.

Conclusion. A procalcitonin-directed antibiotic administration guideline did not result in fewer antibiotic days than did usual-care among patients with suspected lower respiratory tract infection.

Commentary

Procalcitonin is a serum biomarker synthesized in thyroid neuroendocrine cells and is the precursor to calcitonin.¹ It is undetectable in healthy human serum, but in the setting of systemic inflammation caused by bacterial infection, procalcitonin synthesis is induced in many tissues. Since its discovery in 1970, procalcitonin’s potential utility has been sought in various settings, such as guiding the initiation and/or discontinuation of antibiotics.²

In a prospective randomized trial in patients with an acute chronic obstructive pulmonary disease (COPD) exacerbation, treatment success was not better with antibiotics than placebo in patients with a procalcitonin level < 0.1 µg/L.³ Others replicated these results in COPD patients with acute exacerbation of COPD.⁴ Another small randomized trial showed that using procalcitonin in intensive care patients reduced antibiotic duration.⁵ Another small study found similar results in their critical care setting.⁶ Procalcitonin-guided antibiotic treatment produced similar results in patients with aspiration pneumonia.⁷ In summary, previously published studies nearly uniformly report reduced antibiotic duration or initiation using procalcitonin cutoffs without increasing adverse events.

In the current study, Huang and colleagues conducted a multi-center randomized trial in 14 academic US hospitals, while simultaneously attempting quality improvement methods for implementing and maximizing compliance with procalcitonin guidelines for local physicians. This study was able to achieve approximately 65% compliance with the guideline, which is relatively lower than in previously reported studies using procalcitonin guidelines. This study was larger and involved more hospitals than the other studies. Interestingly, this study did not find statistically significant differences in antibiotic usage or duration between the procalcitonin group compared to the usual-care group. While this result can be partially explained by the low rate of compliance with the guideline, the result may actually reflect the real-life pattern of procalcitonin guideline usage in clinicians. These results suggest that procalcitonin-based guidelines attempting to reduce antibiotic usage and exposure may be of low value, contrasting with findings from previous studies.

The Huang et al study is well-designed, had a low rate of follow-up loss and withdrawal, was conducted mostly at urban academic hospitals that had a high level of adherence to Joint Commission pneumonia core measures, and had appropriate statistical analyses; however, several factors should be considered when applying the results of this study to clinical practice. First, the large majority (80.1%) of the study cohort had final diagnoses of a COPD exacerbation, asthma exacerbation, or acute bronchitis. These patients had a moderate degree of disease (required hospitalization in 59% of patients with a mean hospital length of stay of 5 days), but their symptoms were severe enough for the patients to present to the emergency department. Patients with a suspected nonrespiratory infection or a milder degree of infection, especially in the ambulatory care setting, may have different antibiotic prescribing patterns. Also, patients in the ambulatory care setting likely have different causal organisms of their diagnosis. Second, this study excluded patients with severe disease who required ICU admission with either septic shock or respiratory failure, patients with pre-existing diseases that placed them at high risk (eg, immunosuppressed patients), and/or patients who had complications of their infection with either a lung abscess or empyema. This pattern of exclusion was widely similar to the other previous procalcitonin studies, which shows that procalcitonin guidelines should not be applied blindly in critically ill patients, even those not requiring ICU admission. Third, patients were excluded from the study if they were on chronic dialysis, had metastatic cancer, or had a recent surgery because of possible elevation of procalcitonin levels without a bacterial infection.

In conclusion, the current study did not find any difference in antibiotic exposure throughout the course of care (including discharge or hospitalization) of patients with a lower respiratory tract infection who presented to the emergency department when a procalcitonin guideline was implemented. The results of the current study raise questions regarding the new trend of widely accepting procalcitonin-based antibiotic usage.

Applications for Clinical Practice

Procalcitonin is a relatively new marker that is released during a systemic bacterial infection. While prior studies have supported systematic use of procalcitonin-based guidelines to initiate and discontinue antibiotics in order to limit antibiotic exposure, clinicians should be mindful that a procalcitonin antibiotic guideline may be useful in specific patients and should only be used in combination with usual clinical judgment. Clinicians must also recognize the medical conditions that may falsely elevate the procalcitonin level. Most important, the procalcitonin level should not be used as the sole indication to withhold antibiotics in an otherwise appropriately indicated clinical scenario.

—Minkyung Kwon, MD, Scott A. Helgeson, MD, and Vichaya Arunthari, MD
Pulmonary and Critical Care Medicine, Mayo Clinic Florida, Jacksonville, FL

Study Overview

Objective. To determine if nocturnal dexmedetomidine prevents delirium and improves sleep in critically ill patients.

Design. Two-center, double-blind, placebo-controlled, randomized, trial.

Setting and participants. This study was conducted in the intensive care units (ICU) at 2 centers in North America between 2013 and 2016. Adults admitted to the ICU and receiving intermittent or continuous sedatives and expected to require at least 48 hours of ICU care were included in the study. Exclusion criteria were presence of delirium, severe dementia, acute neurologic injury, severe bradycardia, hepatic encephalopathy, end-stage liver disease, and expected death within 24 hours.

Intervention. Patients were randomized 1:1 to receive nocturnal dexmedetomidine (0.2–0.7 mcg/kg/hr) or dextrose 5% in water. Patients, clinicians, bedside nurses, and all study personnel were blinded to study drug assignment throughout the study. All sedatives were halved before the study drug was administered each evening. As-needed intravenous midazolam was used while titrating up the study drug. Study drug was administered nightly until either ICU discharge or an adverse event occurred. Decisions regarding use of other analgesic and sedative therapy, including opioids, oral benzodiazepines, acetaminophen, and nonsteroidal anti-inflammatory drugs, were left to the discretion of the clinician. Sleep-promoting agents such as melatonin or trazodone were not allowed.

Main outcome measures. The primary outcome was the proportion of patients who remained free of delirium during their critical illness. Secondary outcomes included ICU days spent without delirium; duration of delirium; sleep quality; proportion of patients who ever developed coma; proportion of nocturnal hours spent at each Richmond Agitation and Sedation Scale (RASS) score; maximal nocturnal pain levels; antipsychotic, corticosteroid, and oral analgesic use; days of mechanical ventilation; ICU and hospital stay duration; and ICU and hospital mortality.

Main results. 100 patients were randomized, with 50 patients in each group. 89% of patients were mechanically ventilated, and the Prediction of Delirium in ICU (PRE-DELIRIC) score [1] was 54 in the dexmedetomidine group and 51 in the placebo group. Continuous propofol and fentanyl infusion at randomization was used in 49% and 80%, respectively. Duration of median ICU stay was 10 days in the dexmedetomidine group and 9 days in the placebo group. More patients in the dexmedetomidine group (40 of 50 patients [80%]) than in the placebo group (27 of 50 patients [54%]) remained free of delirium (relative risk [RR], 0.44, 95% confidence interval {CI} 0.23 to 0.82; P = 0.006). The median (interquartile range [IQR]) duration of the first episode of delirium was similar between the dexmedetomidine (IQR 2.0 [0.6–2.7] days) and placebo (2.2 [0.7–3.2] days) groups (P = 0.73). The average Leeds Sleep Evaluation Questionnaire score also was similar (mean difference, 0.02, 95% CI 0.42 to 1.92) between the 2 groups. Incidence of hypotension or bradycardia did not differ significantly between the groups.

Conclusion. Nocturnal administration of low-dose dexmedetomidine in critically ill adults reduces the incidence of delirium during the ICU stay, and patient-reported sleep quality appears unchanged.

Delirium is a sudden state of confusion and/or disturbance of consciousness and cognition that is believed to result from acute brain dysfunction, including neurochemical disequilibrium. It often occurs in association with a general medical condition, such as various types of shock, sepsis, surgery, anesthesia, or electrolyte imbalance. Studies have shown that delirium is associated with increased mortality in critically ill patients [2]. Most ICUs use a systematic assessment tool for early detection of delirium, such as the Confusion Assessment Method for the ICU (CAM-ICU), the Intensive Care Delirium Screening Checklist (ICDSC), or the DSM-IV TR score system. The CAM-ICU is the most frequently used tool to evaluate for the presence of delirium in critically ill patients; it is scored as positive if the patient manifests both an acute change in mental status and inattention, and has either a RASS greater than 0 or disorganized thinking [3].

The level of evidence regarding delirium prevention is low. Ear plugs, eye masks, educational staff, supportive reorientation, and music have been studied as nonpharmacologic methods for preventing delirium [4]. From a pharmacologic standpoint, the dopamine D2 antagonist haloperidol has been explored as a therapy for both treating and preventing delirium, since the condition is thought to be associated with anticholinergic and excessive dopaminergic mechanisms. A randomized controlled study in 142 patients who received haloperidol 2.5 mg intravenously every 8 hours found that the duration of delirium did not differ between the haloperidol and the placebo groups [5]. The most feared adverse effects of haloperidol, such as akathisia, muscle stiffness, arrhythmia, or QT prolongation, did not occur more frequently in the haloperidol group. Similar results have been reported by Al-Qadheeb et al [6]. Pharmacologic prophylaxis of delirium using atypical antipsychotics such as quetiapine has also been explored, but the level of evidence for this intervention remains very low. Current American College of Critical Care Medicine guidelines recommend nonpharmacologic management and do not firmly recommend any pharmacologic prevention for ICU delirium [7].

Dexmedetomidine is a selective alpha-2 adrenergic receptor agonist that acts at the locus ceruleus, providing sedation and analgesia. Studies assessing the choice of sedation in the ICU found that the use of dexmedetomidine or propofol, compared to benzodiazepines, is associated with a lower rate of delirium occurrence, especially in mechanically ventilated patients [8,9]. Dexmedetomidine offers several potential advantages over other sedative drugs: it has little effect on cognition, has minimal anticholinergic effect, and may restore a natural sleep pattern. While propofol causes hypotension, respiratory depression, and deeper sedation, dexmedetomidine is associated with lighter sedation, a minimal effect on respiratory drive, and a milder hemodynamic effect. In a randomized controlled trial involving post-surgery ICU patients, dexmedetomidine partially restored a normal sleep pattern (eg, increased percentage of stage 2 non-rapid eye movement sleep), prolonged total sleep time, improved sleep efficiency, and increased sleep quality [10]; by improving overall sleep quality, dexmedetomidine potentially may prevent delirium. Another study that randomly assigned 700 ICU patients who underwent noncardiac surgery to dexmedetomidine infusion (0.1 mcg/kg/hr from ICU admission on the day of surgery until the following morning) or placebo reported a significantly reduced incidence of delirium in the dexmedetomidine group [11]. On the other hand, a 2015 Cochrane meta-analysis that included 7 randomized controlled studies did not find a significant risk reduction of delirium with dexmedetomidine [12].

The current study by Skrobik et al was a randomized, placebo-controlled trial that examined the role of nocturnal dexmedetomidine in ICU delirium prevention in 100 ICU patients. Nocturnal administration of low-dose dexmedetomidine led to a statistically significant reduction in delirium incidence compared to placebo (RR of delirium, 0.44, 95% CI 0.23 to 0.82, which is similar to that suggested by previous studies). This study adds additional evidence regarding the use of dexmedetomidine for pharmacologic delirium prevention. It included many mechanically ventilated patients (89% of study population), strengthening the applicability of the result. Mechanical ventilation is a known risk factor for ICU delirium, and therefore this is an important population to study; previous trials largely included patients who were not mechanically ventilated. This study also supports the safety of dexmedetomidine infusion, especially in lower doses in critically ill patients, without significantly increasing the incidence of adverse events (mainly hypotension and bradycardia). The study protocol closely approximated real practice by allowing other analgesics, including opioids, and therefore suggests safety and real world applicability.

There are several confounding issues in this study. The study was blinded, and there was concern that the bedside nurses may have been able to identify the study drug based on the effects on heart rate. In addition, 50% of patients received antipsychotics. While baseline RASS score was significantly different between the 2 groups, patients in the dexmedetomidine group reached a deeper level of sedation during the study. Also, the protocol mandated halving the pre-existing sedative on the night of study drug initiation, which could have led to inadequate sedation in the placebo group. Placebo patients received propofol for a similar duration but at a higher dose compared to dexmedetomidine patients, and midazolam and fentanyl infusion was used in a similar pattern between the groups. The high exclusion rate (71%) limits the ability to generalize the results to all ICU patients.

Applications for Clinical Practice

ICU delirium is an important complication of critical illness and is potentially preventable. Benzodiazepines are associated with an increased risk of delirium, while there has been increasing interest in dexmedetomidine, a selective alpha-2 adrenergic receptor agonist, because of its potential for delirium prevention. Evidence to date does not strongly support routine use of pharmacologic prevention of delirium; however, dexmedetomidine may be an option for sedation, as opposed to benzodiazepines or propofol, in selected patients and may potentially prevent delirium.

—Minkyung Kwon, MD, Neal Patel, MD, and Vichaya Arunthari, MD, Pulmonary and Critical Care Medicine, Mayo Clinic Florida, Jacksonville, FL

Study Overview

Objective. To determine if nocturnal dexmedetomidine prevents delirium and improves sleep in critically ill patients.

Design. Two-center, double-blind, placebo-controlled, randomized, trial.

Setting and participants. This study was conducted in the intensive care units (ICU) at 2 centers in North America between 2013 and 2016. Adults admitted to the ICU and receiving intermittent or continuous sedatives and expected to require at least 48 hours of ICU care were included in the study. Exclusion criteria were presence of delirium, severe dementia, acute neurologic injury, severe bradycardia, hepatic encephalopathy, end-stage liver disease, and expected death within 24 hours.

Intervention. Patients were randomized 1:1 to receive nocturnal dexmedetomidine (0.2–0.7 mcg/kg/hr) or dextrose 5% in water. Patients, clinicians, bedside nurses, and all study personnel were blinded to study drug assignment throughout the study. All sedatives were halved before the study drug was administered each evening. As-needed intravenous midazolam was used while titrating up the study drug. Study drug was administered nightly until either ICU discharge or an adverse event occurred. Decisions regarding use of other analgesic and sedative therapy, including opioids, oral benzodiazepines, acetaminophen, and nonsteroidal anti-inflammatory drugs, were left to the discretion of the clinician. Sleep-promoting agents such as melatonin or trazodone were not allowed.

Main outcome measures. The primary outcome was the proportion of patients who remained free of delirium during their critical illness. Secondary outcomes included ICU days spent without delirium; duration of delirium; sleep quality; proportion of patients who ever developed coma; proportion of nocturnal hours spent at each Richmond Agitation and Sedation Scale (RASS) score; maximal nocturnal pain levels; antipsychotic, corticosteroid, and oral analgesic use; days of mechanical ventilation; ICU and hospital stay duration; and ICU and hospital mortality.

Main results. 100 patients were randomized, with 50 patients in each group. 89% of patients were mechanically ventilated, and the Prediction of Delirium in ICU (PRE-DELIRIC) score [1] was 54 in the dexmedetomidine group and 51 in the placebo group. Continuous propofol and fentanyl infusion at randomization was used in 49% and 80%, respectively. Duration of median ICU stay was 10 days in the dexmedetomidine group and 9 days in the placebo group. More patients in the dexmedetomidine group (40 of 50 patients [80%]) than in the placebo group (27 of 50 patients [54%]) remained free of delirium (relative risk [RR], 0.44, 95% confidence interval {CI} 0.23 to 0.82; P = 0.006). The median (interquartile range [IQR]) duration of the first episode of delirium was similar between the dexmedetomidine (IQR 2.0 [0.6–2.7] days) and placebo (2.2 [0.7–3.2] days) groups (P = 0.73). The average Leeds Sleep Evaluation Questionnaire score also was similar (mean difference, 0.02, 95% CI 0.42 to 1.92) between the 2 groups. Incidence of hypotension or bradycardia did not differ significantly between the groups.

Conclusion. Nocturnal administration of low-dose dexmedetomidine in critically ill adults reduces the incidence of delirium during the ICU stay, and patient-reported sleep quality appears unchanged.

Delirium is a sudden state of confusion and/or disturbance of consciousness and cognition that is believed to result from acute brain dysfunction, including neurochemical disequilibrium. It often occurs in association with a general medical condition, such as various types of shock, sepsis, surgery, anesthesia, or electrolyte imbalance. Studies have shown that delirium is associated with increased mortality in critically ill patients [2]. Most ICUs use a systematic assessment tool for early detection of delirium, such as the Confusion Assessment Method for the ICU (CAM-ICU), the Intensive Care Delirium Screening Checklist (ICDSC), or the DSM-IV TR score system. The CAM-ICU is the most frequently used tool to evaluate for the presence of delirium in critically ill patients; it is scored as positive if the patient manifests both an acute change in mental status and inattention, and has either a RASS greater than 0 or disorganized thinking [3].

The level of evidence regarding delirium prevention is low. Ear plugs, eye masks, educational staff, supportive reorientation, and music have been studied as nonpharmacologic methods for preventing delirium [4]. From a pharmacologic standpoint, the dopamine D2 antagonist haloperidol has been explored as a therapy for both treating and preventing delirium, since the condition is thought to be associated with anticholinergic and excessive dopaminergic mechanisms. A randomized controlled study in 142 patients who received haloperidol 2.5 mg intravenously every 8 hours found that the duration of delirium did not differ between the haloperidol and the placebo groups [5]. The most feared adverse effects of haloperidol, such as akathisia, muscle stiffness, arrhythmia, or QT prolongation, did not occur more frequently in the haloperidol group. Similar results have been reported by Al-Qadheeb et al [6]. Pharmacologic prophylaxis of delirium using atypical antipsychotics such as quetiapine has also been explored, but the level of evidence for this intervention remains very low. Current American College of Critical Care Medicine guidelines recommend nonpharmacologic management and do not firmly recommend any pharmacologic prevention for ICU delirium [7].

Dexmedetomidine is a selective alpha-2 adrenergic receptor agonist that acts at the locus ceruleus, providing sedation and analgesia. Studies assessing the choice of sedation in the ICU found that the use of dexmedetomidine or propofol, compared to benzodiazepines, is associated with a lower rate of delirium occurrence, especially in mechanically ventilated patients [8,9]. Dexmedetomidine offers several potential advantages over other sedative drugs: it has little effect on cognition, has minimal anticholinergic effect, and may restore a natural sleep pattern. While propofol causes hypotension, respiratory depression, and deeper sedation, dexmedetomidine is associated with lighter sedation, a minimal effect on respiratory drive, and a milder hemodynamic effect. In a randomized controlled trial involving post-surgery ICU patients, dexmedetomidine partially restored a normal sleep pattern (eg, increased percentage of stage 2 non-rapid eye movement sleep), prolonged total sleep time, improved sleep efficiency, and increased sleep quality [10]; by improving overall sleep quality, dexmedetomidine potentially may prevent delirium. Another study that randomly assigned 700 ICU patients who underwent noncardiac surgery to dexmedetomidine infusion (0.1 mcg/kg/hr from ICU admission on the day of surgery until the following morning) or placebo reported a significantly reduced incidence of delirium in the dexmedetomidine group [11]. On the other hand, a 2015 Cochrane meta-analysis that included 7 randomized controlled studies did not find a significant risk reduction of delirium with dexmedetomidine [12].

The current study by Skrobik et al was a randomized, placebo-controlled trial that examined the role of nocturnal dexmedetomidine in ICU delirium prevention in 100 ICU patients. Nocturnal administration of low-dose dexmedetomidine led to a statistically significant reduction in delirium incidence compared to placebo (RR of delirium, 0.44, 95% CI 0.23 to 0.82, which is similar to that suggested by previous studies). This study adds additional evidence regarding the use of dexmedetomidine for pharmacologic delirium prevention. It included many mechanically ventilated patients (89% of study population), strengthening the applicability of the result. Mechanical ventilation is a known risk factor for ICU delirium, and therefore this is an important population to study; previous trials largely included patients who were not mechanically ventilated. This study also supports the safety of dexmedetomidine infusion, especially in lower doses in critically ill patients, without significantly increasing the incidence of adverse events (mainly hypotension and bradycardia). The study protocol closely approximated real practice by allowing other analgesics, including opioids, and therefore suggests safety and real world applicability.

There are several confounding issues in this study. The study was blinded, and there was concern that the bedside nurses may have been able to identify the study drug based on the effects on heart rate. In addition, 50% of patients received antipsychotics. While baseline RASS score was significantly different between the 2 groups, patients in the dexmedetomidine group reached a deeper level of sedation during the study. Also, the protocol mandated halving the pre-existing sedative on the night of study drug initiation, which could have led to inadequate sedation in the placebo group. Placebo patients received propofol for a similar duration but at a higher dose compared to dexmedetomidine patients, and midazolam and fentanyl infusion was used in a similar pattern between the groups. The high exclusion rate (71%) limits the ability to generalize the results to all ICU patients.

Applications for Clinical Practice

ICU delirium is an important complication of critical illness and is potentially preventable. Benzodiazepines are associated with an increased risk of delirium, while there has been increasing interest in dexmedetomidine, a selective alpha-2 adrenergic receptor agonist, because of its potential for delirium prevention. Evidence to date does not strongly support routine use of pharmacologic prevention of delirium; however, dexmedetomidine may be an option for sedation, as opposed to benzodiazepines or propofol, in selected patients and may potentially prevent delirium.

—Minkyung Kwon, MD, Neal Patel, MD, and Vichaya Arunthari, MD, Pulmonary and Critical Care Medicine, Mayo Clinic Florida, Jacksonville, FL

Study Overview

Objective. To determine if nocturnal dexmedetomidine prevents delirium and improves sleep in critically ill patients.

Design. Two-center, double-blind, placebo-controlled, randomized, trial.

Setting and participants. This study was conducted in the intensive care units (ICU) at 2 centers in North America between 2013 and 2016. Adults admitted to the ICU and receiving intermittent or continuous sedatives and expected to require at least 48 hours of ICU care were included in the study. Exclusion criteria were presence of delirium, severe dementia, acute neurologic injury, severe bradycardia, hepatic encephalopathy, end-stage liver disease, and expected death within 24 hours.

Intervention. Patients were randomized 1:1 to receive nocturnal dexmedetomidine (0.2–0.7 mcg/kg/hr) or dextrose 5% in water. Patients, clinicians, bedside nurses, and all study personnel were blinded to study drug assignment throughout the study. All sedatives were halved before the study drug was administered each evening. As-needed intravenous midazolam was used while titrating up the study drug. Study drug was administered nightly until either ICU discharge or an adverse event occurred. Decisions regarding use of other analgesic and sedative therapy, including opioids, oral benzodiazepines, acetaminophen, and nonsteroidal anti-inflammatory drugs, were left to the discretion of the clinician. Sleep-promoting agents such as melatonin or trazodone were not allowed.

Main outcome measures. The primary outcome was the proportion of patients who remained free of delirium during their critical illness. Secondary outcomes included ICU days spent without delirium; duration of delirium; sleep quality; proportion of patients who ever developed coma; proportion of nocturnal hours spent at each Richmond Agitation and Sedation Scale (RASS) score; maximal nocturnal pain levels; antipsychotic, corticosteroid, and oral analgesic use; days of mechanical ventilation; ICU and hospital stay duration; and ICU and hospital mortality.

Main results. 100 patients were randomized, with 50 patients in each group. 89% of patients were mechanically ventilated, and the Prediction of Delirium in ICU (PRE-DELIRIC) score [1] was 54 in the dexmedetomidine group and 51 in the placebo group. Continuous propofol and fentanyl infusion at randomization was used in 49% and 80%, respectively. Duration of median ICU stay was 10 days in the dexmedetomidine group and 9 days in the placebo group. More patients in the dexmedetomidine group (40 of 50 patients [80%]) than in the placebo group (27 of 50 patients [54%]) remained free of delirium (relative risk [RR], 0.44, 95% confidence interval {CI} 0.23 to 0.82; P = 0.006). The median (interquartile range [IQR]) duration of the first episode of delirium was similar between the dexmedetomidine (IQR 2.0 [0.6–2.7] days) and placebo (2.2 [0.7–3.2] days) groups (P = 0.73). The average Leeds Sleep Evaluation Questionnaire score also was similar (mean difference, 0.02, 95% CI 0.42 to 1.92) between the 2 groups. Incidence of hypotension or bradycardia did not differ significantly between the groups.

Conclusion. Nocturnal administration of low-dose dexmedetomidine in critically ill adults reduces the incidence of delirium during the ICU stay, and patient-reported sleep quality appears unchanged.

Delirium is a sudden state of confusion and/or disturbance of consciousness and cognition that is believed to result from acute brain dysfunction, including neurochemical disequilibrium. It often occurs in association with a general medical condition, such as various types of shock, sepsis, surgery, anesthesia, or electrolyte imbalance. Studies have shown that delirium is associated with increased mortality in critically ill patients [2]. Most ICUs use a systematic assessment tool for early detection of delirium, such as the Confusion Assessment Method for the ICU (CAM-ICU), the Intensive Care Delirium Screening Checklist (ICDSC), or the DSM-IV TR score system. The CAM-ICU is the most frequently used tool to evaluate for the presence of delirium in critically ill patients; it is scored as positive if the patient manifests both an acute change in mental status and inattention, and has either a RASS greater than 0 or disorganized thinking [3].

The level of evidence regarding delirium prevention is low. Ear plugs, eye masks, educational staff, supportive reorientation, and music have been studied as nonpharmacologic methods for preventing delirium [4]. From a pharmacologic standpoint, the dopamine D2 antagonist haloperidol has been explored as a therapy for both treating and preventing delirium, since the condition is thought to be associated with anticholinergic and excessive dopaminergic mechanisms. A randomized controlled study in 142 patients who received haloperidol 2.5 mg intravenously every 8 hours found that the duration of delirium did not differ between the haloperidol and the placebo groups [5]. The most feared adverse effects of haloperidol, such as akathisia, muscle stiffness, arrhythmia, or QT prolongation, did not occur more frequently in the haloperidol group. Similar results have been reported by Al-Qadheeb et al [6]. Pharmacologic prophylaxis of delirium using atypical antipsychotics such as quetiapine has also been explored, but the level of evidence for this intervention remains very low. Current American College of Critical Care Medicine guidelines recommend nonpharmacologic management and do not firmly recommend any pharmacologic prevention for ICU delirium [7].

Dexmedetomidine is a selective alpha-2 adrenergic receptor agonist that acts at the locus ceruleus, providing sedation and analgesia. Studies assessing the choice of sedation in the ICU found that the use of dexmedetomidine or propofol, compared to benzodiazepines, is associated with a lower rate of delirium occurrence, especially in mechanically ventilated patients [8,9]. Dexmedetomidine offers several potential advantages over other sedative drugs: it has little effect on cognition, has minimal anticholinergic effect, and may restore a natural sleep pattern. While propofol causes hypotension, respiratory depression, and deeper sedation, dexmedetomidine is associated with lighter sedation, a minimal effect on respiratory drive, and a milder hemodynamic effect. In a randomized controlled trial involving post-surgery ICU patients, dexmedetomidine partially restored a normal sleep pattern (eg, increased percentage of stage 2 non-rapid eye movement sleep), prolonged total sleep time, improved sleep efficiency, and increased sleep quality [10]; by improving overall sleep quality, dexmedetomidine potentially may prevent delirium. Another study that randomly assigned 700 ICU patients who underwent noncardiac surgery to dexmedetomidine infusion (0.1 mcg/kg/hr from ICU admission on the day of surgery until the following morning) or placebo reported a significantly reduced incidence of delirium in the dexmedetomidine group [11]. On the other hand, a 2015 Cochrane meta-analysis that included 7 randomized controlled studies did not find a significant risk reduction of delirium with dexmedetomidine [12].

The current study by Skrobik et al was a randomized, placebo-controlled trial that examined the role of nocturnal dexmedetomidine in ICU delirium prevention in 100 ICU patients. Nocturnal administration of low-dose dexmedetomidine led to a statistically significant reduction in delirium incidence compared to placebo (RR of delirium, 0.44, 95% CI 0.23 to 0.82, which is similar to that suggested by previous studies). This study adds additional evidence regarding the use of dexmedetomidine for pharmacologic delirium prevention. It included many mechanically ventilated patients (89% of study population), strengthening the applicability of the result. Mechanical ventilation is a known risk factor for ICU delirium, and therefore this is an important population to study; previous trials largely included patients who were not mechanically ventilated. This study also supports the safety of dexmedetomidine infusion, especially in lower doses in critically ill patients, without significantly increasing the incidence of adverse events (mainly hypotension and bradycardia). The study protocol closely approximated real practice by allowing other analgesics, including opioids, and therefore suggests safety and real world applicability.

There are several confounding issues in this study. The study was blinded, and there was concern that the bedside nurses may have been able to identify the study drug based on the effects on heart rate. In addition, 50% of patients received antipsychotics. While baseline RASS score was significantly different between the 2 groups, patients in the dexmedetomidine group reached a deeper level of sedation during the study. Also, the protocol mandated halving the pre-existing sedative on the night of study drug initiation, which could have led to inadequate sedation in the placebo group. Placebo patients received propofol for a similar duration but at a higher dose compared to dexmedetomidine patients, and midazolam and fentanyl infusion was used in a similar pattern between the groups. The high exclusion rate (71%) limits the ability to generalize the results to all ICU patients.

Applications for Clinical Practice

ICU delirium is an important complication of critical illness and is potentially preventable. Benzodiazepines are associated with an increased risk of delirium, while there has been increasing interest in dexmedetomidine, a selective alpha-2 adrenergic receptor agonist, because of its potential for delirium prevention. Evidence to date does not strongly support routine use of pharmacologic prevention of delirium; however, dexmedetomidine may be an option for sedation, as opposed to benzodiazepines or propofol, in selected patients and may potentially prevent delirium.

—Minkyung Kwon, MD, Neal Patel, MD, and Vichaya Arunthari, MD, Pulmonary and Critical Care Medicine, Mayo Clinic Florida, Jacksonville, FL