case study respiratory failure

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Reviewed By Behavioral Science Assembly

Submitted by

Lokesh Venkateshaiah, MD

Division of Pulmonary, Critical Care and Sleep Medicine

The MetroHealth System, Case Western Reserve University

Cleveland, Ohio

Bruce Arthur, MD

J. Daryl Thornton, MD, MPH

Assistant Professor

Division of Pulmonary, Critical Care and Sleep Medicine, Center for Reducing Health Disparities

Submit your comments to the author(s).

A 60-year-old man presented to the emergency department complaining of persistent right-sided chest pain and cough. The chest pain was pleuritic in nature and had been present for the last month. The associated cough was productive of yellow sputum without hemoptysis. He had unintentionally lost approximately 30 pounds over the last 6 months and had nightly sweats. He had denied fevers, chills, myalgias or vomiting. He also denied sick contacts or a recent travel history. He recalled childhood exposures to persons afflicted with tuberculosis. 

The patient smoked one pack of cigarettes daily for the past 50 years and denied recreational drug use. He reported ingesting twelve beers daily and had had delirium tremens, remote right-sided rib fractures and a wrist fracture as a result of alcohol consumption. He had worked in the steel mills but had discontinued a few years previously. He collected coins and cleaned them with mercury. 

The patient’s past medical history was remarkable for chronic “shakes” of the upper extremities for which he had not sought medical attention. Other than daily multivitamin tablets, he took no regular medications. 

Hospital course  He was initially admitted to the general medical floor for treatment of community-acquired pneumonia (see Figure 1) and for the prevention of delirium tremens. He was initiated on ceftriaxone, azithromycin, thiamine and folic acid. Diazepam was initiated and titrated using the Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWAS-Ar), a measure of withdrawal severity (1).  By hospital day 5, his respiratory status continued to worsen, requiring transfer to the intensive care unit (ICU) for hypoxemic respiratory failure. His neurologic status had also significantly deteriorated with worsening confusion, memory loss, drowsiness, visual hallucinations (patient started seeing worms) and worsening upper extremity tremors without generalized tremulousness despite receiving increased doses of benzodiazepines.

Physical Exam

White blood cell count was 11,000/mm 3 with 38% neutrophils, 8% lymphocytes, 18 % monocytes and 35% bands

Hematocrit 33%

Platelet count was 187,000/mm 3

Serum sodium was 125 mmol/L, potassium 3 mmol/L, chloride 91 mmol/L, bicarbonate 21 mmol/L, blood urea nitrogen 14 mg /dl, serum creatinine  0.6 mg/dl and anion gap of 14.

Urine sodium <10 mmol/L, urine osmolality 630 mosm/kg

Liver function tests revealed albumin 2.1 with total protein 4.6, normal total bilirubin, aspartate transaminase (AST) 49, Alanine transaminase (ALT) 19 and alkaline phosphatase 47.

Three sputum samples were negative for acid-fast bacilli (AFB).

Bronchoalveolar lavage (BAL) white blood cell count 28 cells/µl, red blood cell count 51 cells/µl, negative for AFB and negative Legionella culture.  BAL gram stain was without organisms or polymorphonuclear leukocytes.

Blood cultures were negative for growth.

Sputum cultures showed moderate growth of Pasteurella multocida.

2D transthoracic ECHO of the heart showed normal valves and an ejection fraction of 65% with a normal left ventricular end-diastolic pressure and normal left atrial size.  No vegetations were noted.

Purified protein derivative (PPD) administered via Mantoux testing was 8 mm in size at 72 hr after placement.

Human immunodeficiency virus (HIV) serology was negative. 

Arterial blood gas (ABG) analysis performed on room air on presentation to the ICU: pH 7.49, PaCO 2 29 mm Hg, PaO 2 49 mm Hg.

After admission to the ICU, the patient was noted to be in acute lung injury (ALI), a subset of acute respiratory distress syndrome (ARDS). The diagnosis of ALI requires all three of the following:  (a) bilateral pulmonary infiltrates, (b) a PaO 2 :FiO 2 ratio of ≤ 300 and (c) echocardiographic evidence of normal left atrial pressure or pulmonary-artery wedge pressure of ≤ 18 mm Hg (2). 

While patients with ALI and ARDS can be maintained with pressure-limited or volume-limited modes of ventilation, only volume assist-control ventilation was utilized in the ARDS Network multicenter randomized controlled trial that demonstrated a mortality benefit.

Noninvasive ventilation has not been demonstrated to be superior to endotracheal intubation in the treatment of ARDS or ALI and is not currently recommended (4).

This is a case of heavy metal poisoning with mercury.  The patient used mercury to clean coins.  Family members who had visited his house while he was hospitalized found several jars of mercury throughout his home.  The Environmental Protection Agency (EPA) was notified and visited the home.  They found aerosolized mercury levels of > 50,000 PPM and had the home immediately demolished. 

Alcoholic hallucinosis is a rare disorder occurring in 0.4 - 0.7% of alcohol-dependent inpatients (5).  Affected persons experience predominantly auditory but occasionally visual hallucinations.  Delusions of persecution may also occur.  However, in contrast to alcohol delirium, other alcohol withdrawal symptoms are not present and the sensorium is generally unaffected.

Delerium tremens (DT) occurs in approximately 5% of patients who withdraw from alcohol and is associated with a 5% mortality rate. DT typically occurs between 48 and 96 hr following the last drink and lasts 1-5 days.  DT is manifested by generalized alteration of the sensorium with vital sign abnormalities.  Death often results from arrhythmias, pneumonia, pancreatitis or failure to identify another underlying problem (6).  While DT certainly could have coexisted in this patient, an important initial step in the management of DT is to identify and treat alternative diagnoses.

Delirium is frequent among older patients in the ICU (7), and may be complicated by pneumonia and sepsis.  However, pneumonia and sepsis as causes for delirium are diagnoses of exclusion and should only be attributed after other possibilities have been ruled out. 

Frontal lobe stroke is unlikely, given the absence of other findings in the history or physical examination present to suggest an acute cerebrovascular event. 

In 1818, Dr. John Pearson coined the term erethism for the characteristic personality changes attributed to mercury poisoning (8).  Erethism is classically the first symptom in chronic mercury poisoning (9).  It is a peculiar form of timidity most evident in the presence of strangers and closely resembles an induced paranoid state.  In the past, when mercury was used in making top hats, the term “mad as a hatter” was used to describe the psychiatric manifestations of mercury intoxication.  Other neurologic manifestations include tremors, especially in patients with a history of alcoholism, memory loss, drowsiness and lethargy.  All of these were present in this patient. 

Acute respiratory failure (ALI/ARDS) can occur following exposure to inhalation of mercury fumes (10). Mercury poisoning has also been associated with acute kidney injury (11). 

Although all of the options mentioned above could possibly contribute to the development of delirium, only mercury poisoning would explain the constellation of findings of confusion, upper extremity tremors, visual hallucinations, somnolence and acute respiratory failure (ALI/ARDS).

Knowledge of the form of mercury absorbed is helpful in the management of such patients, as each has its own distinct characteristics and toxicity. There are three types of mercury: elemental, organic and inorganic. This patient had exposure to elemental mercury from broken thermometers. 

Elemental mercury is one of only two known metals that are liquid at room temperature and has been referred to as quicksilver (12). It is commonly found in thermometers, sphygmomanometers, barometers, electronics, latex paint, light bulbs and batteries (13).  Although exposure can occur transcutaneously or by ingestion, inhalation is the major route of toxicity.  Ingested elemental mercury is poorly absorbed and typically leaves the body unchanged without consequence (bioavailability 0.01% [13]). However, inhaled fumes are rapidly absorbed through the pulmonary circulation allowing distribution throughout the major organ systems.  Clinical manifestations vary based on the chronicity of the exposure (14).  Mercury readily crosses the blood-brain barrier and concentrates in the neuronal lysosomal dense bodies. This interferes with major cell processes such as protein and nucleic acid synthesis, calcium homeostasis and protein phosphorylation.  Acute exposure symptoms manifest within hours as gastrointestinal upset, chills, weakness, cough and dyspnea.

Inorganic mercury salts are earthly-appearing, red ore found historically in cosmetics and skin treatments.  Currently, most exposures in the United States occur from exposure through germicides or pesticides (15).  In contrast to elemental mercury, inorganic mercury is readily absorbed through multiple routes including the gastrointestinal tract.  It is severely corrosive to gastrointestinal mucosa (16).  Signs and symptoms include profuse vomiting and often-bloody diarrhea, followed by hypovolemic shock, oliguric renal failure and possibly death (12).

Organic mercury, of which methylmercury is an example, has garnered significant attention recently following several large outbreaks as a result of environmental contamination in Japan in 1956 (17) and grain contamination in Iraq in 1972 (18).  Organic mercury is well absorbed in the GI tract and collects in the brain, reaching three to six times the blood concentration (19).  Symptoms may manifest up to a month after exposure as bilateral visual field constriction, paresthesias of the extremities and mouth, ataxia, tremor and auditory impairments (12).  Organic mercury is also present in a teratogenic agent leading to development of a syndrome similar to cerebral palsy termed "congenital Minamata disease" (20).

The appropriate test depends upon the type of mercury to which a patient has been exposed.  After exposure to elemental or inorganic mercury, the gold standard test is a 24-hr urine specimen for mercury.  Spot urine samples are unreliable.  Urine concentrations of greater than 50 μg in a 24-hr period are abnormal (21).  This patient’s 24-hr urine level was noted to be 90 μg.  Elemental and inorganic mercury have a very short half-life in the blood.

Exposure to organic mercury requires testing hair or whole blood.  In the blood, 90% of methyl mercury is bound to hemoglobin within the RBCs.  Normal values of whole blood organic mercury are typically < 6 μg/L. This patient’s whole blood level was noted to be 26 μg/L.  This likely reflects the large concentration of elemental mercury the patient inhaled and the substantial amount that subsequently entered the blood.

Mercury levels can be reduced with chelating agents such as succimer, dimercaprol (also known as British anti-Lewisite (BAL)) and D-penicillamine, but their effect on long-term outcomes is unclear (22-25).

• Sullivan JT, Sykora K, Schneiderman J, et al. Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar). Br J Addict 1989;84:1353-1357.
• Bernard GR, Artigas A, Brigham KL, et al. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994;149:818-824.
• The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000;342:1301-1308.
• Agarwal R, Reddy C, Aggarwal AN, et al. Is there a role for noninvasive ventilation in acute respiratory distress syndrome? A meta-analysis. Respir Med 2006;100:2235-2238.
• Soyka M. Prevalence of alcohol-induced psychotic disorders. Eur Arch Psychiatry Clin Neurosci 2008;258:317-318.
• Tavel ME, Davidson W, Batterton TD. A critical analysis of mortality associated with delirium tremens. Review of 39 fatalities in a 9-year period. Am J Med Sci 1961;242:18-29.
• McNicoll L, Pisani MA, Zhang Y, et al. Delirium in the intensive care unit: occurrence and clinical course in older patients. J Am Geriatr Soc 2003;51:591-598.
• Bateman T. Notes of a case of mercurial erethism. Medico-Chirurgical Transactions 1818;9:220-233.
• Buckell M, Hunter D, Milton R, et al. Chronic mercury poisoning. 1946. Br J Ind Med 1993;50:97-106.
• Rowens B, Guerrero-Betancourt D, et al. Respiratory failure and death following acute inhalation of mercury vapor. A clinical and histologic perspective. Chest 1991;99:185-190.
• Aguado S, de Quiros IF, Marin R, et al. Acute mercury vapour intoxication: report of six cases. Nephrol Dial Transplant 1989;4:133-136.
• Ibrahim D, Froberg B, Wolf A, et al. Heavy metal poisoning: clinical presentations and pathophysiology. Clin Lab Med 2006;26:67-97, viii.
• A fact sheet for health professionals - elemental mercury. Available from: http://www.idph.state.il.us/envhealth/factsheets/mercuryhlthprof.htm
• Clarkson TW, Magos L, Myers GJ. The toxicology of mercury - current exposures and clinical manifestations. N Engl J Med 2003;349:1731-1737.
• Boyd AS, Seger D, Vannucci S, et al. Mercury exposure and cutaneous disease. J Am Acad Dermatol 2000;43:81-90.
• Dargan PI, Giles LJ, Wallace CI, et al. Case report: severe mercuric sulphate poisoning treated with 2,3-dimercaptopropane-1-sulphonate and haemodiafiltration. Crit Care 2003;7:R1-6.
• Eto K. Minamata disease. Neuropathology 2000;20:S14-9.
• Bakir F, Damluji SF, Amin-Zaki L, et al. Methylmercury poisoning in Iraq. Science 1973;181:230-241.
• Berlin M, Carlson J, Norseth T. Dose-dependence of methylmercury metabolism. A study of distribution: biotransformation and excretion in the squirrel monkey. Arch Environ Health 1975;30:307-313.
• Harada M. Congenital Minamata disease: intrauterine methylmercury poisoning. Teratology 1978;18:285-288.
• Graeme KA, Pollack CVJ. Heavy metal toxicity Part I: Arsenic and mercury. J Emerg Med 1998;16:45-56.
• Aaseth J, Frieheim EA. Treatment of methylmercury poisoning in mice with 2,3-dimercaptosuccinic acid and other complexing thiols. Acta Pharmacol Toxicol (Copenh) 1978;42:248-252.
• Archbold GP, McGuckin RM, Campbell NA. Dimercaptosuccinic acid loading test for assessing mercury burden in healthy individuals. Ann Clin Biochem 2004;41:233-236.
• Kosnett MJ. Unanswered questions in metal chelation. J Toxicol Clin Toxicol 1992;30:529-547.
• Zimmer LJ, Carter DE. The efficacy of 2,3-dimercaptopropanol and D-penicillamine on methyl mercury induced neurological signs and weight loss. Life Sci 1978;23:1025-1034.

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BEEM Cases 3 – Acute Respiratory Failure: NIPPV & POCUS

BEEM Cases 3 on EM Cases – Acute Respiratory Failure. BEEM Cases  is a collaboration between Andrew Worster of Best Evidence in Emergency Medicine (BEEM) and Emergency Medicine Cases’ Anton Helman, Rory Spiegel and Justin Morgenstern.

Written by Justin Morgenstern (@First10EM), edited by Anton Helman (@EMCases), September 2016

Dypnea & Acute Respiratory Failure: Sometimes the Cause is Not So Obvious

The case….

A 73-year-old woman presents to the emergency department via EMS with increasing shortness of breath and cough over the past day. She has a history of COPD, CHF, hypertension, and hyperlipidemia. On arrival, she is breathing rapidly at 34 breaths a minute and is using all her accessory muscles. Her heart rate is 115, BP 155/95, Temp 37.5 and oxygen saturation 89% on 4L via nasal cannula. You perform a rapid physical exam, but you still aren’t sure exactly what is causing her dyspnea. Your RT turns to you and asks what you’d like to do.

Shortness of breath is a very common chief complaint in the emergency department, but despite our familiarity with this symptom, management is not always straightforward. The differential diagnosis is extensive, including the common cardiorespiratory conditions, but extending to toxicologic, hematologic, neuromuscular, metabolic, and psychiatric causes. Over the past decade, we have seen the widespread adoption of new technologies to help us manage these patients. This post will look at some new evidence on two of those technologies: noninvasive positive pressure ventilation (NIPPV) and ultrasound (POCUS). We will answer 3 questions based on 3 systematic reviews using the BEEM critical appraisal framework:

Question #1

Does noninvasive positive pressure ventilation (NIPPV) reduce mortality in acute respiratory failure?

Jump to Question 1 Discussion

Question #2

Does prehospital CPAP or BiPAP improve clinical outcomes for patients in acute respiratory failure?

Jump to Question 2 Discussion

Question #3

What is the sensitivity and specificity of POCUS using B-lines in diagnosing acute cardiogenic pulmonary edema in patients presenting to the ED with acute dyspnea?

Jump to Question 3 Discussion

Question #1 Does noninvasive positive pressure ventilation (NIPPV) reduce mortality in acute respiratory failure?

Cabrini L, Landoni G, Oriani A. Noninvasive ventilation and survival in acute care settings: a comprehensive systematic review and metaanalysis of randomized controlled trials. Critical care medicine. 43(4):880-8. 2015.

Study details (PICO)

Systematic review and meta-analysis

Key results

This meta-analysis found 78 trials that fit the inclusion criteria, with a total of 7365 patients. For the primary outcome of mortality, they found that noninvasive positive pressure ventilation decreased overall mortality (RR=0.73 [95% CI: 0.66, 0.81]) with a NNT=19.

BE EM   critique

This is the largest review of NIPPV to date and its primary outcome is mortality, the ultimate clinical outcome. Although 60% of the data is from the ICU setting, the results are probably still applicable to the ED and provide convincing evidence that patients with acute respiratory distress (except asthma) should be considered for NIPPV as a first line therapy. The suggestion that early NIPPV is better than late requires further study.

Key EBM point : Heterogeneity. The trials included in this meta-analysis displayed high heterogeneity. This simply means that the trials were different from each other in some way. There are two key types of heterogeneity. Clinical heterogeneity occurs when there is variability in key clinical aspects of trials. For example, two trials may look at different populations of patients or measure different outcomes. Statistical heterogeneity refers to the likelihood that the variability among the different results (one trial might report a 2% benefit whereas another reports a 18% benefit) is due to chance alone. Heterogeneity matters because if trials are too dissimilar it may not be appropriate to combine them into a single statistical analysis.

Case continued…

You start the patient on BiPAP and within 10 minutes her numbers have improved and she looks a lot better. One of the paramedics who brought her in is surprised by the rapid improvement and asks you if they should be starting some kind of non-invasive ventilation in the ambulance before arriving at the emergency department.

Question #2 Does NIPPV improve clinical outcomes in acute respiratory failure?

Goodacre S, Stevens JW, Pandor A. Prehospital noninvasive ventilation for acute respiratory failure: systematic review, network meta-analysis, and individual patient data meta-analysis. Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 21(9):960-70. 2014.

Primary outcome (mortality): Key results

• CPAP reduced morality (OR=0.41; 95% credible interval [Crl] 0.20 to 0.77)
• The effect of BiPAP on mortality was unclear (OR=1.94; 95% Crl = 0.65 to 6.14)

Secondary outcome (intubation):

• CPAP reduced intubations (OR=0.32; 95% Crl 0.17 to 0.62)
• The effect of BiPAP on intubation was unclear (OR=0.40; 95% Crl = 0.14 to 1.16)

The benefits of NIPPV for patients in acute respiratory failure are well documented. Also, NIPPV is likely to be most effective when introduced early. The evidence supporting at least CPAP from this study is encouraging but differences in outcomes between CPAP and BiPAP reflects more upon the lack of large RCTs rather than the actual clinical difference between them. Regardless, the cost of equipping ambulances with NIPPV gear has to be taken into consideration when assessing its effectiveness in the prehospital setting.

The patient is improving, but you still aren’t sure about the diagnosis. There might have been an elevated JVP, but her neck isn’t easy to examine. The lungs sound a little wheezy, but there were probably some fine crackles there as well. You are resigned on waiting for the chest x-ray, when your resident asks if lung ultrasound might help diagnose pulmonary edema.

Question #3 Accuracy of POCUS for Diagnosing Acute Heart Failure

What is the sensitivity and specificity of point of care ultrasound (POCUS) using B-lines in diagnosing acute cardiogenic pulmonary edema in patients presenting to the ED with acute dyspnea?

Al Deeb M, Barbic S, Featherstone R, Dankoff J, Barbic D. Point-of-care ultrasonography for the diagnosis of acute cardiogenic pulmonary edema in patients presenting with acute dyspnea: a systematic review and meta-analysis. Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 21(8):843-52. 2014.

They identified 7 studies that included a total of 1075 patients. Two of the studies were ED studies. The other 5 took place in the ICU, hospital wards, or prehospital environment.

Diagnostic characteristics:

• Sensitivity of B lines of POCUS to diagnose acute pulmonary edema: 94% [95% CI: 81.3%, 98.3%]
• Specificity of B lines of POCUS to diagnose acute pulmonary edema: 92% [95% CI: 84.2%, 96.4%]
• Positive likelihood ratio 12.4 [95% CI: 5.7, 26.8]
• Negative likelihood ratio 0.06 [95% CI: 0.02, 0.22]

The question asked in this review is relevant but as the authors admit, there is no standardized threshold for the diagnosis of acute cardiac pulmonary edema (ACPE) and no definitive gold standard. Like the first study reviewed in this BEEM Cases, this one was too heterogeneous. While this study was exhaustive in searching for ultrasound diagnostics performed at the bedside it was not restrictive in settings, patient demographics, or ultrasound training of provider and this would lead to heterogeneity. Another issue that contributes to the heterogeneity and challenges the validity of the results is the lack of standardization of the ultrasound exam: The identification of ACPE using B-lines via the Volpicelli method is dependent upon patient position as well as position duration.

The conclusion that B-line on ultrasound can confirm the diagnosis when the pretest probability of disease is high or low has little utility. Diagnostic tests are valuable when they can confirm or refute a diagnosis when the pretest probability is indeterminate.

Case Resolution…

The patient rapidly improves after being placed on BiPAP. Your bedside ultrasound was consistent with CHF, but understanding the limitations of the test you also ordered your traditional work-up including blood work, ECG, and chest x-ray. Within a few hours in the department, after treatment with nitroglycerin and furosemide, you are able to titrate down and then discontinue the positive pressure ventilation. On a repeat bedside ultrasound, the b-lines have disappeared. Combining the ultrasound findings with the remainder of your tests, and most importantly your clinical judgement and frequent reassessments of the patient, you diagnose her with an exacerbation of CHF and admit her to the medical team for monitoring and adjustment of her medications.

About the Author: Anton Helman

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Hi Anton, great post! Q # 1 – The majority of trials are on patients with either COPD exacerbation or ACPE. For these 2 categories, NPPV efficacy in terms of ETI reduction and mortality are okay. Bottom line 1: NPPV is first choice in ACPE or COPDex – Acute hypoxemic respiratory failure (except ACPE) is still controversial. Few positive RCTs on pneumonia (Confalonieri M goo.gl/K4EHZV, Brambilla AM goo.gl/uKKDpx, Cosentini R goo.gl/rReh7f), one recent positive RCT on ARDS (Patel BK oo.gl/lKNqkv). Bottom line2: NPPV for pneumonia –> 1. okay in the immunocompromised population, 2. In the immunocompetent population: early application, that is patient selection is the key (and short trial) – ARDS. Patient selection seems the key, however needs further confirmation – Asthma. Primum non nocere!

Q # 2 Pre-hospital NPPV modality of choice might be CPAP. 1.The majority of patients have AHF/ACPE, 2. easier to learn and carry, 3. cheaper

Q # 3 LUS is already in every acute dyspnoea algorythm (Lichtenstein blue protocol goo.gl/yEy6ug) When in doubt (pretest probability indeterminate) more useful if negative (SNOUT) than positive (SPIN), since interstitial syndrome might be due to other causes (pneumonia, ARDS, fibrosis)

Thanks again for your work Roberto

Thanks for the excellent comment Roberto.

With regards to question one, I think you hit on the key issue. Acute respiratory failure is not a single condition, but actually a collection of many different conditions, and NIPPV might (and probably does) have different effects on different conditions. This is a large part of the BEEM focus on the heterogeneity of the underlying trials. Although not the focus of the paper, NIPPV clearly has an indication in COPD and CHF (as well as ARDS and post-extubation, but those are less relevant in the emergency department). There aren’t great studies in asthma, but I think the evidence favours NIPPV. I definitely use NIPPV early in severe asthma. I would not use NIPPV long term in pneumonia. However, I think the key take home for the emergency department, where we have undifferentiated patients, is that NIPPV seems to lower mortality overall, and should be started early while we work on determining the underlying cause of this patient’s respiratory distress.

With regards to pre-hospital NIPPV, ease of use and cost are definitely important issues. (I would also like to see more compatibility between prehospital equipment and inhospital equipment, both for cost and ease of patient care.) Unless we see large advantages to BiPAP, and I agree that CPAP probably makes the most sense for EMS. However, all of the questions are relatively complex. EMS agencies with longer transport time might benefit from BiPAP – although that assumption currently doesn’t have any evidence to back it up.

In terms of lung ultrasound, I will tell you I use it every shift. However, the widespread use of ultrasound and adoption into protocols does not mean that we are practicing evidenced based medicine. I think the numbers here (which are pretty consistent with all the studies I have seen, including that Lichtenstein paper) show that lung ultrasound is about as accurate for ruling in as it is for ruling out (sensitivity and specificity are both in the low to mid 90s). However, the studies that give us those number have a number of issues that could be inflating the accuracy. The diagnosis in many patients is obvious without ultrasound, and the patients who are less obvious clinically are also less obvious on ultrasound. I love ultrasound an will continue to use it, with the caveat that in the initially undifferentiated patient (pretrest probability of 50%), the numbers reported for ultrasound don’t get be above a 95% post test probability if positive, nor do they get me under a 5% post test probability if negative, so I am am constantly aware that my ultrasound diagnosis might be wrong.

Cheers Justin

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• Open access
• Published: 14 September 2023

Causes of hypercapnic respiratory failure: a population-based case-control study

• Yewon Chung 1 , 2 , 3 ,
• Frances L. Garden 1 , 3 ,
• Guy B. Marks 1 , 2 , 3 &
• Hima Vedam 1 , 2 , 3  

BMC Pulmonary Medicine volume  23 , Article number:  347 ( 2023 ) Cite this article

1611 Accesses

2 Citations

Metrics details

There are no population-based data on the relative importance of specific causes of hypercapnic respiratory failure (HRF). We sought to quantify the associations between hospitalisation with HRF and potential antecedent causes including chronic obstructive pulmonary disease (COPD), obstructive sleep apnea, and congestive cardiac failure. We used data on the prevalence of these conditions to estimate the population attributable fraction for each cause.

A case–control study was conducted among residents aged ≥ 40 years from the Liverpool local government area in Sydney, Australia. Cases were identified from hospital records based on PaCO 2  > 45 mmHg. Controls were randomly selected from the study population using a cluster sampling design. We collected self-reported data on medication use and performed spirometry, limited-channel sleep studies, venous sampling for N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, and sniff nasal inspiratory pressure (SNIP) measurements. Logistic regression analyses were performed using directed acyclic graphs to identify covariates.

We recruited 42 cases and 105 controls. HRF was strongly associated with post-bronchodilator airflow obstruction, elevated NT-proBNP levels, reduced SNIP measurements and self-reported opioid medication use. There were no differences in the apnoea-hypopnea index or oxygen desaturation index between groups. COPD had the highest population attributable fraction (42%, 95% confidence interval 18% to 59%).

Conclusions

COPD, congestive cardiac failure, and self-reported use of opioid medications, but not obstructive sleep apnea, are important causes of HRF among adults over 40 years old. No single cause accounts for the majority of cases based on the population attributable fraction.

Peer Review reports

Hypercapnic respiratory failure (HRF) is a commonly encountered clinical scenario for hospital clinicians in a wide range of disciplines. Many patients are known to have a predisposing condition such as severe chronic obstructive pulmonary disease (COPD). However, in some patients presenting with HRF, the underlying cause is not apparent at initial presentation, and there may be multiple underlying potential causes existing concurrently. Although each cause requires disease-specific therapies, most patients require hospitalisation and many benefit from ventilatory support in dedicated respiratory and critical care units. Hence, HRF can be considered a single, albeit heterogeneous entity, that constitutes a significant problem for health facilities worldwide.

Previous studies examining the underlying causative conditions among patients with HRF have typically included participants identified following admission to an intensive care or respiratory admission and requiring ventilatory support therapy [ 1 , 2 , 3 , 4 , 5 ]. Three studies selected cases based on arterial blood gas (ABG) values [ 6 , 7 , 8 ]. and another relied on diagnosis codes suggestive for respiratory failure from hospital records [ 9 ]. Although these studies illustrate the range of conditions contributing to hospitalisation with HRF, none describe the prevalence of these factors in the source population and, hence, are unable to estimate the relative importance of each cause. Previous population-based studies have been limited to studying persons receiving home mechanical ventilation [ 10 , 11 , 12 ], which exclude cases whose underlying disease, comorbidities or socioeconomic factors preclude this intervention. Understanding the relative importance of the causes of HRF at a population level, irrespective of the treatments received, is required to develop investigation and management strategies for patients with undifferentiated HRF, and interventions to reduce hospitalisations associated with this condition.

Using a community-based case control study design, we sought to determine the strength of association between hospitalisation with HRF and the following conditions: COPD, congestive cardiac failure (CCF), obstructive sleep apnea (OSA), respiratory muscle weakness, and the use of opioid and benzodiazepine medications. We selected these causes in consensus based on previous studies and our clinical experience. In addition to estimating the strength of association with HRF, we used data on the prevalence of these conditions in the general community to estimate, for each cause, the population attributable fraction (PAF), an epidemiologic measure to describe the relative importance and public health impact of a risk factor in a population.

This prospective study was based in the City of Liverpool, a metropolitan area within Sydney, Australia [ 13 ]. The study population was restricted to persons aged 40 years and over. A case–control study design was implemented in which cases were people with HRF and controls were randomly selected members of the source population who did not have HRF. Non-English speaking persons were excluded if an interpreter was unavailable. We excluded nursing home residents due to difficulties in obtaining informed consent and accurate study measurements. Participants were reimbursed for their time with a gift card to the value of $40 AUD. Study procedures were approved by the South Western Sydney Local Health District Human Research Ethics Committee and all participants provided written, informed consent.

Cases and controls

Cases were patients who attended Liverpool Hospital between 2016 and 2018. Potential cases were identified based on an ABG, collected within 24 h of presentation, demonstrating PaCO 2  > 45 mmHg and pH ≤ 7.45. We anticipated the number of cases of HRF missed by this screening method to be low due to the increased risk of hospitalisation associated with hypercapnia, the public healthcare scheme in Australia that provides free hospital services to all citizens and most permanent residents, and local data that indicate most people with respiratory conditions from this population who require hospitalisation attend Liverpool Hospital. Medical records were reviewed to exclude suspected nosocomial cases of HRF, or instances where the person had suffered an out-of-hospital cardiac arrest or traumatic injury. Cases were invited to participate first by mail and then by follow-up telephone calls.

Population-based controls were randomly selected using a two-stage geography-based cluster sampling design, implemented from 2018 to 2019. First, we randomly selected 40 census tracts from the 449 comprising this region, the City of Liverpool. The probability of tract selection was proportional to the number of eligible residents in each tract. Next, we undertook ‘random walks’ to select households units within each tract, from which control participants were recruited. Investigators starting from the geographical centre of each tract walked along streets in directions guided by a computer-based random number generator. This method of population-based sampling is a practical method for random selection of participants from a large population when a population list is incomplete or unavailable, and is modified from methods used by the World Health Organization [ 14 ]. Letters of invitation were delivered to each household upon sampling, containing participant information sheets and multiple options for responding to the research team (telephone, e-mail, reply-paid envelope). All selected households received at least two letters of invitation and at least one home visit by study investigators in order to obtain a response, and record the number of eligible participants within each household.

Standardised questionnaires were administered by members of the research team. Data were collected on sociodemographic factors, comorbidities, and medications, including the use of opioids and benzodiazepines, in the preceding two years.

Spirometry was performed using the EasyOne spirometer (NDD Medical Technologies), before and after administration of salbutamol 200 μg via metered dose inhaler and spacer. All spirograms were reviewed by the author (Y.C.) for acceptability and repeatability using published criteria [ 15 ]. N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were measured from venous blood samples by electrochemiluminescent immunoassay (Roche Diagnostics). Sniff nasal inspiratory pressure (SNIP) measurements were taken using a fitted nasal probe connected to a hand-held meter (MicroRPM, CareFusion). Up to 10 manoeuvres were performed per nostril [ 16 ]. Overnight home-based sleep testing was performed using a portable device with airflow (pressure cannula), respiratory movement and oximetry channels (ApneaLink, ResMed). All recordings were reviewed by the author (Y.C.) and excluded if there were fewer than 3 h of adequate flow and oximetry data. Data were scored automatically using ApneaLink software (V10.2). Apneas were defined as at least 90% decrease in airflow for at least 10 s and hypopneas as a decrease by 30% for the same duration associated with desaturation of 3% or more. Investigators conducting measurements were unblinded as to whether participants were cases or controls.

Statistical analysis

Continuous variables are summarised as means with standard deviations (SD) and medians with interquartile ranges (IQR). Groups were compared using independent t-tests or Mann–Whitney U tests, as appropriate. Frequencies and percentages are used to describe categorical variables, and Fisher’s chi-square test used to compare groups. Baseline logistic regression models were used to assess the relationship between the presence or absence of HRF and continuous variables: the post-bronchodilator forced expiratory volume (FEV 1 )/forced vital capacity (FVC) ratio, NT-proBNP levels, maximum SNIP value (SNIP max ) and apnea-hypopnea index (AHI). Receiver operator characteristic (ROC) curves were generated from these models to determine the area under the ROC curve (AUC) in order to assess the predictive value of each of these variables for HRF. For subsequent analyses, participants were classified as having COPD if post-bronchodilator FEV1/FVC was below the lower limit of normal, using Global Lung Initiative reference values [ 17 ]. The diagnosis of CCF was based on NT-proBNP levels ≥ 100 pmol/L (846 pg/mL). Respiratory muscle weakness was recorded if SNIP max was less than 70 cmH 2 O and 60 cmH 2 O, among males and females, respectively. A diagnosis of moderate-to-severe OSA was recorded if the AHI was ≥ 15 events per hour.

We determined the adjusted association with HRF for each potential cause, reported as odds ratios (OR) with 95% confidence intervals (CI). Covariates for each model were informed by a directed acyclic graph (DAG) developed by the authors using the web-based program ‘daggity’ [ 18 ] showing direct and indirect pathways for the development of HRF (Fig.  1 ). Regressions were performed in SAS (Version 9.4). PAF estimates were calculated in STATA (Version 17). Full details of our regression models are provided in the Supplementary Material .

Causal diagram for hypercapnic respiratory failure. Directed acyclic graph illustrating assumed causal relationships between pre-specified exposure variables and the outcome of hypercapnic respiratory failure. In this case, obstructive lung disease has been selected as the exposure (green-shaded variable). Green arrows represent causal paths. Blue-shaded variables represent ancestors of the outcome and red-shaded variables represent ancestors of both the exposure and outcome. Red arrows represent biasing paths. Based on this diagram, the minimum adjustment set of variables to estimate the total effect of obstructive lung disease on hypercapnic respiratory failure are: age, smoking

Power calculation

We estimated 205 participants would be required in each group to detect an odds ratio of 2.8 and 2.0 for risk factors with prevalence values of 5% and 15%, respectively, with 80% power and two-sided alpha of 0.05. Study recruitment was stopped early due to low response rates and the COVID-19 pandemic.

One hundred and forty-seven subjects (42 cases and 105 controls) completed the study, as shown in Fig.  2 .

Participant flowchart. * Estimated source population is based on 2016 Census data (13)

Demographic and clinical characteristics are shown in Table 1 . Compared with controls, cases were older, more likely to have been smokers, and had lower levels of educational attainment and household income. The most frequently reported respiratory conditions were asthma, COPD and OSA. Among cases, 34 (81%) reported at least one respiratory diagnosis, compared with 41 (39%) among controls ( p  < 0.001). The Charlson comorbidity index, a composite predictor of mortality [ 19 ], was significantly higher among cases ( p  < 0.001).

At least one pre-specified cause for HRF was identified in 42 (100%) cases, and 66 (63%) controls ( p  < 0.001) (Table 2 ). Among cases, 37 (88%) had two or more causes and 20 (48%) had three or more potential causes for HRF. The most common cause of HRF in cases was self-reported use of opioid medications (57%), followed by COPD (50%). Mean (SD) FEV 1 in cases was 51 (21) percent predicted. The most frequent potential cause for HRF among controls was moderate-to-severe OSA (34%). The median (IQR) AHI among all controls was 6.6 (3.1, 19.1) events per hour.

The risk of HRF associated with each cause is shown in Table 3 . CCF, COPD, respiratory muscle weakness and opioid use were strongly associated with the presence of HRF. The AUC values for FEV1/FVC, NT-proBNP, AHI and SNIP max as continuous variables were 0.81, 0.74, 0.50 and 0.67, respectively. At the pre-specified cutoff, CCF had the strongest association (OR 13.4, 95% CI 1.40 – 128). Post-hoc analysis showed that when a lower NT-proBNP cut-off value of 35 pmol/L (296 pg/mL) was used to determine the presence of CCF, the magnitude of association was attenuated but remained statistically significant with an OR of 4.25 (95% CI 1.16 – 15.6).

Moderate-to-severe OSA did not appear to be associated with increased risk of HRF, with more controls having this condition compared with cases. There was no difference between groups based on mean AHI, using a 4% desaturation threshold, or using the oxygen desaturation index. There were no significant differences in age, BMI, degree of comorbidity, reported sleepiness, and estimated risk of OSA based on the STOP-Bang score [ 20 ] between participants who did and did not complete the overnight sleep study.

No single cause was identified as being responsible for more than 50% of HRF cases, based on the PAF, as shown in Table 3 . COPD had the highest adjusted PAF at 42% (95% CI 18% – 59%), followed by opioid use which had a PAF of 41% (13% – 59%). Despite its low prevalence in the general population (1%), CCF contributed substantially to the burden of HRF with a PAF of 24% (7% – 38%).

In this population-based case–control study, we show that HRF is a multifactorial condition with no single disease responsible for the majority of cases. In addition to chronic health conditions such as COPD and CCF, opioid use and respiratory muscle weakness are significantly associated with HRF hospitalisations. Interventions to reduce the prevalence of these causes have the potential to substantially reduce HRF-associated hospitalisations in this and other comparable populations.

Of the hypothesised causes, COPD had the highest population attributable fraction. Most previous surveys have shown COPD to be the dominant cause of hospitalisation with HRF [ 1 , 2 , 3 , 7 , 8 ], and COPD is also an important indication for treatment with home non-invasive ventilation therapy [ 12 ]. A prevalence study of hypercapnic COPD exacerbations has been used to approximate the requirements for hospital non-invasive ventilation services [ 21 ]. However, a considerable proportion of our cases did not have objective evidence of airflow obstruction, nor a history of chronic airways disease. Furthermore, we suspect the proportion of cases with COPD to be overrepresented in our study, as we have previously demonstrated that among cases of HRF, the presence of chronic airways disease is associated with a lower risk of death [ 22 ]. Hence, whilst COPD is an important contributor to HRF, it is not the only cause, and clinician judgment is required when assessing undifferentiated patients to identify alternative diagnoses.

In this population, CCF was an important contributor to hospitalisations with HRF. Patients with heart failure have reduced lung compliance and increased airways resistance, experiencing greater mechanical costs of breathing resulting in muscle fatigue and inability to maintain adequate ventilation [ 23 ]. Hypercapnia is present in up to 33% of patients with acute heart failure [ 24 ], and this can occur even in the absence of COPD [ 25 ]. One study of patients with compensated hypercapnia showed CCF to be more frequent than COPD [ 6 ]. The methods used to detect heart failure in previous studies have varied widely, ranging from clinician-reported diagnoses to echocardiographic findings [ 1 , 3 , 6 ]. We used the NT-pro-BNP to dichotomise patients, tolerating a degree of misclassification. NT-pro-BNP levels may be elevated with age, renal impairment and certain medications, but it has good negative predictive value when using low thresholds [ 26 ]. We selected a higher cut-off point to achieve greater specificity, and found the prevalence of CCF in controls to be comparable to previously published data [ 27 ]. Our study confirms the importance of CCF as a contributor to ventilatory failure, and the need to consider this cause among people presenting with HRF.

Self-reported use of opioid medications contributed significantly, with a PAF comparable to that of COPD. In recent decades, Australia and other high-income countries have documented a marked increase in the use of prescription opioids [ 28 ]. The clinical indication for most opioid prescriptions is acute pain [ 29 ], but chronic non-cancer pain is associated with continued opioid use [ 30 ]. Opioids directly suppress respiration but can also contribute to ventilatory failure indirectly via the mediators of sleep-related hypoventilation, obstructive and central sleep apnea [ 31 ]. Among adults with COPD, incident opioid prescriptions are associated with increased risk of adverse respiratory outcomes and death [ 32 ]. However, safety data among patients with chronic respiratory disease are inconsistent, particularly when considering those who receive opioids for refractory breathlessness [ 33 ]. Few previous studies have included drugs as a potential cause for HRF [ 3 , 8 ], generally excluding such patients [ 1 , 7 ]. We found opioid use to be associated with at least a three-fold increase in the risk of HRF, and hence may be an important modifiable risk factor in similar populations. Our results emphasise the need to rationalise opioid use to clinical situations where potential harms are outweighed by the benefits of these medicines.

There was a relatively high prevalence of respiratory muscle weakness among cases, and there was a significant association between reduced muscle strength and HRF. Neuromuscular disease including motor neuron disease, polio and muscular dystrophy accounts for a substantial proportion of home mechanical ventilation users [ 10 ]. We did not differentiate between such disorders and impaired respiratory muscle function due to other condition such as obesity and CCF, potentially leading to overestimates in PAF with respect to this risk factor.

Our study did not show a significant association between moderate-to-severe OSA and hospitalisation with HRF. Our analysis was based on the assumption that OSA could lead to HRF via sleep-related hypoventilation, or via an alternate pathway involving the development of CCF, with or without central sleep apnea and sleep hypoventilation [ 34 ] (Fig.  1 ). The apparent lack of association between OSA and HRF in our study might be explained by the very high prevalence of undiagnosed OSA among controls. A recent Australian study suggested the prevalence of moderate-to-severe OSA to be 20.2% in males and 10.0% of females [ 35 ]. However, a Swiss study demonstrated higher prevalence figures of 49.7% and 23.4% in males and females, respectively [ 36 ]. As such, whilst OSA is frequently diagnosed among patients with HRF, it might represent incorrect attribution as the cause of ventilatory failure. Alternatively, we may have missed a significant association due to the limitations of our testing methods. Previous studies have shown a high frequency of OSA among survivors of HRF, ranging from 51 to 83% when based on objective testing [ 1 , 37 ]. The device we used in our study has 82% sensitivity for the diagnosis of moderate-to-severe OSA [ 38 ], but validation studies have typically excluded highly comorbid people and those with suspected hypoventilation. We also did not manually score data, relying on proprietary software for automatic detection of respiratory events. Hence, although we found a substantial prevalence of undiagnosed OSA which may be amenable to treatment, we did not find an association with HRF hospitalisations.

This study has some weaknesses. We were unable to achieve the recruitment target, but in our analysis we found that our sample size was sufficient to detect with statistical confidence the high magnitude of associations observed between HRF and the causes COPD, CCF and opioid use. Rather than the small groups per se, the primary limitation of this study is the potential selection bias induced by low response and non-participation rates. A relatively small proportion of potentially eligible people proceeded to study participation, despite attempts made by the investigators to minimise inconveniences and provide financial reimbursement for the time provided. Controls may have been more likely to participate if they had symptoms of, or were concerned about, OSA. If this effect had occurred in controls but not cases, it would have led to an underestimation of the association with OSA. Potential cases may have been excluded due to frailty or death. The effect of this selection bias would have been under-estimation of the association with causes known to increase the risk of death, such as CCF. Due to the case–control design, risk factors for the outcome are measured after the occurrence of HRF, although we expect most to be chronic conditions that would have been present prior to hospitalisation. Finally, our results may not be generalisable to other populations depending on socioeconomic and other factors affecting the prevalence of each cause.

Nevertheless, our work has several strengths distinguishing it from previous studies. This is one of few studies that have selected cases based on ABG results. We have provided objective measurements of causes rather than self-reported diagnoses or medical records which may be incomplete. We employed causal diagrams to inform our statistical analysis in keeping with modern epidemiological theory. Importantly, this is the first study of HRF to provide data on a control group, allowing estimation of the association between specific causes and HRF at a population level as well as the relative importance of each cause as reflected in the population attributable fraction.

In summary, our study provides evidence for the multifactorial nature of HRF and the range of potential contributing factors. In addition to COPD, other causes including CCF, opioid use and respiratory muscle weaknesses are significantly associated with HRF hospitalisations. These findings have important implications for the assessment and management of patients with HRF and highlight the need for comprehensive evaluation to ensure that all treatable factors are addressed.

Availability of data and materials

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Abbreviations

Arterial blood gas

Area under the ROC curve

Body mass index

Congestive cardiac failure

Confidence intervals

Chronic obstructive pulmonary disease

Directed acyclic graph

Forced expiratory volume in the first second

Forced vital capacity

• Hypercapnic respiratory failure

Interquartile range

N-terminal pro-brain natriuretic peptide

Obstructive sleep apnea

Partial pressure of carbon dioxide in arterial blood

Population attributable fraction

Receiver operator characteristic

Standard deviation

Sniff nasal inspiratory pressure

Maximum sniff nasal inspiratory pressure

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Acknowledgements

We thank Maryaan Kas, Christine (Linheng) Zhao, Nicole El-Turk and Mary Giurgius for providing assistance with recruitment and data collection.

This work was supported by funding from the Respiratory, Sleep, Environmental and Occupational Health (RSEOH) Clinical Academic Group (CAG) of Maridulu Budyari Gumal (Sydney Partnership for Health, Education, Research and Enterprise, SPHERE) and the 2017 Mid-Career Support Program (Dr Hima Vedam). These bodies were not involved in the study design, data collection, analysis, interpretation of the data and in writing the final manuscript.

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Conception and design of study: Y.C., F.L.G., G.B.M., H.V.; Data acquisition: Y.C.; Analysis and data interpretation: Y.C., F.L.G., G.B.M., H.V.; Drafting and revision of the manuscript: Y.C., F.L.G., G.B.M., H.V.; All authors approve of the final version of the manuscript.

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This study was performed in accordance with the Declaration of Helsinki. This human study was approved by South Western Sydney Local Health District Human Research Ethics Committee- approval: HE17/165. All adult participants provided written informed consent to participate in this study.

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Competing interests

H.V. has received in-kind support from ResMed in the form of ApneaLink devices previously used for another project. ResMed were not involved in this study. Authors Y.C., F.L.G. and G.B.M. have no competing interests to declare.

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Additional file 1: table e1..

Details of regression models used to determine the associations between each cause and the outcome of hypercapnic respiratory failure.

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Chung, Y., Garden, F.L., Marks, G.B. et al. Causes of hypercapnic respiratory failure: a population-based case-control study. BMC Pulm Med 23 , 347 (2023). https://doi.org/10.1186/s12890-023-02639-6

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DOI : https://doi.org/10.1186/s12890-023-02639-6

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Acute respiratory failure (ARF) is defined by acute and progressive hypoxemia caused by various cardiorespiratory or systemic diseases in previously healthy patients. Among ARF, acute respiratory distress syndrome (ARDS) is a serious condition with bilateral lung infiltration, which develops secondary to a variety of underlying conditions, diseases, or injuries. This review summarizes the current standard of care for ARF and ARDS based on current major guidelines in this field. When administering fluid in patients with ARF, particularly ARDS, restrictive strategies need to be considered in patients without shock or multiple organ dysfunction. Regarding oxygenation targets, avoiding excessive hyperoxemia and hypoxemia is probably a reasonable choice. As a result of the rapid spread and accumulation of evidence for high-flow nasal cannula oxygenation, it is now weakly recommended for the respiratory management of ARF in general and even for initial management of ARDS. Noninvasive positive pressure ventilation is also weakly recommended for the management of certain ARF conditions and as initial management of ARDS. Low tidal volume ventilation is now weakly recommended for all patients with ARF and strongly recommended for patients with ARDS. Limiting plateau pressure and high-level PEEP are weakly recommended for moderate-to-severe ARDS. Prone position ventilation with prolonged hours is weakly to strongly recommended for moderate-to-severe ARDS. In patients with COVID-19, ventilatory management is essentially the same as for ARF and ARDS, but awake prone positioning may be considered. In addition to standard care, treatment optimization and individualization, as well as the introduction of exploratory treatment, should be considered as appropriate. As a single pathogen, such as SARS-CoV-2, exhibits a wide variety of pathologies and lung dysfunction, ventilatory management for ARF and ARDS may be better tailored according to the respiratory physiologic status of individual patients rather than the causal or underlying diseases and conditions.

Introduction

Acute respiratory failure (ARF) is defined as acute and progressive hypoxemia developing within hours, days, or up to a month caused by various respiratory, cardiovascular, or systemic disease in previously healthy patients. ARF is distinguished from chronic respiratory failure and acute exacerbations of underlying respiratory disease.

Among ARF, acute respiratory distress syndrome (ARDS) is a serious condition associated with bilateral lung infiltration. ARDS may develop secondary to a variety of underlying conditions, diseases, or injuries (Table 1 ) [ 1 ]. Neutrophil-dominant acute inflammation and diffuse alveolar damage (DAD) with the presence of hyaline membranes are observed on histological examination of lung tissues from patients with ARDS. The pathophysiology of ARDS includes an increase in pulmonary microvascular permeability with resultant pulmonary edema due to tissue injury and disruption of vascular regulatory mechanisms. ARDS was initially described as a single organ dysfunction, but is now recognized as one component of multiple organ dysfunction syndrome.

Currently available guidelines for ARF and ARDS

To date, there are currently no guidelines which cover all aspects of ARF. However, several guidelines for airway and ventilatory management are available and are referred in the following sections. In addition, the Japanese clinical practice guidelines for management of sepsis and septic shock 2020 (J-SSCG 2020) includes several clinical questions and recommendations which can be extrapolated to ARF in general [ 2 ].

With regard to ARDS, the American Thoracic Society (ATS), European Society of Intensive Care Medicine (ESICM), and Society of Critical Care Medicine (SCCM) have published a joint guideline on mechanical ventilation in adult patients with ARDS. In addition, guidelines for ARDS have been published by the Faculty of Intensive Care Medicine (FICM) and Intensive Care Society (ICS) of United Kingdom (jointly as guidelines on the management of acute respiratory distress syndrome: FICM/ICS-ARDS-GL2018), Société de Réanimation de Langue Française (SRLF) of France (management of acute respiratory distress syndrome: SRLF-ARDS-GL2019), Scandinavian Society of Anaesthesiology and Intensive Care Medicine (SSAI; Scandinavian clinical practice guideline on mechanical ventilation in adults with the acute respiratory distress syndrome: SSAI-ARDS-GL2016), and Korean Society of Critical Care Medicine (KSCCM) and Korean Academy of Tuberculosis and Lung Diseases (KATRD) of South Korea (jointly as the clinical practice guideline of acute respiratory distress syndrome: KSCCM/KATRD-ARDS-GL2016) [ 3 , 4 , 5 , 6 , 7 , 8 ]. In Japan, an initial guideline was developed in 2005 by the Japanese Respiratory Society (JRS), with the latest version jointly published in 2022 by the JRS, Japanese Society of Intensive Care Medicine (JSICM), and Japanese Society of Respiratory Care Medicine (JSRCM) as the ARDS clinical practice guideline 2021 (Japanese ARDS-GL2021) [ 9 ]. In addition, the Surviving Sepsis Campaign Guidelines (international guidelines for management of sepsis and septic shock 2021; SSCG2021) also include clinical questions regarding ventilatory management.

Since early 2020, novel coronavirus-induced disease 2019 (COVID-19) has become a major cause of ARF and ARDS. The large number of cases caused by a single microorganism is unprecedented in modern times. The above-mentioned guidelines are generally applicable to ARF and ARDS caused by COVID-19. However, specific guidelines for the management of COVID-19 should also be consulted as many international and regional guidelines for COVID-19 have now been published [ 10 ] based on evidence specific to COVID-19.

Diagnosing ARF and ARDS

ARF is typically diagnosed according to a PaO 2  ≤ 60 Torr at room air or PaO 2 /FIO 2 ratio ≤ 300. ARF can be caused by a range of lung, heart, or other systemic diseases and conditions. American College of Physicians has developed a guideline for the appropriate use of point-of-care ultrasonography in patients with acute dyspnea, and weakly recommends its use in addition to the standard diagnostic pathway when there is diagnostic uncertainty [ 11 ].

The clinical diagnosis of ARDS is currently based on the Berlin definition: (1) PaO 2 /FIO 2 ratio ≤ 300 under positive end-expiratory pressure (PEEP)/continuous positive airway pressure (CPAP) ≥ 5 cmHO 2 ; (2) acute onset within a week; (3) bilateral shadows in the lung fields, and (4) respiratory failure that cannot be explained by cardiac failure or excess fluid alone [ 12 ]. Recently, high-flow nasal cannula oxygenation (HFNC, also called high-flow nasal oxygen therapy: HFNO or nasal high flow therapy: NHFT) and noninvasive positive pressure ventilation (NPPV, also called NIV) have become widely used, with an SpO 2 /FIO 2 ratio ≤ 315 irrespective of PEEP proposed as an alternative criterion of ARDS [ 13 ].

Fluid balance assessments, levels of plasma brain natriuretic peptide (BNP) or serum NT-proBNP, and echocardiographic evaluation are clinically used in differentiating ARDS from hydrostatic pulmonary edema. In JRS/JSICM/JSRCM-GL2021, a systematic review reported a sensitivity of 0.77 and specificity of 0.62 for a cutoff value of 400–500 pg/mL for BNP, sensitivity of 0.50 and specificity of 0.82 for a cutoff value of 1000 pg/mL, and sensitivity of 0.71 and specificity of 0.89 for a cutoff value of 4000 pg/mL for NT-proBNP when differentiating ARDS from hydrostatic pulmonary edema. According to these results, the use of serum BNP or NT-proBNP levels is weakly recommended [ 9 ]. In patients with severe ARDS, measurement of extravascular lung water using transpulmonary thermodilution should be considered. Measurement of pulmonary artery wedge pressure by invasive right heart catheterization is now rarely performed.

After clinical exclusion of hydrostatic pulmonary edema, the diagnosis of ARDS is made according to the aforementioned diagnostic criteria. However, it is still necessary to rule out ARDS mimics, particularly those with established treatments (Table 2 ) [ 1 , 14 ]. Bronchoalveolar lavage is particularly useful in differentiating various respiratory infections, acute eosinophilic pneumonia, cryptogenic organizing pneumonia, interstitial pneumonia, hypersensitivity pneumonitis, alveolar hemorrhage, and drug-induced lung injury.

Management of ARF and ARDS

In this section, the current standard approach to the management of ARF and ARDS is presented based on recent guidelines. Recommendations for ARF are given in SSCG2021, J-SSCG2020, and SRLF-GL2019, and are summarized in Table 3 . For ARDS, recommendations for ventilatory management are summarized in Table 4 , and those for adjunctive therapies are presented in Table 5 . Key topics in the above-mentioned guidelines are discussed below with reference to recent evidence.

• Oxygenation targets

The traditional treatment strategy regarding oxygenation in ARF is to maintain adequate oxygenation to avoid the risk of hypoxemia. On the other hand, it has been customary to aim for an FIO 2  ≤ 60% to avoid hyperoxic lung injury in ventilated patients. However, a recent systematic review and cohort study reported a positive association between hyperoxemia and poor survival. As a result, optimal oxygenation targets have again become a topic of discussion [ 15 , 16 ]. After 2016, six RCTs comparing groups with lower and higher oxygen targets were published, with none reporting a significant difference in primary outcomes between the two groups [ 17 , 18 , 19 , 20 , 21 ]. In these studies, the actual difference between study groups was 15–28 mmHg in PaO 2 or 1–4% in SaO 2 , and PaO 2 was maintained between 70 and 110 mmHg in both groups in all studies. These situations have resulted in inconsistent recommendations between SSCG2021, J-SCG2020, and JRS/JSICM/JSRCM-GL2021 as shown in Tables 3 and 4 . As a recent network meta-analysis demonstrated decreased survival in patients with a PaO 2 target of 55–75 mmHg and patients with a PaO 2  ≥ 150 mmHg, it seems appropriate to follow the traditional oxygenation strategy that avoids excess hypoxemia and hyperoxemia [ 22 ]. In patients with acute exacerbation of chronic obstructive pulmonary disease (COPD), an SaO 2 of 88% to 92% is considered an adequate oxygenation target, as suggested by a recent observational study [ 23 ].

Ventilatory management

In ARF, the choice between the use of nasal cannula, HFNC, NPPV, or invasive positive pressure ventilation (IPPV) is based on the presence of underlying disease and severity of hypoxemia. In the HFNC guidelines by the American College of Physicians, HFNC was weakly recommended for ARF over NPPV due to a systematic review reporting that HFNC for ARF is associated with lower mortality and a lower intubation rate compared to NPPV [ 24 ]. For patients with ARF post-extubation, a separate systematic review suggested that HFNC may reduce the reintubation rate and improve patient comfort compared with conventional oxygen therapy, and thus was also weakly recommended. The European Respiratory Society (ERS)/ATS guidelines recommend bilevel positive airway pressure (bilevel-PAP) for patients with acute exacerbation of COPD accompanied by acute hypercarbia, CPAP for cardiogenic pulmonary edema, and NPPV for post-operative setting and early ARF in immunosuppressed patients [ 25 ]. Regarding ARDS, IPPV has been the gold standard; however, HFNC and NPPV are weakly recommended as alternative options to initial management in JRS/JSICM/JSRCM-GL2021.

The benefit of low tidal volume ventilation with IPPV has been demonstrated not only in ARDS, but also in ARF. Low tidal volume ventilation is weakly recommended for ARF in SSCG2021 and SRLF-GL2019, and strongly recommended for ARDS in JRS/JSICM/JSRCM-GL2021, SSCG2021, SRLF-GL2019 and FICM/ICS-GL2018. In J-SSCG2020, lung protective ventilation is weakly recommended for ARF.

Limiting plateau pressure and high-level PEEP is recommended weakly to strongly in all guidelines, although the most recent Cochrane analysis did not find a survival benefit for high-level PEEP [ 26 ]. Prone position ventilation with prolonged hours is weakly to strongly recommended for moderate-to-severe ARDS in all guidelines. Regarding recruitment maneuvers, JRS/JSICM/JSRCM-GL2021 recommends against their routine use while the SSCG 2021 weakly recommends the traditional recruitment maneuver of applying an airway pressure of 30–40 cm H 2 O for 30–40 s [ 9 , 27 , 28 ]. Early and limited use of muscle relaxants are weakly to strongly recommended for patients with moderate to severe ARDS. There are weak-to-strong recommendations against the use of high-frequency oscillatory ventilation (HFOV).

Fluid management

There are currently no standardized guidelines for fluid management in ARF; however, daily fluid balance assessments are fundamentally important in reducing the risk of iatrogenic pulmonary edema. Even mild fluid overload may worsen pulmonary edema and thereby exacerbate hypoxemia in patients with ARDS due to an increase in pulmonary microvascular permeability. A recent systematic review reported that restrictive fluid management improves oxygenation and prolongs ventilator-free days, but does not improve mortality in patients with sepsis or ARDS [ 29 ]. Based on this evidence, the JRS/JSICM/JSRCM-GL2021 and FICM/ICS-GL 2018 weakly recommend restrictive fluid management [ 4 , 9 ].

On the other hand, stabilization of vital signs with fluid resuscitation is essential in sepsis and septic shock, which is a major cause of ARDS. Accordingly, an appropriate fluid management strategy should be selected in patients with ARDS depending on the presence of other organ dysfunction or hemodynamic shock [ 30 ]. In the most recent RCT for patients with septic shock, a trend toward increased survival was observed in a subgroup with respiratory support, although restrictive fluid management did not show overall survival benefit [ 31 ], supporting the use of the above strategy. In severe cases, echocardiography and measurement of central venous pressure should be performed to monitor fluid responses and inform fluid administration.

Pharmacotherapy

In ARF, pharmacotherapy should be focused on the underlying disease or diseases that are causing hypoxemia. For ARDS, corticosteroids are often administered worldwide including Japan [ 32 ]. However, the results of RCTs for pharmacological treatment of ARDS have been mixed due to diversity in the causes and severity of ARDS and the effects of the type, timing of administration, dosage, and duration of administration of corticosteroids. Accordingly, corticosteroid administration is considered both a standard and exploratory treatment for ARDS. The latest RCT “DEXA-ARDS” included 277 patients with a PaO 2 /FIO 2  ≤ 200 mmHg under PEEP ≥ 10 cmHO 2 and a FIO 2  ≥ 0.5 at 17 Spanish intensive care units. Patients in the dexamethasone group were treated with 20 mg intravenous dexamethasone (methylprednisolone equivalent 100–120 mg) daily for five days and 10 mg for additional five days [ 33 ]. A recent systematic review that included 18 RCTs also demonstrated a net survival benefit for corticosteroids in patients with ARDS of any cause [ 34 ]. Based on these findings, it can be suggested that although older versions such as SSAI-ARDS-GL2016 and KSCCM/KATRD-ARDS-GL2016 are against the use of corticosteroids, their use is weakly to strongly recommended in the more recent JRS/JSICM/JSRCM-GL2021 and FICM/ICS-GL2018. Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) include ARDS and weakly recommend the use of corticosteroids [ 35 ].

A specific neutrophil elastase inhibitor, sivelestat, was developed and approved for the treatment of acute lung injury associated with systemic inflammatory response syndrome in Japan. In the Japanese ARDS guidelines 2016, a systematic review was performed including data from the Japanese phase III trial and the international phase III STRIVE study, with no difference in survival or ventilator-free days observed [ 1 ]. Based on these findings, the latest JRS/JSICM/JSRCM-GL2021 also weakly recommends against the routine use of sivelestat.

In situations where respiratory infections cannot be ruled out, the use of broad-spectrum antibiotic regimens including a macrolide or new quinolone is often considered. Antimicrobial therapy against methicillin-resistant Staphylococcus aureus , Pneumocystis jirovecii , fungi, Mycobacterium tuberculosis , viruses, and SARS-CoV-2 may also be considered as appropriate.

Extracorporeal membrane oxygenation

The benefit of extracorporeal membrane oxygenation (ECMO) has been clarified in recent studies, with ECMO now weakly recommended for severe ARDS in most guidelines. The systematic review of the newest JRS/JSICM/JSRCM-GL2021 included two RCTs (CESAR and EOLIA studies) and found a significant decrease in 60-day and 90-day mortalities but no increase in the incidence of stroke [ 9 ].

However, it is important to recognize and follow the accepted indications and contraindications for ECMO to obtain improved implementation results. In the latest ELSO guidelines, common indications for veno-venous ECMO are: (1) hypoxemic respiratory failure (PaO 2 /FiO 2  < 80 mmHg) after optimal medical management including, in the absence of contraindications, a trial of prone positioning; (2) hypercapnic respiratory failure (pH < 7.25) despite optimal conventional mechanical ventilation (respiratory rate 35 breaths per minute and plateau pressure [Pplat] ≤ 30 cm H 2 O); and (3) ventilatory support as a bridge to lung transplantation or primary graft dysfunction following lung transplantation [ 36 ]. Central nervous system hemorrhage, significant central nervous system injury, irreversible and incapacitating central nervous system pathology, systemic bleeding, contraindications to anticoagulation, immunosuppression, older age (increasing risk of death with increasing age but no threshold is established), and mechanical ventilation for more than seven days with a Pplat > 30 cm H 2 O and an FiO 2  > 90% are listed as relative contraindications to ECMO.

A certain proportion of patients with COVID-19 develop ARF and ARDS depending on patient age, comorbidities, immune status, and SARS-CoV-2 virus genotype among other factors. Although there are rare cases with a rapidly progressive course, the progression of the disease is typically slow and the number of days from the onset of symptoms to the start of artificial ventilation is as high as 3–4 days for the original variant of SARS-CoV-2 [ 37 ]. The rate of severe illness is lower in Omicron variants of SARS-CoV-2 compared to Delta variants; however, the mortality of the patients once admitted to ICU does not differ between Omicron and Delta variants [ 38 ].

In the chaotic early stages of the COVID-19 pandemic, a specific phenotype of COVID-19-induced ARDS with higher lung compliance was proposed and discussed [ 39 ]. However, after the accumulation of numerous cases worldwide over more than two years, a recent systematic review did not find evidence of a specific phenotype of ARDS related to COVID-19 [ 40 ]. These findings indicate that the management of ARF and ARDS in patients with COVID-19 should be the same as for other causes. However, parameters of mechanical ventilation, including PEEP, should be individualized based on the ventilatory and systemic condition of individual patients [ 41 ]. Pharmacological therapies, including corticosteroids, should be administered according to the guidelines and statements specific to COVID-19.

In addition to standard ventilatory management, the benefits of awake prone positioning for non-intubated patients have been posited and examined. Although the results of RCTs are conflicting, a recent systematic review demonstrated a reduced risk of endotracheal intubation with awake prone positioning [ 42 ].

The criteria for the introduction of ECMO and the survival rate in COVID-19 are similar to those in other diseases; however, the duration of ECMO use tends to be longer in patients with COVID-19 [ 43 ]. In a recent systematic review, increased mortality was reported to be associated with older age, male sex, chronic lung disease, longer duration of symptoms, longer duration of invasive mechanical ventilation, higher PaCO 2 , higher driving pressure, and less previous experience with ECMO [ 44 ].

Concluding remarks

ARF and ARDS develop secondary to a wide variety of diseases and conditions, and the mechanisms of hypoxemia are varied. This review summarized the current standard of care for ARF and ARDS based on major guidelines in this field. As has been repeatedly mentioned, “standard” care needs to be continually updated considering new evidence. In addition to standard care, treatment optimization and individualization as well as the introduction of exploratory treatment should be considered appropriate. In light of the fact that even a single pathogen, such as SARS-CoV-2, exhibits a wide variety of pathologies and lung dysfunction, ventilatory management for ARF and ARDS may be suitably tailored according to the respiratory physiologic status of individual patients rather than the causal or underlying diseases and conditions.

Availability of data and materials

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Abbreviations

• Acute respiratory distress syndrome
• Acute respiratory failure

American Thoracic Society

Bilevel positive airway pressure

• Brain natriuretic peptide

Critical illness-related corticosteroid insufficiency

Chronic obstructive pulmonary disease

Coronavirus-induced disease 2019

Continuous positive airway pressure

Diffuse alveolar damage

Extracorporeal Life Support Organization

European Society of Intensive Care Medicine

Faculty of Intensive Care Medicine

High-flow nasal cannula

High-flow nasal oxygen therapy

High-frequency oscillatory ventilation

Intensive Care Society

Invasive positive pressure ventilation

Japanese Respiratory Society

Japanese clinical practice guidelines for management of sepsis and septic shock 2020

Japanese Society of Intensive Care Medicine

Japanese Society of Respiratory Care Medicine

Korean Academy of Tuberculosis and Lung Diseases

Korean Society of Critical Care Medicine

Noninvasive ventilation

Nasal high-flow therapy

• Noninvasive positive pressure ventilation

Positive end-expiratory pressure

Severe acute respiratory syndrome coronavirus 2

Society of Critical Care Medicine

Société de Réanimation de Langue Française

Scandinavian Society of Anaesthesiology and Intensive Care Medicine

Surviving Sepsis Campaign Guidelines

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Fujishima, S. Guideline-based management of acute respiratory failure and acute respiratory distress syndrome. j intensive care 11 , 10 (2023). https://doi.org/10.1186/s40560-023-00658-3

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StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

StatPearls [Internet].

Respiratory failure in adults.

Vincent S. Mirabile ; Eman Shebl ; Abdulghani Sankari ; Bracken Burns .

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Last Update: June 11, 2023 .

• Continuing Education Activity

The respiratory system provides oxygen to and removes carbon dioxide from the body; however, the inability to perform either or both of these tasks results in respiratory failure. Type 1 respiratory failure occurs when the respiratory system cannot adequately provide oxygen to the body, leading to hypoxemia, and can be caused by alveolar hypoventilation, low atmospheric pressure/fraction of inspired oxygen, diffusion defect, ventilation/perfusion mismatch, and right-to-left shunt. Type 2 respiratory failure occurs when the respiratory system cannot adequately remove carbon dioxide from the body, leading to hypercapnia, and can be caused by respiratory pump failure and increased carbon dioxide production. This activity reviews the evaluation and management of respiratory failure and highlights the role of the healthcare team in evaluating and treating patients with this condition.

• Review the etiology of respiratory failure.
• Explain the pathophysiology of respiratory failure.
• Review the physical exam findings associated with respiratory failure.
• Summarize the treatment considerations for patients with respiratory failure.
• Introduction

The respiratory system allows gas exchange between the environment and the body, facilitating the process of aerobic metabolism. Specifically, the respiratory system provides oxygen and removes carbon dioxide from the body. The inability of the respiratory system to perform either or both of these tasks results in respiratory failure. Type 1 respiratory failure occurs when the respiratory system cannot adequately provide oxygen to the body, leading to hypoxemia. Type 2 respiratory failure occurs when the respiratory system cannot sufficiently remove carbon dioxide from the body, leading to hypercapnia. Respiratory failure can be classified based on chronicity (i.e., acute, chronic, and acute on chronic). A thorough understanding of respiratory failure is crucial to managing this disorder. If either type of respiratory failure is not identified and addressed early, it will become life-threatening and lead to respiratory arrest, coma, and death. The approach to adult patients with suspected respiratory failure (both hypercapnia and hypoxic), as well as the diagnosis and treatment of acute and chronic respiratory failure, are discussed in this article. 

Respiratory failure can occur if there is an abnormality with any component of the respiratory system. Components of the respiratory system include the upper and lower respiratory tracts, the central and peripheral nervous systems, in addition to the chest wall and muscles of respiration. [1]  The pathophysiology section of this article will review specific etiologies of respiratory failure.

• Epidemiology

Respiratory failure (RF) is a syndrome caused by a multitude of pathological states; therefore, the epidemiology of this disease process is difficult to ascertain. In 2017, in the United States of America, however, the incidence of respiratory failure was found to be 1,275 cases per 100,000 adults. The case definition used in this study included all diagnosis codes that included respiratory failure as a component. [2]  The epidemiology of respiratory failure is dependent mainly on the cause leading to the failure. Below, we list some common causes of respiratory failure and the relevant trends: 

• Acute myocardial infarction-related (AMI-RF): Between the years 2000 and 2014, 439,436 admissions due to AMI-RF were noted in 57% and required mechanical ventilation in 43% of total cases. [3]
• Acute respiratory failure due to acute respiratory distress syndrome (ARDS) ranges in incidence from 10-80/100,000/y based on where it is recorded worldwide. This is partly due to different practices and thresholds for intubation in these cases and the use of different definitions of ARDs. According to one report, it is estimated that 10% of all patients admitted to ICU and 23% of mechanically ventilated patients meet ARDS criteria. [4]
• Acute respiratory failure related to Coronavirus (COVID-19): It is estimated early in the COVID-19 pandemic that up to 79% of hospitalized patients developed respiratory failure requiring invasive mechanical ventilation. [5]  
• Acute exacerbation of COPD (AECOPD) is the third most common etiology in patients hospitalized because of acute respiratory failure. [6]
• Pathophysiology

T ype 1 respiratory failure:

The distinguishing characteristic of Type 1 respiratory failure is a partial pressure of oxygen (PaO2) < 60 mmHg with a normal or decreased partial pressure of carbon dioxide (PaCO2). Depending on the cause of hypoxemia, the alveolar-arterial (A-a) gradient may be normal or increased. Formulas of the A-a gradient and alveolar gas equation are provided below, as these concepts are helpful in understanding the pathophysiology of respiratory failure.

     A-a gradient:

• PAO2 = Alveolar partial pressure of oxygen
• PaO2 = Arterial partial pressure of oxygen

     Alveolar gas equation: [7]

• FiO2 = Fraction of inspired oxygen
• PB = Barometric (Atmospheric) pressure
• Pwater = Vapor pressure of water at body temperature (37°C)=47 mmHg
• PaCO2 = Partial pressure of arterial carbon dioxide

 Etiologies of Type 1 respiratory failure with normal A-a gradients include:

• Alveolar hypoventilation:  Alveolar hypoventilation increases the arterial partial pressure of carbon dioxide (PaCO2). The alveolar gas equation demonstrates that an increase in PaCO2 causes a decrease in the alveolar partial pressure of oxygen (PAO2). In this situation, the A-a gradient is normal, as the PAO2 and PaO2 decrease in equal magnitudes. When severe, alveolar hypoventilation may progress to Type 2 respiratory failure. [8]  (as discussed later in this section under Type 2 respiratory failure). 
• Low atmospheric pressure/fraction of inspired oxygen:  The alveolar gas equation demonstrates that the alveolar partial pressure of oxygen (PAO2) decreases with low atmospheric pressures (Patm) and with low levels of inspired oxygen (FiO2). In either situation, the A-a gradient remains normal, and the PaCO2 is decreased, given the response to hypoxia is hyperventilation. Clinically, this cause of respiratory failure occurs at high altitudes. [9]

 Etiologies of Type 1 respiratory failure with increased A-a gradients include:

• Interstitial lung disease
• Acute respiratory distress syndrome
• Chronic obstructive pulmonary disease
• Congestive heart failure
• Pulmonary embolism
• Arteriovenous malformation
• Complete atelectasis
• Severe pneumonia
• Severe pulmonary edema

Type 2 Respiratory Failure

Hypercapnic respiratory failure is defined as an increase in arterial carbon dioxide (CO2) (PaCO)> 45 mmHg with a pH < 7.35 due to respiratory pump failure and/or increased CO 2 production. In general, according to the modified alveolar ventilation equation, the PaCO2 level is proportionally related to the rate of CO2 production (VCO2) and inversely associated with the rate of CO2 elimination (i.e., alveolar ventilation) (PaCO2 =VCO2 /VA). The relationship between minute ventilation and CO2 production in response to exercise can be affected by age and pregnancy. [13]  

Alveolar ventilation (VA) is the product of minute ventilation (VE) and the ratio of dead space (VD) to tidal volume (Vt) (VA = VE x [1 - VD/Vt]). While decreased VA is the most common reason for the respiratory failure of hypercapnia, increased CO2 production is a very rare reason. Depending on the cause of respiratory failure, the partial pressure of oxygen (PaO2) may be normal or decreased. The two main paradigms responsible for hypercapnia respiratory failure are either manifested by "won't breathe" due to a central drive issue or "can't breathe" as a result of a peripheral neuromuscular defect, resistive loading (narrow airway) or restrictive defect that lead to hypoventilation and hypercapnia. 

Respiratory pump failure:  The respiratory pump is comprised of the chest wall, the pulmonary parenchyma, the muscles of respiration, as well as the central and peripheral nervous systems. The inability to ventilate can occur if any of the components mentioned above of the respiratory pump fails.

• Decreased central dive: Sedatives (i.e., alcohol, benzodiazepines, and opiates) and diseases of the central nervous system (i.e., encephalitis, stroke, tumor, and SCI) may impair the respiratory drive, resulting in hypoventilation. [14]
• Altered neural and neuromuscular transmission: Amyotrophic lateral sclerosis, botulism, Guillain-Barre syndrome, myasthenia graves, organophosphate poisoning, poliomyelitis, spinal cord injury (SCI), tetanus, and transverse myelitis may impair the function of the respiratory pump, resulting in hypoventilation. [14]
• Chest wall and pleural disorders: Flail chest, kyphoscoliosis, hyperinflation, large pleural effusions, obesity, and thoracoplasty may impair the function of the respiratory pump, resulting in hypoventilation.
• Dead space ventilation: Conditions that increase the V/Q ratio, such as acute respiratory distress syndrome, bronchitis, bronchiectasis, emphysema, and pulmonary embolism, can result in hypoventilation. Hypoventilation typically occurs once dead space ventilation exceeds 50% of total ventilation.
• Muscle abnormalities: Diaphragmatic paralysis, diffuse atrophy, muscular dystrophy, and ruptured diaphragm may impair the function of the respiratory pump, resulting in hypoventilation. 

Increased dead space:  Dead space (VD) refers to areas of the lung that are not anatomically or physiologically able to exchange gas. Tachypnea can contribute to high CO2 by increasing the dead space to tidal volume ratio (VD/Vt). High alveolar VA and the associated ventilation-perfusion mismatch are considered one of the main mechanisms for developing hypercapnia in individuals with COPD. [15]

Increased CO production:  CO2 is a by-product of oxidative metabolism, and high CO2 production may occur due to fever, exercise, hyperalimentation, sepsis, and thyrotoxicosis. High CO 2 production becomes pathologic if the compensatory increase in minute ventilation mechanism fails. [16]  

Alveolar hypoventilation: A lveolar hypoventilation may progress to Type 2 respiratory failure. [8]  (as discussed later in this section under Type 2 respiratory failure). 

• History and Physical

Respiratory failure is a syndrome with a myriad of etiologies; therefore, a thorough history and physical examination are required to narrow the differential diagnosis.

Patients typically present with respiratory symptoms (i.e., dyspnea, cough, hemoptysis, sputum production, and wheezing); however, symptoms from other organ systems (ie, chest pain, decreased appetite, heartburn, fever, and significant weight loss) are important. Loss of smell and/or exposure to sick people or unprotect contact with individuals with coronavirus infection (COVID-19) is essential in suspecting COVID-19 illness and associated respiratory failure, particularly in high-risk patients (older patients, men, and morbidly obese). [17]  For a specific population, the presence of immunocompromised conditions or taking immunosuppressants is also essential in risk-stratifying patients at risk for respiratory failure early on.

For patients already diagnosed with airway disease, it is important to assess inhaler compliance and technique, recent steroid use, as well as exposure to environmental triggers. For patients with hypertension and chronic cough, the use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers should be investigated.

Social history is also crucial when considering respiratory failure. Alcohol use and sexually transmitted diseases may lead to an immunocompromised state, making patients more susceptible to certain infections, while a sedentary lifestyle may increase the risk of pulmonary embolism. Habits such as having birds and hobbies such as diving and flying may have implications when considering etiologies of respiratory failure. Most importantly, a patient's tobacco smoking history should be investigated, including exposure to second-hand smoke, marijuana smoking, smoking e-cigarettes, and vaping. [18]

Finally, an occupational history may be helpful when considering work-related lung disease (i.e., hypersensitivity pneumonitis and pneumoconiosis), while a family history may be beneficial when considering atopic, genetic (ie, alpha-1-antitrypsin deficiency and cystic fibrosis), and infectious diseases (i.e., tuberculosis). [19]

Physical Examination

Signs of respiratory failure may be present throughout the body. Physical examination findings by region appear below:

• General inspection: Accessory muscle use, altered mental status, cachectic, conversational dyspnea, diaphoresis, fever, respiratory distress (i.e., at rest or with exertion), obesity, and purse-lipped breathing
• Head: Cushingoid appearance, central cyanosis, Horner's syndrome, and pale conjunctiva
• Neck: Jugular venous distention, lymphadenopathy, and tracheal deviation
• Chest/thorax: Asymmetrical chest expansion, bradypnea, bronchial breath sounds, Cheyne-Stoke breathing, crackles, decreased breath sounds, dullness to percussion, hyper-resonance to percussion, Kussmaul breathing, kyphoscoliosis, loud P2, paradoxical breathing, pectus carinatum, pectus excavatum, pleural rub, reduced chest expansion, rhonchi, stridor, tachypnea, tactile vocal fremitus, vesicular breath sounds, vocal resonance, wheezes, and whispering pectoriloquy
• Abdomen: Hepatomegaly
• Upper extremities: Asterixis, digital clubbing, peripheral cyanosis, tobacco staining, and tremor
• Lower extremities: Edema, peripheral cyanosis, and unilateral swelling. [20]

As discussed above, respiratory failure is a syndrome caused by a multitude of pathological states. As such, a single algorithm for evaluating respiratory failure does not exist. Appropriate diagnostic studies may include laboratory assays (i.e., complete blood count with the differential, comprehensive metabolic panel with magnesium/phosphorous, procalcitonin, troponin, and thyroid-stimulating hormone), infectious workup (i.e., blood cultures, sputum cultures, respiratory pathogen panel test, and urinary antigen test), and 12-lead electrocardiography. Evaluation of respiratory failure with arterial blood gas, capnometry, radiography, pulse oximetry, and ultrasonography are discussed below.

Arterial Blood Gas

Arterial blood gas (ABG) is the gold standard for diagnosing respiratory failure. At a minimum, the information obtained from an ABG includes pH, partial pressure of arterial oxygen (PaO2), partial pressure of arterial carbon dioxide (PaCO2), and serum bicarbonate (HCO3). It should be noted that the HCO3 obtained from an ABG is a calculated value and may, therefore, be inaccurate. Analysis of an ABG should instead be performed using a measured HCO3 obtained from a basic metabolic panel.

Oxygenation is assessed through the interpretation of the PaO2. Hypoxemia is defined as a PaO2 less than 60 mmHg. Ventilation is assessed through the interpretation of the PaCO2. Hypercapnia is defined as a PaCO2 greater than 45 mmHg.

Information from the ABG can also be used to differentiate acute from chronic respiratory failure by evaluating the renal response to PaCO2. In respiratory acidosis, the kidneys respond by increasing the absorption of HCO3 in the proximal convoluted tube. As this is a slow process, the magnitude of HCO3 absorption in acute respiratory acidosis is less than the magnitude of HCO3 absorption in chronic respiratory acidosis. This difference allows for the distinction between the chronicity in acute and chronic respiratory failure. [21]

Capnometry, the measurement of carbon dioxide in exhaled gas, may be qualitative or quantitative. Colorimetric capnometry is a qualitative measure of carbon dioxide in exhaled gas that relies on the color change of a pH-sensitive indicator. Infrared capnometry is a quantitative measure of carbon dioxide in exhaled gas that relies on measuring the partial pressure of carbon dioxide (pCO2). Quantitative capnometry provides more information than qualitative capnometry. [22]

In the non-pathological state, the partial pressure of carbon dioxide at the end of expiration, or end-tidal pCO2 (PETCO2), approximates the partial pressure of carbon dioxide in the arterial blood (PaCO2). The PaCO2 is typically 2 to 3 mmHg greater than the PETCO2. In the pathological state, where gas exchange is impaired, the difference between the PaCO2 and PETCO2 becomes greater than 3 mmHg due to increased dead space ventilation. [23]

Values obtained from quantitative capnometry can be plotted graphically and displayed as waveform capnography. Analysis of these waveforms allows for detecting pathological states (i.e., apnea, bronchospasm, hyperventilation, and hypoventilation). [24]  

Radiography

Various imaging modalities are available for the evaluation of respiratory failure. Such options include plain films, computed tomography, magnetic resonance, nuclear medicine, angiography, and ultrasonography. [25]  

Pulse Oximetry

Pulse oximetry relies on spectrophotometry, the process of identifying the composition of a substance via measurement of the absorption of specific wavelengths of light transmitted through the substance in question. The composition and structural configuration of hemoglobin are dependent upon molecular oxygen. In the tense state, oxygenated hemoglobin has a lower affinity for oxygen. In the relaxed state, deoxygenated hemoglobin has a higher affinity for oxygen. Pulse oximetry takes advantage of the conformational states of the hemoglobin molecule as deoxygenated hemoglobin absorbs light at wavelengths of 660 nm, and oxygenated hemoglobin absorbs light at wavelengths of 940 nm. Measurement of arterial oxygenation is ensured through the analysis of pulsatile blood. Proprietary algorithms allow for the conversion of light absorption to the fraction of hemoglobin saturated with oxygen, known as oxygen saturation (SpO2). This non-invasive modality is greatly useful in diagnosing and managing respiratory failure. [26]

Ultrasonography

The bedside lung ultrasound in emergency (BLUE)-protocol is the bedside gold standard for the immediate diagnosis of acute respiratory failure. The protocol allows for reproducible analysis and relies on standardized thoracic locations (BLUE points) and ten ultrasonographic signs or profiles. The BLUE protocol is performed by analyzing the ultrasonographic profiles obtained at each of the three BLUE points on each side of the body. The standardized BLUE points are known as the Upper BLUE point, the Lower BLUE point, and the postero-lateral alveolar and/or pleural syndrome (PLAPS)-point. In total, there are six BLUE points. The theory behind and the application of the BLUE protocol are beyond the scope of this article; however, the ten ultrasonographic profiles are grouped with their corresponding clinical states below:

• Normal lung surface: Bat sign, lung sliding, and A-lines
• Interstitial syndrome: Lung rockets
• Lung consolidations: Fractal and tissue-like signs
• Pleural effusions: Quad and sinusoid sign
• Pneumothorax: Stratosphere sign and the lung point.  [27]

Bronchoscopy, echocardiography, nocturnal polysomnography, and pulmonary function tests may also be included in evaluating respiratory failure. Pulmonary consultation is warranted if the aforementioned diagnostic studies are required.

• Treatment / Management

Treatment of respiratory failure should be directed towards the underlying cause while providing support with oxygenation and ventilation, if necessary. The treatment includes supportive measures and treatment of the underlying cause. However, the initial steps in managing patients with acute respiratory failure should start by assessing the airway, breathing, and circulation (ABC). Supportive measures depend on patent airways to maintain adequate oxygenation, ventilation, and correction of blood gas abnormalities.

Correction of Hypoxemia

The goal is to maintain adequate tissue oxygenation, generally achieved with an arterial oxygen tension (PaO2) of 60 mm Hg or arterial oxygen saturation (SaO2), about 90%.

Uncontrolled oxygen supplementation can result in oxygen toxicity and CO2 (carbon dioxide) narcosis. The inspired oxygen concentration should be adjusted at the lowest level (90-94%), which is sufficient for tissue oxygenation.

Oxygen can be delivered by several routes depending on the clinical situations in which we may use a nasal cannula, simple face mask, nonrebreathing mask, or high-flow nasal cannula.

Extracorporeal membrane oxygenation may be needed in refractory cases. [28]

Correction of Hypercapnia and Respiratory Acidosis  

This may be achieved by treating the underlying cause or providing ventilatory support. [29]

Ventilatory Support

Patients with severe acute respiratory failure are usually intubated.   The goals of ventilatory support in respiratory failure are to:

• Correct hypoxemia
• Correct acute respiratory acidosis
• Resting of ventilatory muscles

Common Indications for Mechanical Ventilation Include the Following

• Apnea with respiratory arrest
• Tachypnea with respiratory rate >30 breaths per minute
• Disturbed conscious level or coma
• Respiratory muscle fatigue
• Hemodynamic instability
• Failure of supplemental oxygen to increase PaO2 to 55 to 60 mmHg
• Hypercapnia with arterial pH less than 7.25 [30]

The choice of invasive or noninvasive ventilatory support depends on the clinical situation, whether the condition is acute or chronic, and how severe it is. [31]  It also depends on the underlying cause. Noninvasive ventilation (NIV) is preferred, particularly in cases of chronic obstructive pulmonary disease (COPD) exacerbation, cardiogenic pulmonary edema, and obesity hypoventilation syndrome. [32] [33] [34] [33] [35] [36]

• Differential Diagnosis

The differential diagnosis for respiratory failure is broad and includes, but is not limited to, the following:

• Aspiration pneumonia
• Aspiration pneumonitis
• Atelectasis
• Bacterial pneumonia
• Cardiogenic pulmonary edema
• Cardiogenic shock
• Central sleep apnea
• Cervical cord injury
• Cor pulmonale
• Diaphragmatic paralysis
• Distributive shock
• Drug overdose
• Fat embolism
• Granulomatous lung disease
• Idiopathic pulmonary arterial hypertension
• Kyphoscoliosis
• Myocardial infarction
• Neurogenic pulmonary edema
• Obesity hypoventilation syndrome
• Obstructive shock
• Obstructive sleep apnea
• Pleural effusion
• Pneumothorax
• Pulmonary fibrosis
• Restrictive lung disease
• Pneumoconiosis
• Primary muscle disorders
• Pulmonary arterial hypertension
• Viral pneumonia

 Respiratory failure is a syndrome caused by a multitude of pathological states; therefore, the prognosis of this disease process is difficult to ascertain. In 2017, in the United States of America, however, the in-hospital respiratory failure mortality rate was 12%. The case definition used in this study included all diagnosis codes, which included respiratory failure. [2]  In-hospital mortality rates for patients requiring intubation with mechanical ventilation for asthma exacerbation, acute exacerbation of chronic obstructive pulmonary disease, and pneumonia were found to be 9.8%, 38.3%, and 48.4%, respectively. [37] [38] [39]  Lastly, the in-hospital mortality rate for acute respiratory distress syndrome was found to be 44.3%. [40]

• Complications

Respiratory failure is associated with both pulmonary and extrapulmonary complications, especially in the acute setting. Pulmonary complications include bronchopleural fistula, nosocomial pneumonia, pneumothorax, pulmonary embolism, and pulmonary fibrosis, while extrapulmonary complications include acid-base disturbances, decreased cardiac output, gastrointestinal hemorrhage, hepatic failure, ileus, infection, increased intracranial pressure, malnutrition, pneumoperitoneum, renal failure, and thrombocytopenia. Clinicians should be aware of the conditions mentioned earlier and be prepared to offer prophylactic therapy or proper treatment for such complications when applicable. [41] [42]

• Consultations

Depending on the severity of the respiratory failure, consultation with a Pulmonary specialist may be warranted in the patient's care.

• Deterrence and Patient Education

While patients should be educated on the symptoms of respiratory failure, they should also be aware of the importance of device and medication compliance, as well as modifiable risk factors and how they relate to disease prevention. For instance, the following strategies are efficacious in preventing acute exacerbations of chronic obstructive pulmonary disease: Adherence to pharmacological therapy, pulmonary rehabilitation, smoking cessation, and vaccination (i.e., influenza and pneumococcal). [43]  Unfortunately, not all causes of respiratory failure are preventable. Patients should seek prompt evaluation and treatment if they become symptomatic.

• Enhancing Healthcare Team Outcomes

Diagnosing the underlying cause of respiratory failure and its treatment is challenging as this syndrome can result from numerous pulmonary and extrapulmonary causes. Therefore, consultation with other specialties (i.e., cardiology and neurology) may be mandatory. Moreover, discussing radiographic findings with a radiologist can sometimes be necessary. Additionally, complications from respiratory failure may be due to improper patient positioning and poor adherence to infection control policies. Fortunately, nurses are vital interprofessional healthcare team members, assuring appropriate patient positioning. Nursing is also responsible for feeding, monitoring, and suctioning the patient and can offer patient counseling while serving as a contact point for the various specialties involved in the case. All interprofessional team members are responsible for keeping meticulous records of every interaction and intervention with the patient so that every care team member has access to the same accurate, updated patient information.

Since patients with respiratory failure may require multiple medications, the pharmacist is instrumental in ensuring safe medication administration, medication reconciliation, answering drug questions for the care team, and providing medication counseling for the patient. Finally, respiratory therapists also care for a patient with respiratory failure (i.e., administration of oxygen and chest physiotherapy). All interprofessional team members must engage in meticulous documentation and report any changes in patient status to the appropriate team members for possible corrective action. This interprofessional team works to improve patient care and outcomes through collaborative activity and open communication. [Level 5]

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Disclosure: Vincent Mirabile declares no relevant financial relationships with ineligible companies.

Disclosure: Eman Shebl declares no relevant financial relationships with ineligible companies.

Disclosure: Abdulghani Sankari declares no relevant financial relationships with ineligible companies.

Disclosure: Bracken Burns declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

• Cite this Page Mirabile VS, Shebl E, Sankari A, et al. Respiratory Failure in Adults. [Updated 2023 Jun 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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Acute respiratory failure and COPD

Recognition and care.

Siela, Debra PhD, RN, CCNS, ACNS-BC, CCRN-K, CNE, RRT

Debra Siela is an associate professor of nursing at Ball State University, Muncie, Ind.

The author has disclosed no financial relationships related to this article.

Acute exacerbations of chronic obstructive pulmonary disease (COPD) that lead to acute respiratory failure usually require hospitalization. Understanding the pathophysiology of COPD and what leads to acute respiratory failure in these patients is important. Nurses must be able to determine appropriate evidence-based care management of these patients to work effectively with the healthcare team.

First, review the pathophysiology of COPD, signs and symptoms, and diagnosis. Then, learn how COPD exacerbations can lead to acute respiratory failure and hospitalization in these patients. A case study illustrates one patient's treatment plan.

Mr. B, 72, is brought into the ED by paramedics. He reports that he has had difficulty breathing over the past several days, and the paramedics placed him on oxygen at 2 L/minute by nasal cannula. He states he has a productive cough and has been expectorating yellow mucus.

Mr. B's initial vital signs are: temperature, 101.3° F (38.5° C); heart rate, 122 beats/minute; BP, 160/96 mm Hg; respiratory rate, 40 breaths/minute; and SpO 2 , 84% on oxygen at 2 L/minute by nasal cannula. He is alert and oriented but anxious; his skin is warm and dry; buccal cyanosis is present. Mr. B has bilateral breath sounds with wheezing and crackles in the lung bases, his S1 and S2 heart sounds are normal, no abnormal heart sounds or murmurs are present, and the cardiac monitor shows sinus tachycardia.

Mr. B's medical history is significant for long-standing chronic obstructive pulmonary disease (COPD). He had an upper respiratory infection about 2 weeks earlier. Mr. B continues to smoke two packs of cigarettes per day and uses oxygen at home. He states that he takes captopril for hypertension.

Mr. B's diagnostic testing (including arterial blood gas [ABG]) analysis reveals the following: pH, 7.30; PaO 2 , 52 mm Hg; PaCO 2 , 54 mm Hg; HCO 3 , 30 mEq/L; and a white blood cell count of 20,000/mm 3 . His eosinophil count is elevated. A sputum culture was obtained and the Gram stain was positive. The ED physician's diagnosis is acute respiratory failure from an acute exacerbation of COPD complicated by pneumonia.

COPD incidence and risk factors

The global incidence of COPD in 2010 was 384 million, affecting 11.7% of the population. 1 Approximately 3 million deaths from COPD occur annually worldwide. 2 The Burden of Obstructive Lung Diseases program, run in 29 countries, found a COPD prevalence of 10.1%, with 11.8% in men and 8.5% in adults over age 40. 3,4

COPD is a common, preventable, and treatable disease characterized by persistent respiratory symptoms and airflow limitation from airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases. 5 The abnormalities result in chronic airflow limitations through changes in small airways (less than 2 mm in diameter; bronchiolitis) and parenchymal destruction (emphysema). These changes evolve at different rates over time. Chronic inflammation causes structural changes, narrowing of the small airways, and decreased lung elastic recoil. These structural changes inhibit the ability of the airways to remain open during expiration. The loss of small airways can contribute to airflow limitation and mucociliary dysfunction. 5

The terms emphysema and chronic bronchitis do not describe all of the structural abnormalities in COPD related to airflow limitation. Chronic respiratory signs and symptoms occur prior to the development of airflow limitation and may also occur in acute respiratory events. 5 Chronic respiratory impairment signs and symptoms sometimes manifest in individuals with normal airflow as determined by spirometry, and many smokers without airflow limitation have structural evidence of lung disease. 5

Genetic factors, gender, and occupational and environmental exposures to pollutants are risk factors for COPD. Smoking is the leading environmental risk factor for COPD, but less than 40% of smokers develop the disease. 6 Cigarette smoking is a factor in the decline of volume of air exhaled within the first second of forced expiratory volume (FEV 1 ) related to a dose-response (pack-years). 7 However, the variability of FEV 1 decline is only partially explained by pack-years of smoking. 7,8 Occupational exposure is a risk factor for 19.2% of patients with COPD and 31.1% of never-smokers. 9 Primary occupational dust exposure comes from mining and textile manufacturing. 7

Lung growth and development processes that reduce maximal lung function may identify individuals at risk for COPD. 10,11 Low birthweight is positively associated with FEV 1 in adulthood; childhood lung infections may also play a role. 7,12

Genetic risk factors include an alpha-1 antitrypsin deficiency, which occurs in 1% to 2% of all patients with COPD. 7 Other genetic factors play a role in the development of COPD; genome studies have identified COPD loci that probably contain susceptibility determinants, but have yet to identify specific genes. 7

Pathophysiology

Inflammation is a key component in the pathophysiology of COPD. 5,7 This inflammation is a modification of the normal respiratory tract inflammatory response. Lung inflammation occurs because of oxidative stress, protease-antiprotease imbalance, inflammatory cells, inflammatory mediators, and/or peribronchiolar and interstitial fibrosis. 5,7 The small airway changes and parenchymal destruction often result in airflow limitation and gas trapping with hyperinflation, gas exchange abnormalities (which include outcomes of hypoxemia and hypercapnia), mucus hypersecretion, and in later stages, pulmonary hypertension from hypoxic vasoconstriction of pulmonary arteries. 7

Oxidants from cigarette smoking activate macrophages in the small airways, causing the release of proteinases (also known as proteases) and chemokines that attract other inflammatory cells. 7 This increase in proteinases begins the destruction of lung tissue. Cell death can occur from this increased oxidant stress. Self-repair of damaged alveoli in the adult lung seems to be limited. 7

Changes in small airways cause the most airflow limitation. Goblet mucus-secreting cells proliferate, replacing surfactant-secreting club cells. 7 Phagocytes enter the airways, and smooth muscle hypertrophy can occur. All of these abnormalities cause narrowing of the airway lumen with fibrosis, excess mucus, edema, and cellular infiltration. Reduction of surfactant can increase surface tension, causing collapse. The inflammatory cell collection causes proteolytic destruction of elastic fibers in the bronchioles and alveolar ducts, where fibers are concentrated as rings around the entrance to alveoli. 7

Emphysema includes destruction of lung parenchyma. The walls of these structures become perforated and coalesce into small air spaces into abnormal and much larger air spaces. Many macrophages, neutrophils, and T lymphocytes collect in the bronchioles of smokers. The macrophages cause release of proteinases that result in tissue destruction.

Emphysema is classified into types based on the location of the pathologic findings within the pulmonary acinus. 7 The types are centriacinar (also known as centrilobular), panacinar (also known as panlobular), and localized emphysema (also known as paraseptal). Centriacinar emphysema is associated with cigarette smoking and occurs in the upper lobes and superior segments of the lower lobes. 7 Panacinar emphysema is uniformly distributed within the pulmonary acinus and occurs in basal lung areas. Localized emphysema occurs in isolated areas and is usually found in the apex of the upper lobe. 7,8

Pathophysiologic outcomes

Airflow obstruction . Airflow during forced expiration is the result of the balance between the elastic recoil of the lungs promoting flow and the resistance of the airways limiting flow. Normally, the flow decreases toward the end of expiration as the lungs empty out because of decreased elastic recoil. In COPD, the flow decreases even further earlier in expiration because of airway collapse. Spirometry measures are FEV 1 and the total volume of air produced during expiratory maneuver, or forced vital capacity (FVC). 7 These volumes are low in COPD. The ratio of FEV 1 to FVC (FEV 1 /FVC) is also low in COPD. 7

Hyperinflation . Occurring in COPD to preserve expiratory airflow because it decreases airway resistance, hyperinflation pushes the diaphragm into a flattened position. 7 This can affect the application of abdominal pressure to the chest wall during inspiration. The shortened diaphragm muscle fibers are less able to generate inspiratory pressures, and the flattened diaphragm has to generate greater tension for the transpulmonary pressure to produce tidal breathing. 7

Impaired gas exchange . The partial pressure of oxygen (PaO 2 ) in arterial blood remains near normal until the FEV 1 is less than 50% of predicted. Arterial carbon dioxide does not elevate until the FEV 1 is less than 25%. 7 Ventilation can vary in different areas of the lung due to compliance and airway resistance. Ventilation-perfusion mismatching is the cause of hypoxemia with minimal shunting. 7

Supplemental oxygen is usually sufficient to treat hypoxemia. If supplemental oxygen does not correct the hypoxemia, pathophysiologic problems other than COPD are likely present. 7

Signs and symptoms of COPD

Dyspnea . The best known symptom of COPD, dyspnea is a major cause of disability. 13 Individuals with COPD describe dyspnea in many different ways: breathlessness, increased effort to breathe, chest heaviness, air hunger, or gasping. 14 Dyspnea is caused by respiratory diseases such as COPD resulting from hyperinflation and bronchoconstriction that often lead to hypoxemia and hypercapnia. 15

Disorders of the ventilatory pump (respiratory muscles) that increase the work of breathing or a sense of increased effort to breathe are associated with an increase in airway resistance or decreased compliance. 15 Chemoreceptors in the carotid bodies are activated by hypoxemia, acute hypercapnia, and acidemia. 7 Stimulation of these receptors and other chemoreceptors leads to an increase in ventilation, which can cause the sensation of air hunger. Other receptors include the mechanoreceptors in the lungs stimulated by bronchoconstriction, which give the sensation of chest tightness. J-receptors are sensitive to interstitial edema and pulmonary vasculature, and are activated by acute changes in pulmonary artery pressure. Hyperinflation makes it difficult to take a deep or satisfying breath, and increases the work of breathing. 15

Assessing dyspnea requires determining the quality of the discomfort. Scales such as a Modified Borg Dyspnea Scale or visual analogue can measure dyspnea at rest or immediately after an activity. 15 More extensive dyspnea scales are available to determine intensity during many different activities and can determine the extent of disability. 15

Cough . Often the first symptom, cough in COPD may occur occasionally, every day, or several times each day. Cough in COPD may be productive or unproductive. 16

Sputum . Individuals with COPD often expectorate tenacious sputum with a cough. Cough with the production of sputum regularly over 3 or more months in 2 consecutive years is a classic definition of chronic bronchitis, but this definition may not reflect all sputum production in COPD. 5,17 Purulent sputum often indicates an increase in inflammatory mediators. 18,19

Wheezing and chest tightness . Presence of wheezing and chest tightness varies among days and on the same day. Wheezing may vary and be audible without a stethoscope, and inspiratory and expiratory wheezes may be heard during auscultation. Not all individuals with COPD experience wheezing or chest tightness. 5

Other signs and symptoms . Fatigue, weight loss, and anorexia occur in individuals with severe and very severe COPD. 20-22 These symptoms have prognostic significance and need to be investigated. Symptoms of depression and anxiety need to be assessed in individuals with COPD and can be caused by acute exacerbations. 23

Spirometry . Measuring FEV 1 and FVC, spirometry calculates the ratio of these two measurements (FEV 1 /FVC). 5 Spirometry measurements are compared with reference values based on age, height, gender, and race. 5 The spirometric criterion for diagnosis of airflow limitation or COPD is a postbronchodilator fixed ratio of FEV 1 /FVC less than 0.70. 5 See COPD airflow limitation severity for the Global Initiative for Obstructive Lung Disease (GOLD) classifications. 5

Imaging . Chest X-rays cannot establish a diagnosis of COPD but can exclude other respiratory diagnoses. 5 Changes in the chest X-ray of a patient with COPD include signs of lung hyperinflation (flattened diaphragm, increase in volume of retrosternal air space), hyperlucency of the lungs, and rapid tapering of the vascular markings. 5 Computed tomography of the chest is not recommended to assist in a diagnosis of COPD.

Lung volume and diffusing capacity . Gas trapping in COPD may be recognized in lung plethysmography and can help determine the severity of COPD, but it may not be helpful in managing the patient. Diffusing capacity measurement may help determine the functional impact of emphysema in COPD not related to airflow limitation. 5

Oximetry and ABGs . Pulse oximetry is used to determine arterial oxygen saturation and need for supplemental oxygen. It should be used in patients with clinical signs of acute respiratory failure. If peripheral arterial oxygen saturation is less than 92%, ABGs should be assessed. 24,25

Exercise testing and physical activity assessment . Exercise impairment related to the effects of COPD can be assessed with self-paced walking distances. 26,27 For example, the 6-minute walk test can be used to stratify patients with COPD for clinical trials and interventions aimed at mitigating exacerbations, hospitalizations, or death. 27

Exacerbations and acute respiratory failure

COPD exacerbations are an acute worsening of respiratory symptoms that result in the need for additional therapy. 5 Mild exacerbations are treated with short-acting bronchodilators; moderate exacerbations are treated with short-acting bronchodilators plus antibiotics for bacterial infection and/or oral corticosteroids; and severe exacerbations require treatment in the ED or hospitalization. Severe exacerbations may be associated with acute respiratory failure. 5 Exacerbations usually occur with respiratory viral infections, although bacterial infections, pollution, and ambient temperature may also initiate these events. 5,28 Viral infections are associated with severe, long-lasting exacerbations and often require hospitalization. 5

Sputum production can increase in COPD exacerbation, and purulent sputum suggests increased bacteria in the sputum. 5 Eosinophils are increased in the airways, lung, and blood in many patients with COPD. Eosinophils increase with neutrophils and other inflammatory cells during exacerbations of COPD. In exacerbations associated with increases in sputum and blood eosinophils may respond to systemic corticosteroids. 29

GOLD guidelines recommend that hospitalized patients with COPD have the severity of their acute respiratory failure classified. 5 These severity classes include no acute respiratory failure; acute respiratory failure, non-life-threatening; and acute respiratory failure, life-threatening. See Acute respiratory failure categories for acute exacerbations of COPD for comparisons of the clinical signs among the three classes. 5

Management of non-life-threatening COPD exacerbations with respiratory failure includes assessing the severity of signs and symptoms, supplemental oxygen, use of short-acting bronchodilators and a muscarinic antagonist, and long-acting bronchodilators when the patient is stable. 5 Providers should consider treatment with oral corticosteroids, antibiotics for bacterial infection, and noninvasive ventilation (NIV). 30-38 See Pharmacologic treatments for acute exacerbations . 5

Supplemental oxygen should be titrated to improve to a target saturation of 88% to 92%. 5 NIV should be the first mode of ventilation used in patients with COPD who have acute respiratory failure because it improves gas exchange, reduces work of breathing and the need for intubation, decreases hospitalization duration, and improves survival. 5,39-46 NIV is the standard of care for acute exacerbations of COPD with concomitant administration of appropriate antibiotics, corticosteroids, and bronchodilators. 47 The use of NIV to manage patients with acute exacerbations of COPD has been associated with a 35% reduction in mortality; a 35% reduction in hospital-acquired pneumonia; an 18% reduction in hospital length of stay; a 30% reduction in costs; and 78%, 55%, and 29% reductions in mortality in patients with low, moderate, and high comorbidity burdens, respectively, compared with patients managed with invasive mechanical ventilation. 48

Indications for NIV include at least one of the following: respiratory acidosis with hypercapnia, severe dyspnea, and persistent hypoxemia in spite of supplemental oxygen therapy. 5 NIV should provide mandatory rates up to 30 breaths/minute, inspiratory pressures up to 30 cm H 2 O, positive end-expiratory pressure (PEEP) or expiratory positive airway pressure up to 15 cm H 2 O; and inspiratory flow rates of up to 180 L/minute at 20 cm H 2 O. 49 To effectively manage patients receiving NIV, the bedside team of nurses, acute care NPs, respiratory therapists, and physicians must collaborate and coordinate their efforts.

Nursing care of patients with acute exacerbations of COPD who receive NIV includes continuous assessment of the patient and monitoring of the noninvasive ventilators. See Monitoring and care of patients receiving NIV . 50,51

When invasive mechanical ventilation is needed, these patients will require intensive care. Other indications for intensive care include severe dyspnea that does not respond to treatment, changes in mental status, and persistent or worsening hypoxemia or acidosis with a pH under 7.25 despite supplemental oxygen. See Monitoring and care of patients receiving invasive mechanical ventilation . 52,53

Case study conclusion

After treatment with albuterol, Mr. B is placed on NIV with a face mask interface at a rate of 24 breaths/minute, inspiratory pressures of 25 cm H 2 O, PEEP of 10 cm H 2 O, and inspiratory flow rates of up to 160 L/minute at 20 cm H 2 O and 40% FiO 2 . His pulmonologist orders azithromycin I.V. infusion and oral prednisolone.

After 2 hours of treatment on NIV, Mr. B's ABGs are now pH 7.33, PaCO 2 50 mm Hg, HCO 3 30 mEq/L, and PaO 2 59 mm Hg. His SaO 2 is 86% with slight buccal cyanosis. Hemodynamics include a heart rate, 112 beats/minute, and BP, 154/90 mm Hg. Mr. B is still coughing and expectorating yellow sputum. No changes are made to his ventilator settings.

If Mr. B's pH had initially been less than 7.25 and/or his PaO 2 less than 40 mm Hg with changes in mental status, a decision to intubate with an endotracheal tube and placement on invasive mechanical ventilation would have been considered. In addition, if his ABGs worsened (particularly increased acidosis), or he developed reduced pulse oximetry saturations, other oxygenation indices, and/or dyspnea, it could warrant intubation and invasive mechanical ventilation.

By the next morning, Mr. B's ABGs improved to: pH, 7.37; PaCO 2 , 49 mm Hg; HCO 3 , 30 mEq/L; PaO 2 , 65 mm Hg; and SaO 2 , 90%. He had a heart rate of 92 beats/minute and BP of 140/84 mm Hg. NIV was continued with the same initial settings, including a respiratory rate of 24 breaths/minute. He responded appropriately to commands and questions.

Mr. B was taken off NIV 48 hours after admission. His ABG values were within normal ranges for him and his COPD. His SpO 2 varied between 90% and 92%. Supplemental oxygen was discontinued. However, he remained in the hospital for 2 more days to continue his I.V. infusion antibiotics and glucocorticoids, to mobilize, and to begin pulmonary rehabilitation. He was discharged on day 5 and continued on pulmonary rehabilitation on an outpatient basis for 4 more weeks.

Mr. B was prescribed a bronchodilator p.r.n. for dyspnea/chest tightness and an inhaled corticosteroid twice a day, and was continued on oral azithromycin for 5 more days. He remained on captopril for his hypertension. He was scheduled for a visit to his pulmonologist 2 weeks after hospital discharge.

Many patients with COPD have acute exacerbations that lead to acute respiratory failure and require hospitalization. It is important to understand the pathophysiology of COPD and what leads to acute respiratory failure in these patients. Nurses must learn appropriate management techniques for these patients so they make appropriate clinical judgments. In addition, nurses must take an interactive and team approach to the care and management of patients with COPD who have acute respiratory failure. Partnering with a healthcare team that includes physicians, clinical nurses, acute care NPs, clinical nurse specialists, respiratory therapists, pharmacists, physical therapists, and dietitians is key to appropriate and quality care.

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acute respiratory failure; bronchitis; chronic obstructive pulmonary disease; COPD; dyspnea; emphysema; hypercapnia; hypoxemia; mechanical ventilation

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Case 3 Acute respiratory failure

• Published: December 2019
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This chapter is centred on a case study on respiratory failure. This topic is one of the key challenging areas in critical care medicine and one that all intensive care staff will encounter. The chapter is based on a detailed case history, ensuring clinical relevance, together with relevant images, making this easily relatable to daily practice in the critical care unit. The chapter is punctuated by evidence-based, up-to-date learning points, which highlight key information for the reader. Throughout the chapter, a topic expert provides contextual advice and commentary, adding practical expertise to the standard textbook approach and reinforcing key messages.

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Monitoring and modulation of respiratory drive in patients with acute hypoxemic respiratory failure in spontaneous breathing

• IM - REVIEW
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• Published: 29 August 2024

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• Anna Mocellin 1   na1 ,
• Federico Guidotti 1   na1 ,
• Simone Rizzato 1   na1 ,
• Matteo Tacconi 1   na1 ,
• Giulia Bruzzi 1 ,
• Jacopo Messina 2 ,
• Daniele Puggioni 1 ,
• Athina Patsoura 1 ,
• Riccardo Fantini 1 ,
• Luca Tabbì 1 ,
• Ivana Castaniere 1 ,
• Alessandro Marchioni   ORCID: orcid.org/0000-0003-3720-3517 1 ,
• Enrico Clini 1 &
• Roberto Tonelli 1  

1 Altmetric

Non-invasive respiratory support, namely, non-invasive ventilation, continuous positive airway pressure, and high-flow nasal cannula, has been increasingly used worldwide to treat acute hypoxemic respiratory failure, giving the benefits of keeping spontaneous breathing preserved. In this scenario, monitoring and controlling respiratory drive could be helpful to avoid patient self-inflicted lung injury and promptly identify those patients that require an upgrade to invasive mechanical ventilation. In this review, we first describe the physiological components affecting respiratory drive to outline the risks associated with its hyperactivation. Further, we analyze and compare the leading strategies implemented for respiratory drive monitoring and discuss the sedative drugs and the non-pharmacological approaches used to modulate respiratory drive during non-invasive respiratory support. Refining the available techniques and rethinking our therapeutic and monitoring targets can help critical care physicians develop a personalized and minimally invasive approach.

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Introduction

Acute hypoxemic respiratory failure (AHRF) is a life-threatening condition defined by the onset of severe hypoxemia that demands prompt and appropriate management [ 1 ]. In recent years, non-invasive respiratory supports (NRS), such as non-invasive ventilation (NIV), continuous positive airway pressure (CPAP), and high-flow nasal cannula (HFNC), are increasingly used as a first step in AHRF treatment, despite protective invasive mechanical ventilation (IMV) remains a cornerstone of the management of patients with severe hypoxemia [ 2 ]. The use of NRS has several benefits: it allows the maintenance of spontaneous breathing, thus preserving respiratory muscle function (e.g., it avoids diaphragm dysfunction and atrophy), sparing airways physiology and integrity (e.g., clearance of secretions and cough), and avoiding MV-related complications, such as ventilator acquired pneumonia [ 3 ]. Besides, positive end-expiratory pressure (PEEP) improves hemodynamics, ameliorating cardiac pre-loading and cardiac output [ 4 ]. On the other hand, spontaneously breathing patients should be accurately monitored to promptly detect NRS failure without delaying the initiation of MV when deemed necessary [ 5 ]. In recent years, a new concept has emerged regarding the possible harmful effects of an abnormal activation of respiratory drive in spontaneous breathing AHRF patients. Self-inflicted lung injury (P-SILI) defines a condition of supraphysiological airway pressure and tidal volume (Vt) to which the lung is subjected with the risk of lung damage due to strenuous spontaneous breathing effort [ 6 ]. Even though multiple clinical observations and experimental data suggest the existence of SILI, there is currently no certain evidence on the relevance of this physiological phenomenon. However, mitigating excessive respiratory effort in spontaneously breathing patients is becoming the key in the management of many AHRF patients requiring NRS. This review explores the strategies used to monitor and modulate respiratory drive during spontaneous breathing in patients with AHRF. Most evidence derives from studies and models having acute respiratory distress syndrome (ARDS) as a paradigm. However, AHRF and ARDS appear to belong to the same disease spectrum portrayed by lung injury, hypoxemia, altered respiratory mechanics and alveolar dead space fraction, and increased respiratory drive [ 3 , 7 , 8 ].

Physiology of respiratory drive

Respiratory drive is commonly defined as the intensity of the output of the respiratory centers, determining the mechanical work of the respiratory muscles, i.e., breathing effort [ 9 ]. Recently, Jonkman et al. proposed a more accurate and comprehensive definition of respiratory drive: the time integral of the neuronal network of the respiratory centers, derived from estimates of breathing effort [ 10 ]. This concept includes the evaluation of amplitude, frequency, or both of neural activity [ 10 ]. The respiratory drive determines breathing effort only if neuromuscular transmission and respiratory function are preserved. The neuronal centers located in the medulla and pons receive tonic inputs from different sources to regulate the three phases of the respiratory cycle: inspiration, post-inspiration, and expiration [ 11 ]. The complex web of interconnection interacting and modifying respiratory activity is still partly unknown. Cortical and emotional inputs, such as pain, anxiety and discomfort, may affect both the brain curve (independently from the patient’s metabolic demands) and the respiratory drive through behavioral responses and a direct reflex on medullary respiratory centers [ 12 , 13 ]. Chemical feedback is determined by central and peripheral receptors. The first ones, located in the medulla oblongata, are highly susceptible to pH and PaCO 2 of the cerebrospinal fluid and directly modulate the frequency and intensity of the respiratory center’s output [ 14 ]. The second ones, located in the carotid bodies and also influenced by PaO 2 , stimulate breathing pattern by enhancing the threshold sensitivity of the central chemoreceptors [ 15 ]. Severe hypoxemia can stimulate the peripheral chemoreceptors that increase the neural respiratory drive by improving the ventilatory response to CO 2 . This mechanism can be further enhanced by concomitant hypercapnia (for example, caused by increased dead space) and altered pH that stimulates central and peripheral chemoreceptors [ 16 ]. It is important to note that peripheral chemoreceptors well tolerate mild hypoxemia, being significantly activated by a severe drop in blood PaO 2 . Thus, the most relevant blood gas parameter in the regulation of respiratory drive is PaCO 2 [ 7 ].

Mechanical inputs, determined by lung stretch receptors and activated by lung inflation, inhibit central chemoreceptors, terminating inspiration [ 9 ]. When lung damage occurs with associated atelectasis and alveolar de-recruitment, lung mechanoreceptors’ inhibitory reflex can be reduced, enhancing the output of the respiratory centers [ 10 ].

Inflammatory mediators that activate vagal C-fibers increase respiratory drive. The inflammation occurring during a systemic disease (e.g., sepsis or ARDS) improves the sensitivity of peripheral chemoreceptors to hypoxemia, with stimulation of lung chemoreceptors (C-fibers) and respiratory centers directly by cytokine production [ 17 ].

All the mechanisms described above can be illustrated by two curves:

-the brain curve that expresses the minute ventilation requested by the neural respiratory drive for a given PaCO 2;

-the ventilation curve that describes the actual minute ventilation of the subject for a given PaCO 2 [ 7 ].

If the respiratory flow–generation pathway (from the neural cells to the respiratory muscles) is intact, the brain curve is identical to the ventilation curve. To clarify, “demand equals supply”: the levels of PaCO 2 requested from the brain show a linear correlation with the Vt that the respiratory system can guarantee to deliver a linear correlation [ 11 ].

Factors influencing respiratory drive during AHRF

During AHRF, impaired neuromuscular function and abnormal respiratory system mechanics generate a dissociation between the brain and the ventilation curves [ 11 ]. The resulting PaCO 2 at a given level of respiratory drive is higher than that expected by the brain as the respiratory generation pathway is impaired at different levels [ 7 ]. The ventilation curve is influenced by the respiratory drive, the respiratory rate, the integrity of the inspiratory flow–generation pathway, the ventilator setting, and the patient–ventilator interaction [ 11 ].

Spontaneous breathing limits diaphragm atrophy and dysfunction, permits earlier mobilization, and improves hemodynamics [ 6 , 18 , 19 ]. On the other hand, the high uncontrolled ventilatory drive promotes elevated breathing effort with detrimental effects on lungs and diaphragm [ 20 ]. In AHRF patients, high respiratory drive leads to great inspiratory effort, local alveoli over-distention, and negative pressure pulmonary edema [ 21 ]. The cyclic recruitment of dependent lung zones and the inhomogeneous transmission of stress and strain worsen P-SILI [ 10 ]. In ARDS animal model, inspiratory effort generates an inhomogeneous distribution of transpulmonary pressure variation across the lung, with a greater pressure change in the dependent regions (posterior) than in non-dependent ones (anterior). The result of this uneven distribution of forces during spontaneous breathing is the so-called “pendelluft phenomenon,” which corresponds to an intrapulmonary shift of gas from non-dependent to dependent lung regions without a change in V at the very onset of the inspiratory effort. The consequence is a selective overinflation of dependent regions and simultaneous deflation in the non-dependent lung area, reproducing a mechanism that promotes lung damage through a zonal volutrauma and cyclic opening/closing of the dependent regions (i.e., atelectrauma). Furthermore, significant inspiratory effort, during assisted ventilation, can cause a drop in alveolar pressure below the PEEP, resulting in aggravation of pulmonary edema due to an increase of transvascular hydrostatic pressure. This deleterious mechanism is amplified in case of low ventilatory assistance and high airways resistance. Even though excessive inspiratory effort could theoretically result in worsening of pre-existing alveolar damage, Yoshida et al., in an elegant experimental study, demostred that a self-inflicted lung damage occurs only in severe lung injury; however, in mild lung injury spontaneous breathing may be accompained by an improvement in alveolar damage and respiratory mechaincs. Transposed to the clinical setting, the concept of P-SILI suggests the need for monitoring inspiratory effort especially in spontaneusly breathing patients suffering from severe AHRF undergoing NRS. Furthermore, in addition to the well-known harmful effects on the lung parenchyma, MV can also injure the diaphragm, resulting in muscle dysfunction which is defined as “myotrauma.” Despite it is known that the muscle disuse, as occurs in controlled MV, triggers proteolytic pathways that result in diaphragm atrophy and contractile dysfunction. More recent evidence suggests that myotrauma may also be the result of excessive loading of the muscle. Clinical and experimental studies show that contraction against an excessive load leads to acute diaphragm inflammation and weakness; however, relieve inspiratory loading significantly attenuates muscle fiber injury in an experimental sepsis model. The increase in diaphragm thickness, measured by ultrasound (US), in patients undergoing assisted IMV, is associated with impaired diaphragm function and prolonged MV, introducing the concept of underassistance myotrauma. All these observations suggests that in AHRF patients with hyperactivation of the respiratory drive, a self-inflicted diaphragm injury, due to excessive loading of the muscle, may also be present. A complex approach that combines the achievement of lung and diaphragm protective strategies, the adjustment of ventilation parameters, and the titration of sedation is required to prevent the development of such a harmful condition [ 18 ]. Low respiratory drive should also be avoided because of its potential adverse consequences, which include progressive atrophy of the diaphragm due to weak inspiratory effort, patient–ventilator asynchronies, and sleep fragmentation [ 10 , 11 ].

Strategies for respiratory drive monitoring

During AHRF, the respiratory flow–generation pathway could be affected at different levels according to the disease’s etiology. As the output of the respiratory centers cannot be directly measured, it is essential to identify the best monitoring surrogate of the respiratory drive. To this purpose, various indices of motor and neural output can be determined [ 22 , 23 ] as shown in Table  1 .

Early identification of markers and signs of excessive activation of respiratory drive is necessary to assume appropriate ventilatory and pharmacologic strategies and promptly detect NRS failure [ 18 ].

Assessing respiratory drive starts with bedside clinical evaluations. A common symptom during AHRF is dyspnea, directly linked to high drive activation. Dyspnea is the result of multiple sensory feedback from chemoreceptors and mechanoreceptors and depends on the integrity of sensory information (further modified by emotions like anxiety and pain) and the motor answer [ 24 , 25 ]. Dyspnea is often considered the clinical result of the discrepancy between the desired ventilation (brain curve) and the actual ventilation achievable (ventilation curve) [ 7 ]. It could be measured with scales and scores (e.g., Borg or Visual Analogue Scale) [ 26 ]. However, as patients may be non-responsive or uncooperative, it can be helpful to objective signs of dyspnea and increased inspiratory effort [ 27 ]. A valuable indicator to observe is the tracheal tug, characterized by the downward motion of the trachea with each inspiratory effort. While the degree of tug may differ among patients, its presence is consistently meaningful as the respiratory muscles induce tugging when the diaphragm pulls the entire mediastinum downward during each inspiratory effort [ 28 ]. Another clinical sign is the assessment of the sternomastoid muscle. Phasic contraction of the sternomastoid is frequently observed in patients with acute respiratory failure, and it is associated with a forced expiratory volume in the first second less than half that observed in patients without such contraction [ 29 , 30 ]. Lastly, the inspection of the suprasternal fossa can also be helpful. As swings in pleural pressure (P Pl ) become more negative, the suprasternal fossa is visibly excavated with each inspiration. This excavation is directly proportional to swings in esophageal pressure (P es ) [ 31 ]. Even if shortness of breath is frequently associated with severe hypoxemia, some clinical conditions leading to AHRF may lack dyspnea and clinical signs of inspiratory effort [ 32 ]. The recent SARS-CoV-2 pandemic has revealed that some patients may not manifest dyspnea even in severely reduced PaO 2 because of the “happy hypoxemia” phenomenon. In this kind of patients, during the initial phase of the illness, there is no increased airway resistance and dead space ventilation, so the lung’s compliance is substantially preserved, and the breathing effort seems to remain unchanged [ 33 ]. As such, instrumental methods for evaluating and estimating respiratory drive may help clinicians in detecting harmful hyperactivation of the respiratory drive.

One of the most accurate methods to assess the inspiratory effort is measuring the airway occlusion pressure ( P 0.1), defined as the negative airway pressure developed in the first 100 ms during the inspiratory phase developed against an airway occlusion [ 34 ]. In spontaneously breathing mechanically ventilated patients, a value above 3.5 cm H 2 O indicates a high respiratory drive, thus reflecting a vigorous respiratory muscle contraction [ 35 ]. It is not influenced by behavioral reaction (the usual time reaction is superior to 150 ms) nor abnormal respiratory mechanics [ 34 ]. However, it is unreliable in severe respiratory muscle weakness, and there is no evidence about its utility during NRS [ 36 ].

Assessing the diaphragm electrical activity (EAdi) may provide an accurate estimate of the breathing effort. To perform the measurement, an esophageal catheter with multiple electrodes measures the change in the discharge of motor neurons to the diaphragm over time [ 37 ]. Hence, it is the most accurate surrogate of respiratory drive, even in low muscle strength. However, the invasiveness of the measurement, the low availability of intensive care unit (ICU) ventilators able to record it, and the absence of normal reference values [ 38 ] significantly reduce its use in clinical practice.

To date, esophageal manometry pressure with P es swing (∆ P es ) assessment is considered the gold standard for the inspiratory effort evaluation during spontaneous breathing [ 18 ]. P es represents an accurate surrogate of the P Pl that allows the calculation of the inspiratory transpulmonary pressure during static condition in patients undergoing IMV, providing a reliable measure of the lung stress. During spontaneous breathing ∆ P es coincides with the dynamic transpulmonary pressure, while in assisted MV, the dynamic transpulmonary pressure is affected by pressure support (PS) and PEEP as well as the inspiratory effort measured as ∆ P es . While the dynamic transpulmonary pressure may represent the global stress applied to the lung parenchyma during assisted and un-assisted spontaneous breathing, some clinical observations show that the inspiratory effort (i.e., ∆ P es ) is the most important component associated with P-SILI. Currently, there is no evidence that allows us to estabish a harmful threshold of ∆ P es ; however, values over 10–12 cm H 2 O might be considered a threshold risk for P-SILI development, and its monitoring over time could be very useful in the early identification of NRS failure [ 39 ]. The major limitations of this technique are the invasive monitoring (it requires a nasogastric tube with an esophageal balloon), the high cost, and the need for specific expertise in performing the calibration and the measurements [ 40 ].

Nasal pressure swings (∆ P nose ) is a physiological variable that reflects the airway pressure ( P aw ) swings captured in the upper respiratory tract during tidal breathing. It has been recently demonstrated that ∆ P nose has a strong correlation with ∆ P es regardless tha application of HFNC or NIV. In contrast to ∆ P es , ∆ P nose can be easily measured at the patient’s bedside with a “nasal plug” inserted in the nostril, not influencing inspiratory effort or respiratory rate [ 41 ]. Recently, in a real-life cohort of patients with AHRF undergoing HFNC, ∆ P nose showed high accuracy in predicting early NRS failure [ 42 ].

US could be helpful in monitoring inspiratory effort [ 43 ]. Vivier et al. found a significant correlation between the thickening fraction (TF) as assessed by US and the diaphragmatic pressure–time product per breath (PTPdi per breath = average inspiratory pressure × time/number of breaths) in 12 patients treated with NIV with three increasing PS levels following extubation [ 44 ]. Further, Umbrello et al. found a significant correlation between TF and Esophageal Pressure–Time Product (PTP es ) and P0.1 [ 45 ], in a population of patients who met the criteria for a spontaneous breathing trial with pressure support ventilation (PSV) following major elective surgery. Although US may provide an accurate estimate of breathing effort, it is an operator-dependent technique, making it challenging to reproduce. Further, no reference cutoff has been identified.

Pharmacological modulation of respiratory drive

The strict monitoring of respiratory drive aims at its modulation, after signs of hyperactivation are detected. As mentioned, P-SILI is supposed to occur during spontaneous breathing secondary to high respiratory drive. Hence, keeping the breathing effort and respiratory rate within the physiological threshold may reduce the risk of further lung damage [ 46 ]. For this reason, applying a sedative strategy aimed at controlling respiratory drive could improve NRS success rate and thus reduce the need for IMV. This concept has been introduced by Kassis et al. [ 47 ] with the name of “lung-protective sedation,” based on the interaction between patient and ventilator, to target synchrony instead of arousal. In this case, sedation should be evaluated by direct measures of synchrony and effort.

Important to note is that sedation in hypoxemic spontaneously breathing patients is still perceived as an insidious issue and unstandardized practice, leading to very limited use in daily routine (between 25 and 40% of patients) [ 48 ].

To date, the use of sedative drugs in AHRF patients under NRS has consistently aimed to improve interface tolerance. As HFNC is per se better tolerated than NIV [ 49 ] to our knowledge, there are no studies that have investigated the use of sedative drugs in patients with AHRF treated with HFNC. Conversely, one of the most frequent causes of premature interruption of NIV is mask intolerance due to pain, discomfort, delirium, or claustrophobia [ 50 , 51 ].

Ideally, sedation in hypoxemic patients should be performed with no/minimal respiratory depression and no/minimal impairment of the upper airways, maintaining the patient easily arousable [ 52 , 53 ]. In this regard, Yang and colleagues conducted a meta-analysis to assess the clinical efficacy of using sedative and analgesic drugs during NIV. They concluded that the use of sedative drugs in this subset of patients reduces the intubation rate and delirium and shortens the duration of stay in the ICU [ 54 ].

From a pharmacological point of view, sedatives may directly dampen the respiratory drive [ 10 ]. However, sedative regimens are usually titrated based on scales assessing the neurological status of the patients (i.e., arousal), such as the Richmond Assessment Sedation Scale (RASS), Riker Sedation–Agitation Scale (SAS), and Ramsay Sedation Scale (RSS) [ 55 ]. However, available data suggest that arousal level poorly correlates with patient respiratory effort and ventilator synchrony [ 56 , 57 ]. Moreover, clinical studies based on hypoxemic patients on NRS aimed at assessing the impact of sedation on respiratory effort as the primary outcome are lacking. The most used drugs for sedation during NIV are dexmedetomidine, opioids, benzodiazepines, and propofol. The characteristics of each agent are discussed below and summarized in Table  2 .

Dexmedetomidine

Dexmedetomidine is a short-acting selective α 2 -adrenergic agonist that stimulates receptors located in the locus coeruleus to provide sedation and anxiolysis [ 58 ]. Further, it acts on the spinal cord to enhance analgesia without significant respiratory depression. It also causes sympatholysis via central and peripheral mechanisms [ 59 ]. In animal models, there is increasing evidence that dexmedetomidine can provide protective effects for the lungs exposed to acute damage through anti-inflammatory, anti-apoptotic, and antioxidant properties [ 60 ]. The effects of dexmedetomidine on the respiratory system resulted in minimal changes in respiratory frequency and a slight reduction in minute ventilation, leading to a modest increase in PaCO 2 [ 61 ]. In an observational study conducted on 33 spontaneously breathing patients, sedation with dexmedetomidine did not result in changes in the diaphragmatic TF measured by diaphragmatic US [ 62 ]. Compared with any sedation strategy (in particular with remifentanil and propofol) or placebo during NIV, dexmedetomidine has shown a better profile regarding intubation rates, delirium, ICU length of stay, and length of NIV. There were no significant differences in all-cause mortality [ 59 , 63 , 64 ]. The most reported adverse reactions in patients receiving dexmedetomidine are hypotension, hypertension, and bradycardia (occurring in approximately 25, 15, and 13% of patients, respectively), generally resolved with no treatment [ 65 ].

Opioids have been historically used for sedation during NIV [ 66 ], even though they can cause concentration-dependent hypoventilation and increased irregularity of breathing [ 67 ]. In a prospective observational cohort study, 12 adult patients received a continuous sufentanil infusion at 0.2 to 0.3 micro g x kg −1  × hr −1 during PSV [ 68 ]. Sufentanil infusion did not affect respiratory drive measured through P0.1.

Remifentanil, a short-acting opioid with μ-selectivity, is widely used for the sedation of critically ill patients with AHRF [ 69 ]. Used as a single sedative agent, it allows to obtain the desired level of awake sedation with little effects on minute volume, respiratory pattern, blood gases, and hemodynamics compared to other opioids [ 70 ]. Low doses of remifentanil generate a slight decrease in the patient’s respiratory rate without significant changes in Vt and respiratory drive, as quantified by P0.1 [ 71 ]. EAdi was assessed in thirteen intubated patients who were administered increasing doses of remifentanil during PSV [ 72 ]. The authors showed that remifentanil did not modify EAdi but only respiratory timing. Remifentanil seems to obtain a more significant reduction of respiratory rate than dexmedetomidine; thus, the effect on minute ventilation is more appreciable [ 73 ]. Moreover, remifentanil seems to have a superior analgesic effect compared to dexmedetomidine [ 74 ]. Observational studies showed that sedation with remifentanil has resulted feasible and safe during NIV [ 75 , 76 ]. However, to our knowledge, no randomized controlled trials (RCT) have ever been conducted to assess its use in spontaneously breathing patients with AHRF.

Propofol is a short-acting intravenous anesthetic that positively modulates the inhibitory function of γ-aminobutyricacid (GABA) type A (GABA A ) receptors and leads to central nervous system depression, resulting in sedation and anesthesia [ 77 ]. Clouzeau and colleagues conducted an observational study on ten adult patients sedated with target-controlled infusion (TCI) of propofol during poorly tolerated NIV with good results [ 78 ]. The very low concentration used allowed patient cooperation and did not compromise spontaneous respiration, ensuring an effective and safe technique. In one case, excessive respiratory depression was observed. Interesting data about the influence of propofol on respiratory drive arise from a prospective crossover RCT conducted by Vaschetto and colleagues [ 79 ]. During PSV, increasing the depth of sedation with propofol determined a progressive significant decrease in neural drive (measured through electrical activity of the diaphragm) and respiratory effort (∫ electrical activity of the diaphragm/min). However, deep propofol sedation increased patient–ventilator asynchronies, while light sedation did not [ 80 ].

Benzodiazepines

Benzodiazepines are molecules that enhance the effect of the neurotransmitter GABA at the GABA A receptor, resulting in sedative, hypnotic, and anxiolytic effects [ 81 ]. Benzodiazepines affect respiration in several ways. First, they modulate the muscular tone, leading to an increased risk of upper airway obstruction; further, they flatter the ventilatory response curve to carbon dioxide. Indeed, benzodiazepines dampen the respiratory reaction to hypoxia, while hypercapnia has occurred [ 82 ].

The effects of midazolam on respiratory muscles at a dosage of 0.1 mg/kg were studied in nine healthy volunteers. After infusion, the ratio of gastric pressure ( P ga ) on P es changes (Δ P ga / Δ P es index) significantly decreased, indicating reduced diaphragmatic activity [ 83 ]. Flumazenil can reverse this effect, as confirmed by the measurement of EAdi after its administration in patients sedated with midazolam [ 84 ].

In the past, benzodiazepines were one of the most used pharmacological classes for sedation practices of patients on NIV [ 85 ]. Its use is currently limited due to its low safety profile and poor handling. Among benzodiazepines, midazolam is one of the most used drugs, showing hypnotic, sedative, and amnestic properties [ 86 ]. However, compared to dexmedetomidine, it showed worse outcomes in NIV sedation, such as the duration of mechanical ventilation and the length of the ICU stay [ 87 , 88 ].

Ketamine is a non-competitive antagonist of the N-methyl-D-aspartic acid (NMDA) receptor that can induce a state of “dissociative anesthesia.” Ketamine is an excellent analgesic drug, similar to opioids but with a lower incidence of respiratory drive depression [ 89 ]. It is also an ideal agent for maintaining homeostasis (cardiovascular stability, maintenance of respiratory reflexes), especially in patients who require ongoing maximal sympathetic activity [ 90 ]. Ketamine has a minimal impact on controlling respiratory centers; however, it may be effective in achieving control of respiratory drive through indirect mechanisms [ 91 ]. To date, no studies have assessed this sedative’s effectiveness and safety profile during NRS.

Non-pharmacological control of respiratory drive

High respiratory drive and its causes should be addressed to adjuvate pharmacological measures to prevent lung and diaphragm injuries. As mentioned before, non-respiratory factors may increase respiratory drive. In this line, pain, discomfort, metabolic acidosis, fever, and other precipitating factors should be promptly identified and corrected [ 3 ]. Besides sedation, clinicians might consider non-pharmacological strategies aimed at preserving respiratory drive activation within the physiological threshold. To provide the patient the highest comfort while being assisted with NRS includes the rotation of interfaces, optimizing ventilatory settings to improve ventilator–patient interaction, and the management of anxiety and pain. Non-pharmacological strategies aimed at maximizing the control of respiratory drive are briefly illustrated below and summarized in Fig.  1

Schematic representation of the causes of hyperactivation of the respiratory drive and the pharmacological and non-pharmacological options to control them. This figure represents the vicious cycle that can be triggered by lung damage leading to AHRF. Cortical, biochemical, mechanical, and inflammatory stimuli result in hyperactivation of the respiratory drive, leading to an increase in the mechanical work of respiratory muscles, thus initiating a vicious cycle that culminates in the formation of P-SILI. Non-pharmacological possibilities are mentioned in the pink boxes, while pharmacological options are listed in the green boxes to control this cycle. AHRF acute hypoxemic respiratory failure ; P-SILI patient self-inflicted lung injury, PSV pressure support ventilation, ECCO 2 R extracorporeal carbon dioxide removal

The use of relaxing music might be considered a low-cost, side-effectless option to control anxiety and its consequences on respiratory drive [ 92 ] . Classical music [ 92 ] or relaxing music [ 93 ] seem to be the most appropriate choices for this type of hospital setting. The main modalities in which it can be used are music therapy, conducted by certified music therapists, and therapeutic music listening, administered by nurses.

Music positively influences ICU inpatients in the physiological, psychological, and social spheres [ 92 ], and it is likely to reduce anxiety and depression and improve sleep quality [ 94 ].

A RCT has described a favorable interaction between music rhythm and the breathing pattern of critically ill subjects receiving ventilatory support [ 93 ]. Indeed, music seemed able to override metabolic inputs by decreasing anxiety and increasing comfort, thus dampening and decreasing the behavioral drive [ 7 ]. Conversely, another RCT focused on respiratory comfort during NIV recently failed to demonstrate a beneficial impact of musical intervention compared to conventional care [ 95 ]. Further studies are warranted on the interaction between music and respiratory drive [ 94 ]. No study has been conducted on the impact of music in modulating respiratory effort in ICU patients with AHRF and supported through NRS.

Awake prone position

The prone position (PP) was first proposed for patients with ARDS in the 1970s [ 96 ], later developed within a multimodal approach of such pathology [ 97 ].

Physiological effects of pronation include changes in inflation, ventilation, and perfusion, permitting decompression of the dorso-caudal dependent zone. The increased functional residual capacity and the homogeneous inflation and perfusion result in reduced lung stress and, thus, in a lowering of the respiratory drive hyperactivation [ 98 , 99 ]. Awake prone position (APP) improves diaphragmatic function and reduces inspiratory effort [ 99 ].

During the recent COVID-19 pandemic, the so-called “awake pronation” in non-invasive mechanically ventilated patients was often performed. This practice is feasible and has been associated with a reduction in intubation rate [ 100 ], especially in patients undergoing HFNC [ 101 ], and work of breathing during CPAP [ 98 ]. High-quality evidence available is RCT derived from studies enrolling only COVID-19 patients in non-intubated patients [ 100 , 102 ].

Regarding the respiratory drive, Whatheral et al. [ 102 ] noted seven trials reporting changes in respiratory rate, but significant heterogeneity in the timing outcome assessment precluded the pooling of data for statistical analysis.

According to available literature, the use of this practice outside the respiratory intensive care unit (R-ICU) or ICU setting should be discouraged [ 99 ]. In patients in conventional oxygen therapy (COT) who do not receive NRS-type respiratory support, the practice of pronation remains controversial [ 99 , 100 ]. Available studies show dyshomogeneity in the duration of pronation, with variability between 1 and 12 h [ 100 , 101 ]; however, it appears that the impact of the practice is related to the duration of APP [ 99 ]. More data are needed on the effect of APP in non-COVID-19 patients with AHRF. Indeed, ESICM 2023 task force was unable to make a recommendation for or against awake for patients with non-COVID19 AHRF [ 103 ]. Further research is warranted to explore the effect of APP on mortality, inspiratory effort, and work of breathing in non-COVID-19 patients with AHRF [ 99 ].

Extracorporeal carbon dioxide removal

Extracorporeal carbon dioxide removal (ECCO 2 R) aims to reduce the amount of CO 2 via an extracorporeal circuit: this will move the metabolic hyperbola downward, thus reducing the current PaCO 2 and minute ventilation level [ 104 ]. The primary endpoint of ECCO 2 R in ARDS is to reduce the injury due to mechanical ventilation. Crotti et al. [ 105 ] described an innovative approach using extracorporeal membrane oxygenation in awake spontaneously breathing patients: CO 2 removal relieved work of breathing and permitted extubation in many patients (bridge to lung transplant or affected by Chronic Obstructive Pulmonary Disease), only a few patients with ARDS were able to perform the spontaneous breathing trial. To date, the burden of ECCO 2 R-related complications is too high to consider this method to reduce the respiratory drive in non-intubated patients with mild ARDS [ 103 ].

Adequate setting and respiratory support

The use of sedative drugs during NRS in spontaneously breathing patients with AHRF should be limited to physician and nurses with experience in management of sedative therapy and its adverse effects, with adequate patient monitoring, in a high-intensity setting such as R-ICU or ICU. This implies the need for adequately trained staff and good resource availability. It is also important to emphasize that, to reduce respiratory drive, these drugs should always be considered adjuncts to a respiratory support system (HFNC or NIV), which still plays a primary role in this context. It is not certain that all approaches proposed for AHRF in the ICU are reproducible in alternative settings, either in terms of patient safety or efficacy (i.e., awake pronation [ 99 ]). There is a lack of studies regarding sedation in patients with AHRF undergoing NRS that compare multiple medications and different approaches to respiratory support. High-flow nasal oxygen (HFNO) is the currently suggested first-line intervention [ 2 ], but the optimal non-invasive management of AHRF is still debated. New evidence is emerging that is shedding light on the type of patient who would benefit the most from non-invasive ventilatory support to reduce respiratory effort activation [ 106 , 107 ].

Needs for research and further perspective

A notable concern is the need for RCTs and comparative effectiveness studies among the currently available sedative drugs. The ideal sedative drug to be used in spontaneously breathing patients with AHRF should not only dampen but should also preserve ventilatory drive, keep safe effects on airway patency, avoid the onset of delirium, promote natural sleep, have a low impact on hemodynamics, and produce anxiolysis (Fig.  2 ). Additionally, considerations should extend to the drug’s economic viability, environmental sustainability, and ease of implementation in healthcare settings. Presently, no specific drug fully meets all these criteria.

Characteristics of the ideal sedative drug

Including patients receiving HFNO therapy in RCTs seems imperative, as the indication for AHRF is now clearly established and included in the new ARDS definition [ 2 , 8 ]. High tolerance and ease of use of HFNO could facilitate the shift of analog sedation from a method focused on improving patient tolerance and ventilation synchrony to one aimed at preventing P-SILI onset.

Most importantly, it should be assessed whether reducing respiratory drive in patients exhibiting overactivation can decrease P-SILI and, consequently, prevent technique failure and the need for increased invasiveness.

Considering monitoring, sedation, and proper respiratory support choice as not dissociable pillars of the management of spontaneously breathing AHRF patients would allow for identifying and attaining a safe level of inspiratory effort. This could form the basis for a new concept of “protective non-invasive respiratory support” (Fig.  3 ). This process, in turn, necessitates the concurrent advancement of minimally invasive and cost-effective techniques for monitoring inspiratory effort, enabling the identification of the subset of patients who would benefit from such an approach. Artificial intelligence (AI) will likely play a pivotal role in integrating data, vital parameters, and sedation levels to enhance the monitoring of non-invasive respiratory support.

“Lung-protective sedation” model. Preliminary assessment: search for signs and symptoms of discomfort and implement non-pharmacological strategies to reduce them. By integrating the preliminary assessment and measuring respiratory drive, it is possible to decide whether sedation is needed or not. If sedation is initiated, it is necessary to achieve the correct level of sedation and control of the respiratory drive through close monitoring. P0.1 Airway occlusion pressure, ΔP es Esophageal pressure swings, ΔP nose Nasal pressure swings, EAdi Diaphragm electrical activity, BPS-NI Behavioral pain scale non-intubated patients, US ultrasound, RSS Ramsay sedation scale, OAA/S observer’s assessment of alertness/sedation, RASS Richmond assessment sedation scale, BIS bispectral index

Conclusions

The use of NRS has recently surged to manage patients with AHRF [ 2 ]. Keeping spontaneous breathing preserved requires clinicians to forecast potential consequences of P-SILI through close monitoring of inspiratory effort and respiratory drive. Clinical patient evaluation focused on respiratory rate and accessory muscle involvement is feasible but lacks objectivity. The ideal tool to quantify the activation of the respiratory drive should balance non-invasiveness, low cost, and reproducibility. In this line, diaphragmatic US and ∆P nose assessment seem promising techniques. Once signs of hyperactivation are detected, a pharmacological approach to dampen respiratory drive is welcomed. In this scenario, dexmedetomidine appears to have the best risk–benefit profile as a sedative drug for pain, discomfort and anxiety control, and delirium prevention. A (i.e., selecting the appropriate NRS mode, APP, and interface rotation in case of NIV). Further evidence is needed to enable a more standardized procedure in the NRS setting. The integrated approach of the methods examined should aim at a protective, non-invasive respiratory support strategy modeled upon the profile of the patient’s inspiratory effort.

Data Availability

Not applicable.

Abbreviations

• Acute hypoxemic respiratory failure

Artificial intelligence

Acute respiratory distress syndrome

Bispectral index

Behavioral pain scale non-intubated patients

Conventional oxygen therapy

Continuous positive airway pressure

Diaphragm electrical activity

γ-Aminobutyric acid

γ- Aminobutyric acid type A

High-flow nasal cannula

High-flow nasal oxygen

Intensive care unit

Invasive mechanical ventilation

Mechanical ventilation

Non-invasive ventilation

N-methyl-D-aspartic acid

• Non-invasive respiratory support

Observer’s assessment of alertness/sedation

Airway occlusion pressure

Airway pressure

Positive end-expiratory pressure

Esophageal pressure

Gastric pressure

Pleural pressure

Prone position

Pressure support

Patient self-inflicted lung injury

Pressure support ventilation

Diaphragmatic pressure–time product

Esophageal pressure–time product

Richmond assessment sedation scale

Respiratory intensive care unit

Randomized controlled trial

Ramsay sedation scale

Riker sedation–agitation scale

Target-controlled infusion

Thickening fraction

Tidal volume

Esophageal pressure swing

Nasal pressure swings

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Acknowledgements

The authors would like to thank Arianna Rech for language editing.

Open access funding provided by Università degli Studi di Modena e Reggio Emilia within the CRUI-CARE Agreement.

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Anna Mocellin, Federico Guidotti, Simone Rizzato, Matteo Tacconi these authors share first authorship.

Authors and Affiliations

Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University Hospital of Modena, University of Modena Reggio Emilia, Modena, Italy

Anna Mocellin, Federico Guidotti, Simone Rizzato, Matteo Tacconi, Giulia Bruzzi, Daniele Puggioni, Athina Patsoura, Riccardo Fantini, Luca Tabbì, Ivana Castaniere, Alessandro Marchioni, Enrico Clini & Roberto Tonelli

Internal Medicine Unit, University of Rome, Roma 1, Rome, Italy

Jacopo Messina

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Contributions

AMocellin, FG, MT, SR, AP, GB, JM, and DP wrote the paper and produced figures. RF, IC, and LT designed the review and produced the figures. AMarchioni and EC designed the review and wrote the paper. RT designed the review, wrote the paper, and edited the manuscript. All authors have read and approved the final version of the manuscript.

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Correspondence to Alessandro Marchioni .

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Conflict of interest.

RT, RF, LT, IC, AMarchioni, and EC declare patent N. 102021000007478 “APPARATO PER IL RILEVAMENTO ED IL MONITORAGGIO DELLA PRESSIONE NASALE” released on March 28th 2023 by the Italian Ministry of Enterprises and Made in Italy. RT, RF, LT, AMarchioni, and EC are co-founders of IREC ltd (VAT 02959080355) (Reggio Emilia, Italy). RT received travel support and fees from GSK, SEDA, Guidotti, United HealthCare Services. AMocellin, FG, SR, MT, AP, GB, JM, and DP have no competing interests with any organization or entity with a financial interest in competition with the subject, matter, or materials discussed in this manuscript.

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Mocellin, A., Guidotti, F., Rizzato, S. et al. Monitoring and modulation of respiratory drive in patients with acute hypoxemic respiratory failure in spontaneous breathing. Intern Emerg Med (2024). https://doi.org/10.1007/s11739-024-03715-3

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Received : 10 June 2024

Accepted : 10 July 2024

Published : 29 August 2024

DOI : https://doi.org/10.1007/s11739-024-03715-3

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