What's new in pulmonary and critical care medicine

The following represent additions to UpToDate from the past six months that were considered by the editors and authors to be of particular interest. The most recent What's New entries are at the top of each subsection.

ASTHMA

Approval of albuterol-budesonide for asthma in the United States (January 2023)

International guidelines have increasingly embraced concomitant use of as-needed inhaled glucocorticoid and a short-acting beta-agonist (SABA) as a therapeutic option for asthma, but combination inhalers have limited availability. A combination inhaler (albuterol-budesonide) has now been approved by the US Food and Drug Administration (FDA) for as-needed therapy in patients ≥18 years with asthma [1]. Although use of as-needed albuterol-budesonide is a reasonable approach for patients with mild persistent asthma or for those with intermittent asthma at high risk for serious exacerbations, it may not be widely available until early 2024. (See "Treatment of intermittent and mild persistent asthma in adolescents and adults", section on 'Combination inhaled glucocorticoid and short-acting beta-agonist as needed'.)

Persistence of asthma control after stopping omalizumab therapy (November 2022)

Omalizumab, an anti-IgE monoclonal antibody, is an effective add-on therapy for uncontrolled moderate-to-severe asthma but the optimal duration of therapy and the persistence of benefit after discontinuation are unclear. In an analysis of the French national healthcare database that included over 19,000 patients with asthma (over 2000 children) who received omalizumab for a median duration of approximately 4.5 years, rates of asthma hospitalizations were reduced by 75 percent and the need for oral corticosteroids by 30 percent after two years of treatment [2]. Among patients with asthma control during treatment, symptoms remained controlled in a significant percentage one, two, and three years after discontinuation (76, 44, and 33 percent in children and 70, 39, and 24 percent in adults, respectively). These findings indicate a lasting benefit after discontinuation of omalizumab in patients with controlled asthma and provide a basis for anticipatory guidance for those who discontinue treatment. (See "Anti-IgE therapy", section on 'Observations post-treatment'.)

Insulin resistance in severe asthma (November 2022)

Several studies have identified an increased prevalence of asthma and difficult-to-control asthma among obese individuals, although the exact reason for the association is not known. A recent study of patients with severe asthma included extensive metabolic phenotyping as well as long-term follow-up [3]. Patients with insulin resistance demonstrated more rapid decline in lung function and increased resistance to beta-agonist and oral glucocorticoid therapies compared with patients having normal insulin sensitivity. Whether targeting insulin resistance can impact these severe asthma features requires further investigation. (See "Severe asthma phenotypes", section on 'Asthma associated with obesity'.)

Mepolizumab for childhood asthma in urban under-served populations (October 2022)

Among adults and adolescents with severe eosinophilic asthma, treatment with mepolizumab (a monoclonal antibody to interleukin-5) reduces exacerbation rates; however, data in children are limited. Mepolizumab was compared with placebo in a trial of children and adolescents recruited from low-income, primarily urban environments in the United States who presented with poorly controlled asthma and elevated blood eosinophils. Mepolizumab reduced asthma exacerbation rates compared with placebo in this population (1.0 versus 1.3 per year, relative risk 0.73), but the improvement was less than that observed in prior trials of adults and adolescents (relative risk approximately 0.50) [4]. Whether this lesser performance is due to ongoing environmental exposure, higher levels of noneosinophilic inflammation, biologic changes between childhood and adult asthma, or other differences in the overall study populations is not well understood. (See "Treatment of severe asthma in adolescents and adults", section on 'Mepolizumab'.)

COPD

New GOLD strategy for initial COPD pharmacologic management (January 2023)

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2023 report identifies key changes for patients with COPD [5], specifically more aggressive initial bronchodilator therapy:

●Single-agent long-acting bronchodilator therapy for less severe symptoms and low exacerbation risk (Group A).

●Dual long-acting bronchodilator therapy for more severe symptoms and low exacerbation risk (Group B).

●Dual long-acting bronchodilator therapy for high exacerbation risk, regardless of symptoms (Group E, replacing previous Groups C and D categories).

It also redefines a COPD exacerbation as an event characterized by dyspnea and/or cough and sputum that worsens over ≤14 days with possible tachypnea and/or tachycardia caused by airway infection, pollution, or other insult to the airways. This new definition decouples exacerbations from their treatment, which had confounded earlier approaches. A new classification for severity of exacerbations was also outlined. (See "COPD exacerbations: Clinical manifestations and evaluation" and "Stable COPD: Initial pharmacologic management", section on 'Assessing disease pattern and severity'.)

Long-acting morphine not effective for severe breathlessness in COPD (December 2022)

Chronic breathlessness is a frequent symptom in patients with chronic obstructive pulmonary disease (COPD). Opiates are sometimes used for palliation of breathlessness, but the appropriate dosing and potential efficacy are uncertain. In a recent placebo-controlled trial of approximately 160 patients with moderate-to-severe COPD and severe breathlessness, extended release morphine (8 to 32 mg daily, increased stepwise) failed to improve breathlessness intensity or daily activity level but did increase serious treatment-related adverse events, including hospitalizations and death [6]. These findings support our practice of not using long-acting opioids for COPD-related dyspnea, except for individuals in hospice settings. (See "Management of refractory chronic obstructive pulmonary disease", section on 'Opioid therapy, for palliation'.)

Oral antihyperglycemic agents and prevention of COPD exacerbations (November 2022)

Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose co-transporter 2 (SGLT-2) inhibitors are antihyperglycemics increasingly used for the treatment of type 2 diabetes not controlled by metformin. In a recent study of patients with chronic obstructive pulmonary disease (COPD) and new initiation of an antihyperglycemic agent, patients who began GLP-1 receptor agonists or SGLT-2 inhibitors were less likely to be hospitalized for COPD exacerbations than similar patients receiving sulfonylureas, through as yet undefined mechanisms [7]. Future trials are needed to determine whether use of GLP-1 receptor agonists or SGLT-2 inhibitors are preferable to other antihyperglycemic agents in patients with diabetes mellitus and risk for COPD exacerbations. (See "COPD exacerbations: Prognosis, discharge planning, and prevention", section on 'GLP-1 receptor agonists and SGLT-2 inhibitors, for diabetic patients'.)

CRITICAL CARE

No difference in survival with high- versus low-dose protein diets in critically ill adults (February 2023)

The optimal amount of protein required to nutritionally support critically ill patients is unknown. A recent randomized trial of over 1300 mechanically ventilated patients (mostly for medical conditions) reported no significant difference in survival to hospital discharge or 60-day mortality when prescribed high versus usual daily protein administration [8]. Until further studies demonstrate clear benefit from high protein prescriptions ≥2.2 g/kg per day, we continue to prescribe ≤1.2 g/kg of protein per day for most patients and reserve higher amounts (up to 2 g/kg per day) for those who are severely ill. (See "Nutrition support in critically ill patients: An overview", section on 'Protein'.)

Restrictive versus liberal fluid regimen does not impact mortality in refractory sepsis (February 2023)

The optimal approach to adults with sepsis refractory to initial fluid resuscitation is unclear. In a recent trial of over 1500 patients with sepsis-induced hypotension refractory to initial resuscitation, 90-day mortality was not significantly different between a restrictive fluid regimen (prioritizing vasopressors and lower intravenous fluid volumes) or a more "liberal" regimen (prioritizing higher volumes of intravenous fluids before vasopressor use) [9]. Vasopressors were administered earlier and for longer periods in those who received the restrictive regimen without excess adverse effects. This study suggests that fluid restriction with early initiation of vasopressors compared with more liberal fluid administration similar to current practice does not decrease mortality. (See "Evaluation and management of suspected sepsis and septic shock in adults", section on 'Volume'.)

New anesthesia society guidelines for neuromuscular blockade (January 2023)

Both the American Society of Anesthesiologists (ASA) and European Society of Anaesthesiology and Intensive Care (ESAIC) have published new guidelines on the management of neuromuscular blockade during anesthesia [10,11]. In addition to other recommendations, both guidelines strongly recommend using quantitative neuromuscular monitoring (eg, electromyography or accelerometry) rather than qualitative assessment and confirming a train-of-four ratio ≥0.9 before extubation. They also recommend using sugammadex for reversal rather than neostigmine for patients who have received rocuronium or vecuronium and who have residual block at or deeper than a train-of-four ratio of 0.4. Our recommendations are consistent with these guidelines. (See "Monitoring neuromuscular blockade", section on 'When and how to monitor neuromuscular blockade' and "Clinical use of neuromuscular blocking agents in anesthesia".)

Artificial intelligence systems to detect sepsis (January 2023)

Targeted Real-Time Early Warning System (TREWS) is a bedside tool which uses artificial intelligence (AI) to alert the clinicians to the risk of sepsis [12,13]. Two studies recently reported that use of TREWS reduced sepsis-related mortality by 3 percent when a provider responded to and confirmed the alert within three hours compared with patients whose alert was not confirmed by a provider within the same timeframe. However, only 38 percent of evaluated alerts had provider-confirmed sepsis, suggesting limited specificity of the system. Further data are needed before AI systems such as TREWS can be routinely used to reliably identify sepsis. (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis", section on 'Identification of early sepsis (qSOFA, NEWS)'.)

High-flow oxygen for acute respiratory failure due to COVID-19 (January 2023)

In patients with acute hypoxemic respiratory failure due to coronavirus disease 2019 (COVID-19), high-flow oxygen delivered via nasal cannulae (HFNC) is used to lower intubation rates. In a recent randomized trial in >700 patients with respiratory failure due to COVID-19, use of HFNC resulted in lower intubation rates compared with standard low-flow oxygen (45 versus 53 percent) without an impact on mortality or ventilator-free days [14]. These results, along with outcomes from a prior trial, support our practice of switching to HFNC in adults with COVID-19 who have advanced respiratory needs rather than increasing low-flow oxygen (eg, above 6 L per minute). (See "COVID-19: Respiratory care of the nonintubated hypoxemic adult (supplemental oxygen, noninvasive ventilation, and intubation)", section on 'Noninvasive modalities'.)

Haloperidol does not decrease mortality in mechanically ventilated patients with delirium (December 2022)

Haloperidol is frequently used to treat delirium in critically ill adults. A recent randomized trial of 1000 mechanically ventilated patients found that treatment of delirium with haloperidol did not alter the number of days alive outside the hospital at 90 days compared with placebo [15]. Limitations of the trial include a lack of data on other sedatives used and possible poor enrollment of patients with hypoactive delirium. These findings support prior studies that suggest that haloperidol can be safely used to treat delirium in ventilated patients but confers no mortality benefit. (See "Sedative-analgesic medications in critically ill adults: Properties, dose regimens, and adverse effects", section on 'Antipsychotics'.)

Prevalence of long COVID (December 2022)

The true prevalence of long COVID-19 is unknown due to varying definitions and methods of analysis. A meta-analysis of 54 studies (>1 million patients) estimated that 6.2 percent of individuals who had symptomatic COVID-19 between March 2020 and January 2022 experienced at least one long COVID symptom [16]. Persistent fatigue was most common, followed by ongoing respiratory problems and cognitive dysfunction. The estimated duration was 9 months after hospital discharge and 4 months for individuals who were not hospitalized These data shed light on the true prevalence of long COVID-19. Whether this rate also applies to the omicron variant requires additional study. (See "COVID-19: Evaluation and management of adults with persistent symptoms following acute illness ("Long COVID")".)

Reduced ventilatory response to hypercapnia by opioid alternatives (December 2022)

Opioids are known to decrease the ventilatory response to hypercapnia. Whether other drugs commonly used in place of opioids can cause similar effects was studied in 19 healthy volunteers using carbon dioxide rebreathing technology [17]. Individuals were treated with oral quetiapine (100 mg to 400 mg twice daily), paroxetine (40 mg daily), or either drug combined with oxycodone (10 mg daily) and compared with oxycodone alone or placebo. Paroxetine alone and paroxetine combined with oxycodone decreased the ventilatory response to hypercapnia while quetiapine alone or combined with oxycodone did not cause such an effect. This study highlights potential harm associated with opioid alternatives but further study is needed to determine if this effect is clinically relevant and persistent in the long term. (See "Control of ventilation", section on 'Alterations in ventilatory response to CO2 and O2'.)

Aggressive early mobilization not of benefit in ventilated patients (December 2022)

Early mobilization within the first 72 hours in stable mechanically-ventilated patients is one strategy to decrease muscle weakness associated with post-intensive care unit syndrome and is supported by the American Thoracic Society, American College of Chest Physicians, and Society of Critical Care Medicine. In a recent, multicenter randomized trial of 750 ventilated patients, aggressive early mobilization (increased duration of sedation minimization and daily physiotherapy) did not impact the number of days alive outside of the hospital or three-month mortality when compared with conventional early mobilization strategies [18]. Moreover, it was associated with an increased rate of adverse events, mostly arrhythmia, oxygen desaturation, and altered blood pressure. These findings support current protocols rather than aggressive mobilization. (See "Post-intensive care syndrome (PICS)", section on 'Prevention'.)

No difference between pressure support and T-piece breathing trials in ventilated patients (December 2022)

In mechanically ventilated patients, spontaneous breathing trials (SBTs) are typically done to determine readiness for extubation, but the optimal method for performing SBTs is uncertain (ie, pressure support ventilation [PSV]- or T-piece SBTs). A recent multicenter trial of over 960 patients at high risk of extubation failure reported no difference in the number of ventilator-free days or rate of successful extubation or reintubation when PSV-SBT was compared with T-piece SBT [19]. However, most patients received prophylactic noninvasive ventilatory support immediately following extubation which may have minimized the difference between the groups. We continue to suggest PSV-SBT rather than T-piece SBT in patients at high risk of extubation failure, although the latter may be acceptable in select patients. (See "Initial weaning strategy in mechanically ventilated adults", section on 'Choosing ventilatory support'.)

Xylazine adulteration of illicit drugs (December 2022)

Xylazine is an alpha-2 agonist and a chemical analogue of clonidine that is used in veterinary medicine for sedation and analgesia. In humans, xylazine overdose has caused major toxicity consisting of coma, apnea, bradycardia, and hypotension as well as severe, necrotic skin ulcerations after repeated parenteral use. Xylazine is increasingly found as an adulterant in illicit drugs, especially heroin and fentanyl, with rising reports of serious side effects. As a result, the US Food and Drug Administration has issued an alert to health care professionals and a letter to stakeholders [20]. Xylazine poisoning is on the differential diagnosis for patients with suspected opioid overdose that does not respond to naloxone administration. Treatment consists of supportive care. There is no rapid diagnostic testing for xylazine poisoning or safe antidote. (See "Clonidine and related imidazoline poisoning", section on 'Imidazoline agents'.)

LUNG TRANSPLANTATION

Modern incidence and consequences of primary graft dysfunction after lung transplant (January 2023)

Primary graft dysfunction (PGD) is a known risk factor for outcomes after transplant, but changes in patient selection and perioperative care may impact the incidence and consequences of PGD. In the multicenter Lung Transplant Outcomes Group (LTOG) study, incidence of grade 3 PGD at 48 or 72 hours was higher among patients enrolled from 2011 and 2018 compared with the previous 2002 to 2010 LTOG study (26 versus 17 percent) [21]. Patients with grade 3 PGD at 48 or 72 hours had prolonged postoperative mechanical ventilation, increased hospital length of stay, and a nearly 10 percent absolute increase in one-year mortality compared with the rest of the cohort. Continued efforts are needed to prevent and mitigate PGD. (See "Primary lung graft dysfunction", section on 'Survival'.)

PULMONARY VASCULAR DISEASE

Aspirin for venous thromboembolism prophylaxis in multiple-trauma patients (January 2023)

Aspirin is an effective alternative for venous thromboembolism (VTE) prophylaxis in patients undergoing elective orthopedic surgery, but it’s role in trauma-related orthopedic surgery is not well-defined. The PREVENT CLOT trial has now evaluated aspirin in trauma patients with fractures and undergoing surgical fracture fixation [22]. In this trial, which randomized over 12,000 patients, aspirin was noninferior to low molecular weight heparin. Differences in rates of death, pulmonary embolism, deep venous thrombosis, bleeding, and other complications were not clinically significant. This trial supports a role for aspirin for VTE prophylaxis in multiple-trauma patients with orthopedic injuries, but more evidence is needed to determine the optimal timing (initiation) and duration of aspirin therapy before its use can become routine. (See "Venous thromboembolism risk and prevention in the severely injured trauma patient", section on 'Aspirin'.)

Dose of LMW heparin for VTE prevention in pregnancy (November 2022)

Low molecular weight (LMW) heparin is used for venous thromboembolism (VTE) prophylaxis during pregnancy and postpartum, but optimal dosing has been unclear. The Highlow trial evaluated dosing in 1110 pregnant individuals with a prior VTE receiving LMW heparin for VTE prophylaxis from the first trimester to six weeks postpartum [23]. Compared with weight-adjusted intermediate dosing, those assigned to daily fixed low-dose (60 mg) LMW heparin had a slightly higher rate of VTE (1 percent in both groups antepartum, 2 versus 1 percent postpartum); the difference did not reach statistical significance. Bleeding risk was 4 percent in each group. While we continue to perform an individualized risk assessment for each patient, this trial provides reassurance for the efficacy of fixed low-dose LMH heparin, especially antenatally. (See "Use of anticoagulants during pregnancy and postpartum", section on 'LMW heparin'.)

Low molecular weight heparin dose adjustment in trauma patients (October 2022)

Low molecular weight heparin (LMWH) is administered to adult trauma patients to reduce the risk of venous thromboembolism (VTE), but questions remain about dosing and monitoring. In a meta-analysis of observational studies including heterogeneous multisystem trauma patients, those who attained prophylactic anti-Xa levels had a lower rate of VTE than those who did not [24]. However, dose adjustment to achieve prophylactic anti-Xa levels paradoxically did not reduce VTE compared with standard fixed enoxaparin dosing. While there is likely a role for LMWH dose adjustment based on anti-Xa levels in trauma patients, the optimal protocol and trauma population that would benefit have not been determined. (See "Venous thromboembolism risk and prevention in the severely injured trauma patient", section on 'Monitoring and adjustment'.)

SLEEP MEDICINE

Position statement on obstructive sleep apnea in the transportation industry (October 2022)

The American Academy of Sleep Medicine (AASM) has published a position statement on recognizing and treating obstructive sleep apnea (OSA) in commercial drivers and other individuals in safety-sensitive transportation occupations [25,26]. The documents outline roles for key stakeholders, including legislators, employers, law enforcement, payers, health care professionals, and vehicle operators. The AASM recommends that commercial drivers be referred to a sleep medicine specialist for clinical sleep evaluation and diagnostic testing in the presence of a body mass index (BMI) ≥40 kg/m², fatigue or sleepiness while on duty, involvement in a sleepiness-related crash or accident, or a BMI ≥33 kg/m² plus either type 2 diabetes or hypertension requiring two or more medications. (See "Drowsy driving: Risks, evaluation, and management", section on 'Special considerations in commercial drivers'.)

OTHER PULMONARY MEDICINE

Anticoagulation in hereditary hemorrhagic telangiectasia (February 2023)

Hereditary hemorrhagic telangiectasia (HHT) is a vascular disorder with increased risk of bleeding, but individuals with HHT also have an increased risk of thrombosis and may require anticoagulation. In a new study that followed 119 individuals with HHT receiving antithrombotic therapy, the rate of dose reduction or premature drug discontinuation was 50 percent [27]. Multivariate analysis identified prior gastrointestinal bleeding as the main risk factor for dose reduction or discontinuation; the choice of anticoagulant (warfarin or a direct oral anticoagulant [DOAC]) was not predictive. Individuals with HHT can receive anticoagulation but require especially close monitoring. Current guidelines suggest warfarin if an oral anticoagulant is needed, but DOACs may be considered on a case-by-case basis. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'Individuals who require anticoagulation (VTE and AF)'.)

Apixaban and rivaroxaban after bariatric surgery (February 2023)

The anticoagulants apixaban and rivaroxaban are typically given at a fixed dose without drug monitoring. Two areas of concern are use in individuals with a very high body mass index (BMI) and use following bariatric surgery, which disrupts the gastrointestinal anatomy and might affect absorption. In a retrospective series of 102 adults who required anticoagulation for venous thromboembolism (VTE) after bariatric surgery, there were no episodes of VTE recurrence in individuals treated with apixaban and one recurrence in an individual treated with rivaroxaban; this individual had multiple other risk factors (foot ulcers, boot immobilization, and a BMI of 54 kg/m²) [28]. When these anticoagulants are used in individuals with a high BMI and/or post-bariatric surgery, measurement of a trough level is used to ensure absorption. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'High BMI and post-bariatric surgery'.)