Mechanical ventilation

Convalescent Plasma for Individuals with Acute Respiratory Distress Syndrome Induced by COVID-19

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Among patients with ARDS requiring mechanical ventilation, mortality was lower in those who received convalescent plasma compared with standard care — but questions remain.

Administering convalescent plasma (CP) to patients with COVID-19 has been debated since the pandemic’s earliest months. Now, Belgian investigators have conducted a trial of CP in 475 mechanically ventilated patients with COVID-19–induced acute respiratory distress syndrome (ARDS) who were enrolled between September 2020 and March 2022 and randomized 1:1 to receive CP or standard care. Most participants were immunocompetent, and only about 10% had been vaccinated against SARS-CoV-2. CP was collected between April 2020 and May 2021, when the ancestral and Alpha strains predominated and before more-recent SARS-CoV-2 variants emerged.

About 80% of the CP group received CP with a neutralizing antibody titer of ≥1:320 (against ancestral SARS-CoV-2) and the remainder received CP with a neutralizing titer of ≥1:160. About 200 participants had been infected with the ancestral strain; only 16 were infected during the Omicron era. Almost all patients received glucocorticoids, but only about 5% received a second immunomodulator (an anti-IL-6 agent) and 5% received remdesivir. Mortality was significantly lower in the CP group (35%) than in the standard care group (45%). The mortality difference between groups was seen only in those who had been mechanically ventilated for ≤48 hours. Rates of bacteremia were 26% (CP) and 29% (standard care). Overall, almost 80% of participants had ventilator-associated pneumonia.

Comment

Several considerations affect the application of these results to clinical practice in the pandemic’s current phase. First, only a small proportion of study participants had Omicron, which is less susceptible than previous variants to CP collected early in the pandemic. Second, mortality and complication rates (e.g., bacteremia, ventilator-associated pneumonia) were higher in this trial than in more-recent studies, perhaps reflecting the severity of the early pandemic and the lower probability of vaccination. In my own practice, I consider CP only when I’m caring for an immunocompromised patient with progressive COVID-19, evidence of persistent SARS-CoV-2 replication despite other treatments, and for whom I can obtain contemporaneously collected CP.

Medical case..A 52-year-old woman was admitted to the ICU

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A 52-year-old woman was admitted to the ICU because of respiratory failure. She originated from India but ran a coffee shop in Canada for 10 years. She developed right knee arthritis 3 years earlier. Following consultations from orthopaedics and rheumatology, she was diagnosed as having rheumatoid arthritis and eventually treated with methotrexate for 18 months. This was stopped 1 month prior to admission because of the development of anemia and nausea. She presented to the hospital with bilateral leg swelling and pain of 3 days’ duration and marked dyspnea worsening over 2 to 4 weeks.

On examination, she was afebrile with a clear chest. There was bilateral leg swelling and the right knee was warm and tender and flexed at 10°. Her laboratory test results revealed the following values: hemoglobin, 11.1 g/dL (111 g/L); WBC count, 34,000/ μL (34.0 × 10^9/L); sodium, 129 mEq/L (129 mmol/L); creatinine, 2.0 mg/dL (176 μmol/L); BUN, 30.5 mg/dL (10.9 mmol/L); and calcium, 11.9 mg/dL (2.97 mmol/L). Her initial chest radiograph (posteroanterior and lateral) (Figs 135-A, 135-B, respectively) and representative images of a chest CT scan (Figs 135-C, 135-D) as well as a knee radiograph (Fig 135-E) are shown. Two days later, she developed worsening lung infiltrates shown on her repeat chest radiograph (Fig 135-F) and was admitted to the ICU to receive mechanical ventilation support. Bronchoscopy and BAL findings were negative. An open lung biopsy was performed, and specimens are shown in Figures 135-G and 135-H. The most likely diagnosis is:

A. Methotrexate-induced lung disease.
B. Miliary TB with ARDS.
C. Metastatic osteosarcoma.
D. Sarcoidosis.

This patient presents with a long history of a monoarthritis treated aggressively as rheumatoid arthritis with methotrexate. She has evidence of systemic infection and hypercalcemia. The knee radiograph demonstrates marked destructive changes compatible with an infectious process. The chest radiographs show a miliary pattern confirmed by the CT scan. The hematoxylin-eosin-stained lung biopsy specimen (see Fig 135-G) demonstrates granulomatous inflammation. Areas of diff use alveolar damage with hyaline membranes consistent with ARDS (not shown on the
biopsy) were also seen. Tissue culture confirmed the presence of Mycobacterium tuberculosis and the Zeihl-Neelsenstained specimen (see Fig 135-H) demonstrates acid-fast bacilli (choice B is correct).

A negative BAL finding in the setting of miliary TB is not uncommon and cannot be used to exclude the diagnosis. Hypercalcemia has been reported with all granulomatous diseases, including TB. While methotrexate can cause drug-induced lung disease, it less frequently causes granulomatous lung inflammation compared with TB and would not account for the hypercalcemia and knee changes (choice A is incorrect). There is no evidence of a malignancy in the lung biopsy (choice C is incorrect). Sarcoidosis certainly could account for the military pattern seen on chest CT scan and hypercalcemia. However, this diagnosis would not explain the rapid progression to respiratory failure with ARDS or the finding with the Zeihl-Neelsen stain (choice D is incorrect).

Occasionally, patients with TB develop respiratory failure and require support by mechanical ventilation. A retrospective 2-year study in two medical ICUs in France identified 99 patients with pulmonary TB, most with immunodeficiency. Mechanical ventilation support was required in 50 of these patients, and 22 patients met criteria for ARDS. The 30-day mortality rate was 26%. Factors predictive of a poor outcome included delay in diagnosis, increased number of organ failures, serum albumin level > 2 g/dL (>20 g/L), and increased number of lobes involved on chest radiograph. A previous study indicated that hospital mortality in patients with TB who required support by mechanical ventilation was significantly greater than patients with nontuberculous pneumonia requiring support by mechanical ventilation and similar to the hospital mortality for patients with ARDS of any cause. The majority of the patients with TB requiring support by mechanical ventilation developed ARDS. This observation appears more common among patients with miliary TB than patients with tuberculous pneumonia.

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Trends in Mechanical Ventilation Among Patients Hospitalized With Acute Exacerbations of COPD in the United States, 2001 to 2011

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BACKGROUND:  The use of noninvasive ventilation (NIV) in acute exacerbation of COPD has increased over time. However, little is known about patient factors influencing its use in routine clinical practice.

METHODS:  This was a retrospective cohort study of 723,560 hospitalizations for exacerbation of COPD at 475 hospitals between 2001 and 2011. The primary study outcome was the initial form of ventilation (NIV or invasive mechanical ventilation [IMV]). Hierarchical generalized linear models were used to examine the trends in ventilation and patient characteristics associated with receipt of NIV.

RESULTS:  After adjusting for patient and hospital characteristics, initial NIV increased by 15.1% yearly (from 5.9% to 14.8%), and initial IMV declined by 3.2% yearly (from 8.7% to 5.9%); annual exposure to any form of mechanical ventilation increased by 4.4% (from 14.1% to 20.3%). Among case subjects treated with ventilation, those aged ≥ 85 years had a 22% higher odds of receiving NIV compared with those aged < 65 years, while blacks (OR, 0.86) and Hispanics (OR, 0.91) were less likely to be treated with NIV than were whites. Cases with a high burden of comorbidities and those with concomitant pneumonia had high rates of NIV failure and were more likely to receive initial IMV. Use of NIV increased at a faster rate among the admissions of the oldest patients relative to the youngest.

CONCLUSIONS:  The use of NIV for COPD exacerbations has increased steadily, whereas IMV use has declined. Several patient factors, including age, race, and comorbidities, influenced the receipt of NIV. Further research is needed to identify the factors driving these patterns.

Clonidine Infusions—Do They Have a Role in the PICU?

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The requirement for mechanical ventilation remains one of the primary reasons for ongoing care in the PICU setting. The presence of an endotracheal tube for mechanical ventilation in the pediatric patient mandates the need for ongoing sedation and analgesia. Although the exact suffering endured during mechanical ventilation may be impossible to estimate in preverbal infants and children, the adult literature gives us some insight into such issues. In a follow-up study performed 12 months after discharge from the ICU of 113 adults who survived for more than 1 year, approximately one fourth of the patients who initially would have chosen mechanical ventilation would have refused this therapy if the pain or discomfort would have been any greater.[1] Additional factors other than physical pain may further increase the requirements for sedation and analgesia during mechanical ventilation. These include emotional pain from separation from parents, disruption of the day-night cycle, unfamiliar people, and the incessant noise of machines and monitors. These factors mandate the need for compassionate and humanitarian interventions during ongoing care in the PICU setting. Although nonpharmacologic measures may decrease the impact of these factors, pharmacologic intervention is generally necessary during mechanical ventilation in the PICU patient.

Given these concerns, the potential for complications with inadequate sedation during mechanical ventilation, and scientific data suggesting the deleterious effects of untreated pain, the current trend in most PICUs is to aggressively sedate infants and children during mechanical ventilation. In the majority of PICUs, this is accomplished with a combination of a benzodiazepine (usually midazolam) and an opioid (morphine or fentanyl). Although we have been successful in the goal of achieving effective sedation in the majority of patients, the prolonged use of sedative and analgesic agents may result in adverse effects, including tolerance, physical dependency, and withdrawal if the agents are abruptly discontinued.[2,3] Furthermore, the ongoing use of these agents may cause respiratory depression limiting weaning from mechanical ventilation and decrease gastrointestinal motility preventing enteral feeding. In an effort to decrease or eliminate such problems, attention has turned to the use of adjunctive agents which may decrease the requirements for benzodiazepines and opioids thereby limiting their adverse effect profile.

In this issue of Pediatric Critical Care Medicine, Hunseler et al[4] present the results of a multicenter study evaluating the effects of a clonidine infusion on fentanyl and midazolam requirements during sedation for mechanical ventilation. From the start, Hunseler et al[4] are to be congratulated for undertaking this difficult, labor intensive study which was conducted at several pediatric centers throughout Germany. The study design (prospective, blinded, and randomized) and conduct were exemplary and provide the basis for obtaining valuable information without the inherent deficiencies of less robust trials. From the start, the authors note that their trial is the first prospective, randomized trial in the literature evaluating the effects of the α2-adrenergic agonist, clonidine, in providing sedation during mechanical ventilation. Over a 4- to 5-year period, they were able to enroll a total of 219 patients, ranging in age from 1 day to 2 years. The patients were stratified and the data analyzed in 3 age ranges: 1–28 days, 29–120 days, and 121 days to 2 years. The multicenter trial included 21 university and tertiary care neonatal ICU and PICUs. On day 4 of mechanical ventilation, the patients were randomized to receive a continuous infusion of clonidine (1 μg/kg/hr) or saline placebo. The infusion was continued for 72 hours. Dosages of fentanyl and midazolam were adjusted using the Hartwig sedation scale with a goal score ranging from 9 to 13. The Hartwig scale was chosen given its widespread use in Germany. Following the termination of the infusion, withdrawal was evaluated and graded using the Finnegan score. The primary outcome was the requirements for fentanyl and midazolam.

Unfortunately, only the youngest age group (1–28 d) demonstrated any significant difference with a decrease in both fentanyl and midazolam requirements. Additionally, there was a decrease in the sedation and withdrawal scores in this age group. No differences were noted in the other two age groups; however, a pharmacokinetic analysis demonstrated significantly lower clonidine plasma concentrations in these two groups when compared with the 1- to 28-day-old patients. This left the authors to conclude that their findings were perhaps related to inadequate plasma concentrations of clonidine.

Although not addressed in their article, the primary question relates to the reasons for differences in choice of medications across national and continental lines. In the United States, clonidine is used primarily as an adjunct to regional anesthesia and occasionally administered orally to treat withdrawal following the prolonged administration of various sedative and analgesic agents.[3,5] Clonidine is rarely administered via the IV route.

Like clonidine, dexmedetomidine is a centrally acting, α2-adrenergic agonist and exhibits the same physiologic effects. However, it possesses an affinity eight times that of clonidine for the α2-adrenergic receptor with a differential α1 to α2 agonism of 1:1,600, and a half-life of 2–3 hours, thereby allowing its titration by IV administration. Dexmedetomidine is currently approved by the U.S. Food and Drug Administration for two indications in adults including the short-term (24 hr or less) sedation of adult patients during mechanical ventilation and for monitored anesthesia care. Despite the lack of specific pediatric indications, it continues to be used extensively in PICUs and operating rooms throughout the United States.[6] Its pharmacokinetic properties have been well studied in the pediatric population in various clinical scenarios and in the presence of comorbid conditions including congenital heart disease.[7] Unfortunately, like clonidine, there are few prospective, randomized trials determining its true utility in the neonatal and pediatric population and its lack of formalized approval by regulatory boards limits its use in some centers. The decision to use clonidine may be driven by costs. Although acquisition costs vary, currently at our institution, a vial of clonidine (1,000 μg in 10 mL) costs approximately $13.58. Therefore, the medication cost for an infusion at 1 μg/kg/hr for a 10-kg patient would be $3.26 compared with $46.61 for a dexmedetomidine infusion at 0.5 μg/kg/hr. The latter calculation assumes an acquisition cost of $77.68 for a 2-mL dexmedetomidine vial (100 μg/mL). The cost of dexmedetomidine may decrease slightly as hospitals start using a new diluted version (200 μg/50 mL vial) which costs $64.73 per vial.

Although the primary purpose of the current study was to decrease fentanyl and midazolam requirements and perhaps the prevalence of withdrawal and physical tolerance, the potential benefits may extend far beyond these issues. In the recent years, concern has been expressed regarding the long-term neurocognitive effects of agents that act as agonists at gamma amino butyric acid (GABA) receptors or antagonists at the n-methyl-d-aspartate receptor.[8,9] Animal data have clearly shown that prolonged exposure to these agents during the early vulnerable stages of neuronal development can lead to accelerated apoptosis and potentially long-term neurocognitive effects. To date, the human data are conflicting, and there is no clear evidence on which to base strict clinical guidelines. However, if these concerns are valid, the issues would seem to pertain not only to the operating room but also to the prolonged use of such agents in the ICU setting. The available animal studies suggest that the α2-adrenergic agents do not cause accelerated apoptosis and may be protective, blunting the effect of other agents.[10–12]Furthermore, as this issue has been shown to be a dose-related phenomenon, any intervention which can decrease the use of the potentially implicated agents may be beneficial.

Although the benzodiazepines remain a time-honored agent for sedation in the ICU, additional concerns continue to mount regarding the potential impact that these agents have on long-term consequences of a prolonged ICU stay including delirium. Delirium may occur in up to 80% of critically adults. It may be either a marker for or a direct cause of both short-term and long-term mortality of ICU patients.[13] Although the etiology is multifactorial, the sedation regimen may play a role. The most compelling evidence suggests that medications which act through the GABA system increase the likelihood of delirium. Most notable of the GABA agonists in the role of delirium are the benzodiazepines including both midazolam and lorazepam.[14]Riker et al[15] compared dexmedetomidine (0.2–1.4 μg/kg/hr) with midazolam (0.02–0.1 mg/kg/hr) in 375 medical/surgical adult ICU patients that required sedation for mechanical ventilation. There was no difference in the time spent at the targeted Richmond Agitation Sedation Scale scores; however, there was a decrease in the prevalence of delirium (54% vs 76.6%) and a decrease in the time to tracheal extubation (3.7 d vs 5.6 d) in the patients who received dexmedetomidine. The lack of non-rapid eye movement sleep with the prolonged use of specific sedative agents is one of the physiologic factors that may lead to delirium during prolonged ICU stays. Unlike the benzodiazepines, α2-adrenergic agonists do not disrupt the sleep cycle and may play a role in decreasing the prevalence of delirium. The latest rendition of the sedation guidelines from the American College of Critical Care Medicine in conjunction with the Society of Critical Care Medicine and the American Society of Health-System Pharmacists reflects these new concerns and recent clinical findings. In their summary of the literature regarding sedation of adults in the ICU, they noted that the data provided class +2B evidence suggesting that sedation strategies using nonbenzodiazepine sedatives (either propofol or dexmedetomidine) may be preferred over sedation with benzodiazepines (either midazolam or lorazepam) to improve clinical outcomes in mechanically ventilated adult ICU patients.[16]

The increasing literature and evidence-based medicine in both the adult and pediatric population suggest that sedation regimens incorporating the α2-adrenergic agonists may offer several benefits. The exact benefit may vary from the adult to the pediatric population, and therefore, we are compelled to encourage future studies which more clearly define these benefits in the pediatric-aged patient. To date, there are limited trials comparing these agents to commonly used agents (fentanyl and midazolam) or using them as adjuncts to these agents. There are no data examining optimal dosing regimens for these agents, and as the current study by Hunseler et al[4] demonstrates, we need to further examine the dosing regimens if we want to maximize the benefits of clonidine. Studies are also need to directly compare the two currently available α2-adrenergic agonists, dexmedetomidine and clonidine, to determine if one is superior in regards to its efficacy and its adverse effect profile. Although there are currently cost differences, this may fade as dexmedetomidine enters the generic world.

Dexmedetomidine Use in the ICU Are We There Yet?

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Abstract

Background Long-term sedation with midazolam or propofol in intensive care units (ICUs) has serious adverse effects. Dexmedetomidine, an alpha-2 agonist available for ICU sedation, may reduce the duration of mechanical ventilation and enhance patient comfort.

Methods Objective: The objective was to determine the efficacy of dexmedetomidine versus midazolam or propofol (preferred usual care) in maintaining sedation, reducing duration of mechanical ventilation, and improving patients’ interaction with nursing care.

Design: Two phase 3 multicenter, randomized, double-blind trials were conducted.

Setting: The MIDEX (Midazolam vs. Dexmedetomidine) trial compared midazolam with dexmedetomidine in ICUs of 44 centers in nine European countries. The PRODEX (Propofol vs. Dexmedetomidine) trial compared propofol with dexmedetomidine in 31 centers in six European countries and two centers in Russia.

Subjects: The subjects were adult ICU patients who were receiving mechanical ventilation and who needed light to moderate sedation for more than 24 hours.

Intervention: After enrollment, 251 and 249 subjects were randomly assigned midazolam and dexmedetomidine, respectively, in the MIDEX trial, and 247 and 251 subjects were randomly assigned propofol and dexmedetomidine, respectively, in the PRODEX trial. Sedation with dexmedetomidine, midazolam, or propofol; daily sedation stops; and spontaneous breathing trials were employed.

Outcomes: For each trial, investigators tested whether dexmedetomidine was noninferior to control with respect to proportion of time at target sedation level (measured by Richmond Agitation Sedation Scale) and superior to control with respect to duration of mechanical ventilation. Secondary end points were the ability of the patient to communicate pain (measured by using a visual analogue scale [VAS]) and length of ICU stay. Time at target sedation was analyzed in per-protocol (midazolam, n = 233, versus dexmedetomidine, n = 227; propofol, n = 214, versus dexmedetomidine, n = 223) population.

Results Dexmedetomidine/midazolam ratio in time at target sedation was 1.07 (95% confidence interval (CI) 0.97 to 1.18), and dexmedetomidine/propofol ratio in time at target sedation was 1.00 (95% CI 0.92 to 1.08). Median duration of mechanical ventilation appeared shorter with dexmedetomidine (123 hours, interquartile range (IQR) 67 to 337) versus midazolam (164 hours, IQR 92 to 380;P = 0.03) but not with dexmedetomidine (97 hours, IQR 45 to 257) versus propofol (118 hours, IQR 48 to 327; P= 0.24). Patient interaction (measured by using VAS) was improved with dexmedetomidine (estimated score difference versus midazolam 19.7, 95% CI 15.2 to 24.2; P <0.001; and versus propofol 11.2, 95% CI 6.4 to 15.9; P <0.001). Lengths of ICU and hospital stays and mortality rates were similar. Dexmedetomidine versus midazolam patients had more hypotension (51/247 [20.6%] versus 29/250 [11.6%]; P = 0.007) and bradycardia (35/247 [14.2%] versus 13/250 [5.2%]; P <0.001).

Conclusions Among ICU patients receiving prolonged mechanical ventilation, dexmedetomidine was not inferior to midazolam and propofol in maintaining light to moderate sedation. Dexmedetomidine reduced duration of mechanical ventilation compared with midazolam and improved the ability of patients to communicate pain compared with midazolam and propofol. Greater numbers of adverse effects were associated with dexmedetomidine.

 

Commentary

Sedation is commonly used in the intensive care unit (ICU) to reduce patient discomfort, improve tolerance with mechanical ventilation, prevent accidental device removal, and reduce metabolic demands during respiratory and hemodynamic instability.[1,2]Continuous and deep sedation have been associated with increased risk of delirium, longer duration of mechanical ventilation, increased length of ICU and hospital stays, and long-term risk of neurocognitive impairment, post-traumatic stress disorder, and mortality.[3–7] Sedation interruption and protocolized sedation have been associated with decreased length of ICU stay and reduced duration of mechanical ventilation.[4,5] Whether combining sedation interruption and protocolized sedation improves outcome is controversial. Whereas some studies show a benefit,[6] others show no difference.[8]

Commonly used first-line sedative medications, including propofol and midazolam, and less commonly used medications, such as lorazepam, have many side effects. There exists wide intra- and inter-individual variability,[9] resulting in unpredictable drug accumulation with benzodiazepines.[10] Lorazepam is associated with propylene glycol-related acidosis and nephrotoxicity. Propofol causes hypertriglyceridemia, pancreatitis, and propofol-related infusion syndrome.[11,12] Dexmedetomidine is a potent alpha-2 adrenoceptor agonist with an affinity for the alpha-2 adrenoceptor that is eight times higher than that of clonidine.[13] Prior data suggest that dexmedetomidine reduced duration of mechanical ventilation and resulted in earlier extubation.[14,15] In critically ill patients, use of dexmedetomidine has been associated with lower risk of delirium and coma compared with propofol, lorazepam, and midzolam.[15,16] However, safety and efficacy of prolonged dexmedetomidine infusion in the ICU have not been evaluated.

The PRODEX (Propofol vs. Dexmedetomidine) and MIDEX (Midazolam vs. Dexmedetomidine) trials attempted to answer this question with higher doses of dexmedetomidine for longer duration when compared with propofol and midazolam in mechanically ventilated patients. Both studies provide important clinical evidence that dexmedetomidine is an effective sedative agent compared with propofol and midazolam. Use of dexmedetomidine is associated with easier communication with patients, better assessment of pain (from the perspective of the caregiver), reduced delirium, and decreased time to extubation as compared with propofol. However, this finding did not translate into reduction of length of ICU or hospital stay. Among the strengths of the study are that it was a well-conducted, large, multicenter, double-blind, randomized controlled study. The trial employed frequent sedation assessment, daily sedation stops, and a double-dummy design to reduce the risk of bias.

Several important limitations to the study deserve further consideration. The weaning from mechanical ventilation and criteria for extubation were not standardized. Spontaneous breathing trials were performed in only about half of the sedation stops, as compared with approximately 60% of those screened in the Awakening and Breathing Controlled trial.[6] Whereas the incidence of neurocognitive disorders, including delirium, anxiety, and agitation, was evaluated throughout the study, the long-term neurocognitive and functional outcomes with dexmedetomidine have not been examined. Sedation was assessed from the caregivers’ perspective only, and future studies should include the patients’ perspective of quality of sedation. Also, this study included only patients with light to moderate sedation; thus, these findings may not be applicable to patients requiring deep sedation. In the first 24 hours of the PRODEX trial, discontinuation of dexmedetomidine was more frequent because of a lack of efficacy. As acknowledged by the authors of the PRODEX and MIDEX trials, most clinicians and centers do not consider dexmedetomidine an equivalent alternative to propofol and midazolam for long-term sedation. These trials, nevertheless, reassure clinicians regarding the safety of dexmedetomidine in terms of higher doses over a long period of time.

Recent guidelines of the Society of Critical Care Medicine recommend using non-benzodiazepine agents, such as propofol or dexmedetomidine, over benzodiazepines as a first-line sedative agent, and dexmedetomidine in patients at risk for delirium that is not related to alcohol and benzodiazepine use.[11] The opioid-sparing[11] effect of dexmedetomidine may reduce opioid requirements in critically ill patients. The most common side effects of dexmedetomidine are hypotension and bradycardia, and this limits its use in patients who are dependent on their cardiac output, such as patients in the acute phase of shock.

 

Recommendation

In carefully selected critically ill patients receiving prolonged mechanical ventilation, dexmedetomidine is safe and may be preferred as an alternative non-benzodiazepine agent to maintain light to moderate sedation. However, long-term outcomes, including neurocognitive effects, and the safety of dexmedetomidine are unknown.

Source: medscape.com