Essentials of Airway Management: The Best Tools and Positioning for First-Attempt Intubation Success

Evan D. Schmitz MD

Pulmonary and Critical Care Medicine

Abstract

Head position during endotracheal intubation affects first-attempt success, as does the different tools available and the location. It is important to be skilled in the operation of a variety of laryngoscopes (video or direct) as well as introducers (plastic/steel stylets and bougies). Difficult airways should always be anticipated and proper preparation such as upper airway assessment performed. The following is a review of endotracheal intubations performed outside of the operating room.

Objectives

• Discuss how different locations in the hospital can affect endotracheal intubation success.
• Learn the difference between simple head positioning and the sniffing position and why one should be chosen over the other. MRI images of the head and neck in each position will be reviewed.
• Learn about different types of laryngoscope blades.
• Understand the dangers of video laryngoscopy as well as the benefits and when to choose direct laryngoscopy.
• Define endotracheal intubation first-attempt success.
• The benefits of using a bougie as opposed to a stylet to increase first-attempt success rate with a review of the supportive literature.
• Case presentations.

Abbreviations

• AF – atrial fibrillation
• ARDS – acute respiratory distress syndrome
• BiPAP – bilevel positive airway pressure
• CAD – coronary artery disease
• COPD – chronic obstructive pulmonary disease
• Ó – delta
• DM – diabetes mellitus
• DVT – deep vein thrombosis
• ED – emergency department
• ETT – endotracheal tube
• FiO2 – fraction of inspired oxygen
• HFNC – high flow nasal canula
• HTN – hypertension
• ICU – intensive care unit
• LA – laryngeal axis
• LV – line of vision
• MRI – magnetic resonance imaging
• NIDDM – non-insulin dependent diabetes mellitus
• NRB – non-rebreather mask
• OA – oral axis
• OR – operating room
• OSA – obstructive sleep apnea
• PA – pharyngeal axis
• PCO2 – partial pressure of carbon dioxide
• PE – pulmonary embolism
• RCA – right coronary artery
• SpO2 – pulse oximeter oxygen saturation
• Sz – seizure

Introduction

Ideal positioning can make the difference between a successful endotracheal intubation or death. Many times, intubations are performed in emergency situations, and positioning is not always ideal depending on the type of surface. In the OR, ideal conditions exist regarding adequate supplies and time (1). Conditions can be very different outside of the operating room (OR) especially during a code blue. The average time of intubation is 37 seconds in the emergency department (ED) (2). During the COVID-19 pandemic, intubations were being performed as quickly as 15 seconds in the intensive care unit (ICU) to prevent cardiac arrest in patients with severe adult respiratory distress syndrome (ARDS) (3).

Hospital beds are cumbersome and can cause poor positioning making intubation difficult. If possible, it is always a good idea to have a few towels available to help with head positioning. Towels can be rolled up and placed between the shoulder blades to aid in simple head extension. Towels can also be used to flex the neck on the chest and extend the head on the neck into the sniffing position. Pillows can be added if needed in morbidly obese patients.

Previous studies published in the Journal of Anesthesia comparing head positioning with regards to line of vision (LV), oral axis (OA), pharyngeal axis (PA), and laryngeal axis (LA) proved that all axes can never be perfectly aligned (Figure 1) (4). The same authors concluded that routine use of the sniffing position appears to provide no significant advantage over simple head extension for tracheal intubation (5).

The sniffing position improved glottic exposure in 18% of patients and worsened it in 11% in comparison with simple head extension in patients intubated in the operating room. Multivariant analysis showed that patients with reduced neck mobility and obesity did better in the sniffing position.

The angle between the LV to the LA, ó, decreases significantly when placed in simple head extension (B) and the sniffing position (C) compared with neutral positioning (A) (Figure 1). In simple head extension ó is the smallest approximating 20^o. The smaller the ó, the easier it is to access the glottis. Bougie introducers like the AIROD® telescopic steel bougie with a 20^o bend at the proximal end as well as elastic bougies with a coude (bent) tip allow easy transition from the LV to the laryngeal axis LA in simple head extension Figure 2 (6-10).

Figure 1.  Evaluation of the four axes (mouth axis [MA], pharyngeal axis [PA], laryngeal axis [LA], line of vision [LV] and the α, β, and ό angles in the three positions (4).

Figure 2. AIROD® aligned perfectly with the laryngeal view (LV) with the head in simple extension. Transition to the laryngeal axis (LA) is easy due to the specialized 20^o tip.

The different video laryngoscopes all offer indirect views of the glottis (Figure 3).

 

Figure 3. Different types of video and direct laryngoscopes.

For those on C-spine precautions, a hyperangulated Glidescope® or C-MAC® can help with the acute angles involved without the need for significant neck movement. Although video laryngoscopes may improve the view of the glottis because they do not guarantee a direct pathway to the vocal cords, disaster may occur during intubation. Additional tools and expertise should be available immediately because once sedatives and paralytics are given you may no longer be able to ventilate the patient.

In 2017 Baptiste et al. (11) published a study showing that severe life-threatening complications were higher in those ICU patients who were intubated using video laryngoscopy 9.5% vs 2.8% in those who were intubated with direct laryngoscopy with the numbers needed to harm of 14.6. Blood, emesis, secretions, damaged screen, and sudden battery failure can all obscure the video images, complicating intubation with video devices. It is therefore recommended that operators be comfortable using direct laryngoscopes as well as bougies in case of video device failures.

Prior to intubation, airway assessment should be performed to determine whether a difficult airway may be present. If any of the following characteristics are present, then a difficult airway should be expected and precautions taken:

• Mouth opening < 3.5 cm
• Thyromental distance < 6.5 cm
• BMI > 30 kg/m²
• Amplitude of head and neck movement < 80^o
• Mallampati score > 3
• Cormack and Lehane classification > 2

Figure 4. Mallampati scores classes 1-4 and Cormack and Lehane classification grades 1-4.

In addition to these measurements, a difficult airway is present if the airway is obstructed by emesis, blood, foreign object or swelling; if the patient has a short neck, large tongue, facial trauma; or if cervical spine immobilization is needed.

Increased complications arise during intubation when a difficult airway is present, especially in an unstable patient. Adverse events related to endotracheal intubation in the ED have been reported at 12% (11). Only 70% of patients intubated in the ICU are successfully intubated upon first-attempt (12). A successful first-attempt intubation is defined as the placement of an endotracheal tube into the trachea upon the initial insertion of the laryngoscope into the oropharynx. If the laryngoscope must be removed and a second-attempt performed, it is considered a failure. Failure to intubate with the first-attempt contributes considerably to morbidity and mortality (13).

The choice of the correct endotracheal introducer can make the difference between first-pass success and failure (Figure 5).

Figure 5. Types of airway introducers.

The standard endotracheal tube stylet is used most often during direct laryngoscopy. This stylet may be bent when used with a curved Macintosh blade or without a bend when used with a straight Miller blade. The former is the most common method. An elastic bougie has an advantage over the standard stylet as it can be placed through the vocal cords and into the trachea, allowing better access especially with anterior airways during direct laryngoscopy with a Macintosh or Miller blade.

The BEAM (Bougie Use in Emergency Airway Management) trial is attracting renewed interest in intubation with a bougie rather than a stylet (2). In the BEAM trial, first-attempt success using an elastic bougie was compared to a stylet during laryngoscopy in an emergency department.

First-attempt success was achieved in 98% of patients compared to 87% in all patients. In patients with at least one difficult airway characteristic, first-attempt success using an elastic bougie was 96% compared to 82% using a stylet.

In the First-Attempt Endotracheal Intubation Success Rate Using a Telescoping Steel Bougie (3), intubation first-attempt success rate was 97% in the ICU. Subgroup analysis of first-attempt intubation success using the AIROD® to intubate in patients with a difficult airway was 96%.

The average time to intubate was 15 seconds. During multiple intubations, the AIROD® was used to lift the epiglottis and move excess oropharyngeal tissue, improving the view of the glottis without causing any trauma to the airway (Figure 6).

Figure 6. Video of AIROD® lifting the epiglottis.

The hyperangulated Glidescope® stylet can be used with the Glidescope®, curved Macintosh blade, and C-MAC® blade. The AIROD® can be used with any direct or video laryngoscopy in any configuration: curved, hyperangulated, or straight.

The elastic bougie cannot make the acute turn required with hyperangluated laryngoscopes and should be avoided with this device unless the hyperangulated Glidescope® stylet is placed first and becomes caught up on the superior angle of the vocal cords. If this occurs, leave the Glidescope® in position and gently remove the hyperangulated Glidescope® stylet. While maintaining the acute angle, introduce an elastic bougie into the ETT and advance the tip into the trachea. Then slide the ETT down the bougie and into the trachea. 

An alternative is to use the AIROD® steel bougie from the beginning, along with the Glidescope®. Load an ETT from the bulbous tip of the AIROD®, then shape to accommodate airway anatomy (Figures 7 and 8).

Figure 7. AIROD® shaped to accommodate airway anatomy.

Figure 8. ETT advancing down the AIROD®.

Use the proximal tip to lift the epiglottis and expose the vocal cords. Then advance the AIROD® two cm into the trachea followed by the ETT.

Case Presentations

Case 1

54-year-old man with severe coronary artery disease on aspirin and Plavix® with a history of a seizures associated with alcohol withdrawal became unresponsive and a code blue was called. He was found to be apneic with oxygen saturation in the 50s. He was stimulated by the hospitalist and became responsive. He was transferred to the ICU, where he became completely unresponsive again and stopped breathing. He was immediately ventilated with a bag-valve mask, and oxygenation improved to 100%. He then bolted up out of bed and became very combative. Propofol was given and he was laid supine and ventilated with a bag-valve mask. Inspection of his oropharynx revealed a very large tongue, and some missing and multiple sharp teeth with mouth opening of only 2 fingerbreadths. There was blood and emesis in his oropharynx that was suctioned. A Miller 4 blade was inserted into the oropharynx but only a grade 4 view could be obtained. The AIROD® was inserted into the oropharynx in the fully extended and locked position and the proximal tip was used to gently lift the epiglottis, exposing the vocal cords, and improving the view to a grade 2. The AIROD® was advanced 2 cm past the vocal cords and an assistant advanced an 8.0 endotracheal tube down the AIROD® until it was grasped, and the endotracheal tube was advanced successfully past the vocal cords while the assistant held the distal end of the AIROD®. The AIROD® was removed intact without any oropharyngeal or vocal cord trauma.

Case 2

A 63-year-old  5’5 110 kg woman with COPD, morbid obesity, obstructive sleep apnea, atrial fibrillation, diabetes mellitus, and anxiety suffered a cardiac arrest and was successfully resuscitated with placement of a drug eluting stent into the right coronary artery. One week later she required intubation for acute respiratory failure. She was extubated the following day and developed stridor, which resolved with pain medication and racemic epinephrine. Two days later, she developed acute respiratory failure again, with stridor that resolved after receiving 4 mg IV Versed. A diagnosis of paroxysmal vocal cord dysfunction was made. The next day she developed similar symptoms that responded to additional Versed® and Precedex®. The next morning, she became anxious after the Precedex® was stopped and once again developed acute stridor with respiratory failure, responding to Zyprexa® and Versed® momentarily. She was comfortable throughout the day until her stridor resumed, and despite BiPAP she was unable to adequately ventilate. She became obtunded, prompting intubation.

In addition to stridor, her Mallampati was 4, she had a sharp, prominent full set of teeth, an airway opening 1.5 cm, a large tongue with excessive oropharyngeal tissue, false cords, and vocal cord swelling. The AIROD® was preloaded with a 7.0 ETT that had attached to it a 10 mL syringe onto the distal end and tucked it under the patient’s right shoulder with the tip lying flat and pointing laterally, protected with a sterile OR towel. The AIROD® lay at a 45^o to the neck. She was given 20 mg of etomidate and immediately ventilated with a bag-valve mask. A Miller 4 blade was gently inserted into the mouth, revealing a grade 4 view with purulent mucus in her oropharynx. The AIROD® was grasped and used to manipulate the false cords, revealing the true vocal cords while cricoid pressure was applied. A grade 2 view was obtained. The cords were adducted with a posterior glottal chink. The AIROD® was gently passed 2 cm through the tiny opening at the bottom of the vocal cords and used to dilate the area with the smooth bulbous tip. The ETT was then advanced into the trachea while the respiratory therapist held the distal end of the AIROD®. The AIROD® was removed intact without any evidence of oropharyngeal trauma. Successful first-attempt intubation occurred without complications. Bronchoscopy confirmed no tracheobronchial tree trauma.

Case 3

A 71-year-old  5’10’’ tall 101 kg man with non-insulin dependent diabetes mellitus, hypertension, and obesity was intubated 18 days prior for severe ARDS secondary to SARS-CoV-2. He subsequently lost his airway, and the attending physician was unable to intubate using the Glidescope®; so an emergency tracheostomy was performed with placement of a 5.0 Shiley. The evening of the 24^th day of ventilation, he was unable to be ventilated effectively with his PCO2 rising to 73 mmHg with a pH of 7.13. He was on a propofol drip and 10 mg vecuronium was given while he was being ventilated through the 5.0 tracheostomy. He was actively bleeding from his nasopharynx. A Miller 4 blade was gently inserted into his mouth revealing a bloody and swollen oropharynx. A pre-loaded AIROD® was used to gently displace tissue, revealing a grade 1 view. The AIROD® was inserted 1 cm past the vocal cords and the ETT was then advanced slowly into the trachea with no assistant holding the AIROD®. The AIROD® was pulled back as the endotracheal tube was advanced down the trachea, abutting the tracheostomy tube. The ETT balloon was inflated and the AIROD® was removed intact without any evidence of acute oropharyngeal trauma. The single-handed first-attempt intubation was performed in 19 seconds. This was followed by the exchange of the 5.0 tracheostomy for an 8.0 tracheostomy. Bronchoscopy confirmed no acute oropharyngeal or tracheal trauma with the tracheostomy in the correct position in the trachea.

Case 4

A 68-year-old 5’10 126 kg smoker with a past medical history significant for COPD, on home oxygen with multiple intubations in the past was admitted. He had a past medical history of  pulmonary embolism on Eliquis®, deep venous thrombosis with an inferior vena cava filter, obstructive sleep apnea, and obesity. He was diagnosed with COVID-19 pneumonia and treated with BiPAP at 100% FiO₂ for six days in the ICU. He developed ARDS and altered mental status, prompting intubation. Obese, large neck with limited neck mobility, micrognathia, large very dry tongue, sharp teeth with some missing, and a mouth opening 2 cm. He received propofol 200 mg IV and succinylcholine 200 mg IV. A Miller 4 blade gently inserted into oropharynx revealed an anterior glottis with false cords. The AIROD® was used to probe the false cords and advanced gently 5 cm, feeling the tracheal rings to ensure placement in the trachea. An 8.0 ETT was slowly advanced into the trachea using the single-handed first-attempt technique. An endotracheal balloon was inflated and the AIROD® removed intact without any evidence of acute oropharyngeal or tracheal trauma.

Case 5

28-year-old 5’9 man 97 kg with a past medical history significant for alcoholism was admitted. He was currently drinking two liters of vodka daily, had a history of  alcoholic cardiomyopathy and esophageal varices, drank hand sanitizer “to remain drunk”, and developed acute shortness of breath, and felt that his “throat was closing”. He developed very severe stridor with respiratory distress and was transferred to the ICU. Audible stridor could be heard as he arrived. He was in severe respiratory failure, sitting up, and very anxious. He was drooling bloody secretions. He was placed on a 15 L/min 100% FiO₂ non-rebreathing mask. He was obese, had a large large neck with limited mobility, mouth opening 2 cm, protruding large tongue, full set of teeth, micrognathia with severe stridor, and was barely moving any air. He was given 4 mg IV Versed®. A tracheostomy kit was at bedside with a surgeon present. He was given 100 mg IV propofol, then laid flat and quickly placed in the SNIFF position. Bag-valve-mask was performed. SpO2 100%. An additional 100 mg IV propofol was given. A Miller 4 blade barely lifted the tongue when fresh blood was encountered. The blade was advanced gently, and bloody secretions suctioned. A crowded anterior hamburger oropharynx, bleeding with mucosal sloughing and false cords was encountered. The AIROD® pre-loaded with a 6.5 ETT was gently advanced underneath the epiglottis and advanced 3 cm, followed by advancement of the 6.5 ETT. Bag-valve ventilation occurred with poor CO2 detector color change. The ETT was left in place while bag-valve-mask ventilation was performed. SpO2 100%. The AIROD® was pre-loaded with a 7.0 ETT. A second-attempt revealed an air bubble anterior to the ETT. The 6.5 ETT was removed as the AIROD® was advanced towards the air bubble. The AIROD® was used to probe the hamburger glottis and to peel back the false cords revealing a small view of the right vocal cords, followed by advancement of the AIROD® 3 cm. A 7.0 ETT was slowly advanced into the trachea and balloon inflated with no assistant holding the AIROD®. No evidence of acute oropharyngeal trauma. Bronchoscopy revealed no tracheobronchial trauma and confirmed acute adenoviral necrotizing pharyngitis.

Conclusion

Anticipation of a difficult airway should always be considered, and having the necessary tools available can improve first-attempt endotracheal intubation success. Optimizing head positioning can be performed quickly and will help with glottic exposure. Knowing how to use multiple laryngoscopes as well as introducers can make the difference between life and death.

Conflicts of Interest

Evan D. Schmitz, MD is the inventor of the AIROD® and CEO of AIROD Medical, LLC.

Acknowledgments

The author thanks H. Carole Schmitz and Bille J. Maciunas for their editorial comments.

References

1. Sasano N, Morita M, Sugiura T, Sasano H, Tsuda T, Katsuya H. Time progression from the patient's operating room entrance to incision: factors affecting anesthetic setup and surgical preparation times. J Anesth. 2009;23(2):230-4. [CrossRef] [PubMed]
2. Driver B, Prekkar M, Klein L, et al. Effect of use of a bougie vs endotracheal tube and stylet on first-attempt intubation success among patients with difficult airways undergoing emergency intubation a randomized clinical trial. JAMA. 2018;319(21):2179-2189. [CrossRef] [PubMed]
3. Schmitz ED. Decreasing COVID-19 patient risk and improving operator safety with the AIROD during endotracheal intubation. J of Emergency Services. EMSAirway. 11/2020.
4. Adnet F, Borron SW, Dumas JL, Lapostolle F, Cupa M, Lapandry C. Study of the "sniffing position" by magnetic resonance imaging. Anesthesiology. 2001 Jan;94(1):83-6.[CrossRef] [PubMed]
5. Adnet F, Baillard C, Borron SW, et al. Randomized study comparing the "sniffing position" with simple head extension for laryngoscopic view in elective surgery patients. Anesthesiology. 2001 Oct;95(4):836-41. [CrossRef] [PubMed]
6. Schmitz ED, Park K. First-Attempt Endotracheal Intubation Success Rate Using A Telescoping Steel Bougie. Southwest J Pulm Crit Care. 2021;22(1):36-40. doi: [CrossRef]
7. Schmitz ED, Park K. Emergency intubation of a critically ill patient with a difficult airway and avoidance of cricothyrotomy using the AIROD®. J of Emergency Medical Services. 2021;22(1):36-40. 
8. Schmitz ED. Single-use telescopic bougie: case series. Southwest J Pulm Crit Care. 2020;20(2):64-8. [CrossRef]
9. Schmitz ED. AIROD® Case Series: A New Bougie for Endotracheal Intubation. J of Emergency and Trauma Care. 2020;5(2):22.
10. Schmitz ED. The Importance of Head Positioning During Endotracheal Intubation. EMSAirway. Jul 27, 2021. Available at: https://emsairway.com/2021/07/27/the-importance-of-head-positioning-during-endotracheal-intubation/#gref (accessed 4/18/23).
11. Lascarrou JB, Boisrame-Helms J, et al. Video Laryngoscopy vs Direct Laryngoscopy on Successful First-Pass Orotracheal Intubation Among ICU Patients: A Randomized Clinical Trial. JAMA. 2017;317(5):483-493. [CrossRef] [PubMed]
12. Higgs A, McGrath BA, Goddard C, Rangasami J, Suntharalingam G, Gale R, Cook TM; Difficult Airway Society; Intensive Care Society; Faculty of Intensive Care Medicine; Royal College of Anaesthetists. Guidelines for the management of tracheal intubation in critically ill adults. Br J Anaesth. 2018 Feb;120(2):323-352. [CrossRef] [PubMed]
13. Brown CA 3rd, Bair AE, Pallin DJ, Walls RM; NEAR III Investigators. Techniques, success, and adverse events of emergency department adult intubations. Ann Emerg Med. 2015 Apr;65(4):363-370.e1. [CrossRef] [PubMed]

Cite as: Schmitz ED. Essentials of Airway Management: The Best Tools and Positioning for First-Attempt Intubation Success. Southwest J Pulm Crit Care Sleep. 2023;26(4):61-69. doi: https://doi.org/10.13175/swjpccs015-23 PDF

March 2023 Critical Care Case of the Month: A Bad Egg

Richard A. Robbins, MD

Phoenix Pulmonary and Critical Research and Education Foundation

Gilbert, AZ

History of Present Illness

You are asked to see a 35-year-old man who was admitted to the ICU from the ER the previous night with an exacerbation of his chronic obstructive pulmonary disease (COPD). He has a long history of COPD and came to the ER for COVID-19 testing because he was at a party where a friend was later found to COVID-19. He denies any change in his chronic respiratory symptoms but his spirometry was significantly worse than his baseline in the ER and despite his protests he was admitted. He was treated with empiric antibiotics (amoxicillin and clavulanic acid), corticosteroids (methylprednisolone 125 mg every 6 hours), bronchodilators (albuterol/ipratropium every 4 hours) and oxygen. He says his breathing has not improved and he wants to go home. He has had gradually increasing shortness of breath for the past 8-10 years. He has minimal cough but denied any fevers, systemic symptoms, or wheezing.  

PMH, FH, and SH

He had a history of multiple pneumothoraces which eventually led to bilateral pleurodesis. He has had not pneumothoraces since. He had a benign bone tumor removed about 25 years ago and a history of manic-depression. There is no FH of any similar type of problems. He does smoke about 3/4 pack of cigarettes per day and has more than occasional marijuana use.

Physical Exam

Physical examination was unremarkable expect for a well-healed scar on the left thigh.

Spirometry

Previous spirometry performed as an outpatient showed his FVC 2.54 L (53% of predicted) with an FEV1 1.25 L (31% of predicted). These improved to 2.99 L and 1.52 L after a bronchodilator. His spirometry last night in the ER was FVC 1.63 L (29 % predicted) and FEV1 0.80 L (18 % predicted).

Radiography

A chest radiograph was performed (Figure 1).

Figure 1. PA (panel A) and lateral (panel B) chest x-ray.

What should be done at this time? (Click on the correct answer to be directed to the second of five pages)

1. Continue his antibiotics, corticosteroids and bronchodilators
2. Order an alpha-1 antitrypsin level
3. Transfer to the floor
4. 1 and 3
5. All of the above

Cite as: Robbins RA. March 2023 Critical Care Case of the Month: A Bad Egg. Southwest J Pulm Crit Care Sleep. 2023;26(3):28-30. doi: https://doi.org/10.13175/swjpccs009-23 PDF 

The Effect of Low Dose Dexamethasone on the Reduction of Hypoxaemia and Fat Embolism Syndrome After Long Bone Fractures

Dr. Akash K

Dr. Madhuchandra R

Department Of Orthopaedics, Karnataka Institute Of Medical Sciences, Hubli, India

Abstract

Background: A dangerous and sometimes fatal consequence of post-traumatic long bone fractures is fat embolism syndrome (FES). The reported incidence of FES ranges from 2% to 22%. FES can also lead to critical illness with fatality rates between 10 to 36%. This study's objective was to determine whether prophylaxis of the fat emboli syndrome could be achieved with lower doses of dexamethasone than had previously been recommended. Thus, prevention of respiratory insufficiency and disruption of homeostasis are essential.

Methods: A total of 583 adult cases of long bone shaft fracture patients between January 2020 to December 2021 were randomly divided into a trial group (n= 252) and a control group (n=331) by simple randomization. The trial group received dexamethasone 8mg/day for 3 days and the control group was given placebo. FES was diagnosed using Gurd’s diagnostic criteria and the FES morbidity and death rates in each group were examined.

Results: Five patients (0.151%) in the control group and 1 patient (0.39%) in the trial group developed FES but the difference was not significant (p>0.05). SpO2 values were significantly elevated in the dexamethasone-treated group compared to the control group 24 hours after admission (p<0.05) and the elevation persisted on the third post admission day (p<0.05).

Conclusion: Dexamethasone in low doses reduces post-traumatic hypoxia in patients with long bone fracture. However, our study was underpowered to show a reduction in FES.

Introduction

Fat emboli occur in all long bone fractures with the most severe resulting in fat embolism syndrome (FES). The reported incidence of FES ranges from 2% to 22% with fatality rates of 10-36% (1-3) with FES resulting in the adult respiratory distress syndrome a 50–90% mortality rate (1-3). Unfortunately, this is particularly common in young people in their second and third decades of life who sustain polytrauma and/or femur fractures in high-velocity traffic accidents (2,3). The majority of trauma patients may experience a subclinical form of FES, which manifests as  hypoxaemia alone (3-6).

FES resulting in systemic symptoms is a rare clinical outcome. Following a traumatic incident, fat droplets are released into the bloodstream resulting in fat embolization. This results in immediate tissue damage as well as a systemic inflammatory response that produces symptoms in the lungs, skin, nervous system, and retina (7,8). Most instances of FES occur after trauma but rare cases of FES have been reported to occur after bone marrow transplantation, osteomyelitis, pancreatitis, alcoholic fatty liver, and even liposuction (9,10). Although the classic triad of pulmonary distress, mental status changes, and petechial rash is usually not seen, hypoxia 24 to 48 hours after pelvic or long-bone fractures is common (11-13).

FES has no pathognomonic characteristics and laboratory and radiographic findings are nonspecific (14,15). Early detection of FES may allow supportive pulmonary treatment and other life-saving interventions to stop the pathophysiologic cascade and stop clinical deterioration. The majority of curative methods created expressly for FES have failed (16,17). There have been several attempts to avoid FES since it is such a serious issue in trauma patients (4). With varying degrees of success, heparin, dextran, albumin, hypertonic glucose, aspirin, and early fracture stabilization, have all been attempted (4). Steroids have also been studied as a preventative as well as a therapeutic agent in fat embolism in various studies.

When fat droplets act as emboli and are trapped in the pulmonary microvasculature and other microvascular beds, such as the brain, they may cause clinical symptoms to appear 24-72 hours after trauma (and particularly after fractures). Embolization starts out very slowly and reaches its peak in 48 hours or more. A long-acting corticosteroid having a half-life of 36 to 72 hours is dexamethasone. This study's objective was to determine whether prophylaxis of the fat emboli syndrome could be achieved with lower doses of dexamethasone than had previously been recommended (17).

Patients and Methods

From January 2020 to December 2021, 583 adult patients between the ages of 18 and 60 with long bone fractures without a history of chronic heart, lung, liver, or renal failure were recruited from patients at KIMS Hospital Hubli. There were 211 cases observed in women and 372 cases in men. The injuries resulted from motor accidents (426), falls (127), and crush injuries (30). Fracture sites included 128 femur fractures, 285 tibia and fibula fractures, 79 humerus fractures, and 91 pelvic injuries. The patients were randomized into two groups, one receiving dexamethasone and the other receiving a placebo (Table 1).

Table 1. Demographic data

Click here to display Table 1 in a separate, enlarged window.

The following patient information was recorded: gender, age, weight, time from injury to admission, primary fracture location, type of fracture, FES morbidity, and number of fatalities. All patients received traditional medical care, early hypovolemic shock correction, fracture stabilization, and symptomatic therapy (2). The trial group received dexamethasone 8mg/day for 3 days and the control group was given placebo. All patients were monitored (heart rate, BP, SpO2 ,respiratory rate, urine output, and arterial blood gases) every 6 hours for 3 days. We considered hypoxaemia with any pO2 <70mm Hg and classified all patients in 3 categories; severe (pO2<60mm Hg), mild hypoxaemia (pO2 >60- <70 mm Hg) and normal (pO2>70mm Hg). All patients signed an informed consent form. The study was approved by the Ethics Committee of our institute hospital.

Treatment and diagnosis for FES

Patients were identified using “Gurd’s Diagnostic criteria score”(Table 2), and those whose score was 2 major or 1 major and 4 minor were diagnosis as FES.

Table 2. Gurd’s Diagnostic Criteria Score*

*Two major criteria or 1 major criterion and 4 minor criteria suggest a diagnosis of FES. Click here to view Table 2 in a separate and enlarged window.

Data analysis

Utilizing statistical tools, the analysis was conducted (SPSS 20.0). P< 0.05 was regarded as statistically significant when comparing the patients' age, main fracture location, fracture type, and incidence of FES using the chi-squared test and single-factor analysis of variance, respectively.

Results

FES occurred in the dexamethasone group and control group, with 1 and 5 cases, respectively (Table 3). Statistical analysis revealed that there was no statistically significant difference between the groups for sex, age, weight, injury to admission time, main fracture site, fracture type, or medication time.

Table 3. Incidence of FES

Click here to view Table 3 in a separate, enlarged window.

Twenty-four hours after admission, steroid treated patients displayed a statistically significant higher PaO2 value compared to the control group (p<0.05) and this difference persisted through the 3rd post admission day (p<0.05, table 4).

Table 4. Partial pressures of oxygen (in mm Hg) in patients treated with IV dexamethasone and controls.

Click here to view Table 4 in a separate and enlarged window.

Discussion

Much higher dosages of dexamethasone have been used to treat some pathological conditions in order to reduce inflammation, inhibit the immune system, impact the hemopoietic system, and alter metabolism (18-28). The mechanical-chemical hypothesis of fat embolism hypothesizes that neutral triglycerides are hydrolyzed into glycerol and free fatty acids by lipoprotein lipase from the lungs. The free fatty acids lead to inflammation and endothelial damage. Corticosteroids likely act on FES by reducing this inflammation. Due to a lack of clear diagnostic markers, treating FES may prove challenging. There have been few publications on the use of adrenal steroids to prevent high-risk FES patients, although the results have been ambiguous at low doses (31). Observational clinical research revealed that short-range and high doses may be helpful in reducing plasma free fatty acid concentrations, maintaining PaO2 levels, and reducing the occurrence of long bone fractures in individuals with FES. Dexamethasone may be a more effective drug treatment for FES (32). The dose of dexamethasone used in our study was relatively small and short, and complications related to hormones such as stress ulcer, aseptic necrosis of the femoral head, and bleeding tendency did not occur. It should be noted that drug prevention must be based on early, accurate fracture fixation, early corrective hypovolemic shock, and other standard procedures (33). This is true even if drug usage in this population clearly has a preventative impact. Ashbaugh and Petty (34) suggested corticosteroid therapy for treating FES in 1966 and gave laboratory data proving its therapeutic impact in the experimental animal given an intravenously administered FFA injection. Rokkanen et al. (35) found that 5 mg/kg of dexamethasone administered at 1 and 48 h after burn injury failed to enhance nuclear translocation of the GR, and to suppress the overproduction of proinflammatory cytokines such as TNF-α and IL-1β, neither did it increase the release of anti-inflammatory cytokine IL-10. In experiments with animals, Kreis et al. (36) showed that corticosteroids increased oxygenation and lowered the pathological alterations seen in lung biopsies. Alho et al. (37) conducted research on the use of intravenous methyl prednisolone sodium succinate in the prevention of fat embolism syndrome. A total of 60 individuals with at least two fractures were included in his study (pelvic, femoral or tibial fractures).methyl prednisolone reduces signs of  hypoxaemia, bilateral "snow storm" infiltrations of the lungs, petechial rash, mental disturbances, pyrexia, anemia and thrombocytopenia. Varying degrees of the syndrome were observed in two patients given methylprednisolone and in 15 patients in the control group. Babalis et al. (39) results support the prophylactic administration of methylprednisolone in small dosage to prevent post traumatic hypoxaemia and probably FES in patients with isolated lower limb long bone fractures, especially when early fracture stabilization is not possible. Therefore, every study has demonstrated the effectiveness of steroids as a preventative treatment for the fat embolism syndrome.

Although our results showed a trend towards reduction in FES after long bone fractures, the results were not statistically significant. This is likely because our study turned out to be underpowered. We had anticipated an incidence of FES between 2-20% reported in the literature rather than the 1.1% found in our study.

Conclusion

The study's objective was to determine whether prophylaxis of the fat emboli syndrome could be achieved with lower doses of dexamethasone than had previously been recommended. Among the several prophylactic drugs that have been researched so far for the fat embolism syndrome, dexamethasone have shown to be relatively beneficial. The frequency of  hypoxaemia and fat emboli syndrome decreased with intravenous dexamethasone at 8 mg per day for three days. Dexamethasone is a long-acting symptoms that emerge 24-72 hours after trauma (and particularly after fractures). Fat embolization begins slowly and reaches its maximum around 48 hours.

The limitation of our study is that it lacked sufficient power to demonstrate a reduction in FES. Furthermore, no method has been developed to pinpoint precisely who could benefit from steroid prophylaxis. We based our study assuming an incidence of FES of about 5%. However, we found an incidence of only about 1.5%. The lower incidence is probably due to our use of Gurd’s criteria which is more restrictive than the criteria used in other studies. Based on our observed incidence of FES of 1.5% with a reduction to 0.4% we estimate that over 2500 patients would be needed to show a statistically significant reduction in FES.

Our study shows that  hypoxaemia is reduced by a relatively low dose of dexamethasone administered for a relatively short length of time. It may prevent FES but our study was underpowered to show a difference.

Declaration

Human subjects: Consent was obtained or waived by all participants in this study. Karnataka Institute Of Medical Sciences ethics committee. issued approval 327/2020-21. The study was approved by the institutional ethics committee. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissues. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all

authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work

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Cite as: K A, R M. The Effect of Low Dose Dexamethasone on the Reduction of Hypoxaemia and Fat Embolism Syndrome After Long Bone Fractures. Southwest J Pulm Crit Care Sleep. 2023;26(1):11-17. doi: https://doi.org/10.13175/swjpccs059-22 PDF

Unintended Consequence of Jesse’s Law in Arizona Critical Care Medicine

Adrienne Lee Jones-Adamczyk, RN, MSN, ACNP-BC, ACHPN, HEC-C

Patricia Ann Mayer, MD, MS, HEC-C

Banner Gateway Medical Center

Gilbert, AZ USA

Abstract

Jesse’s Law, passed in Arizona as a reaction to a surrogate acting against the interests of a specific patient, now prevents intensivists and surrogates who are acting appropriately from discontinuing unwanted interventions in dying hospice patients. The law prohibits statutory surrogates from authorizing discontinuance of artificial nutrition and hydration unless they can present “clear and convincing evidence” to a court that the patient would agree. This law is causing undue harm to hospice patients at end of life by delaying withdrawal of unwanted medical interventions, interfering with accepted and established surrogate decision-making precepts, and negating informed consent because surrogates are unaware that artificial nutrition and hydration cannot be easily discontinued after initiation. The authors offer a case example followed by an ethical analysis of this presumably unintended consequence of the law.

Abbreviations

• ANH:     artificial nutrition and hydration
• ICU:       intensive care unit
• LST:       life sustaining treatment
• PVS:      persistent vegetative state
• SDM:     surrogate decision maker
• TBI:       traumatic brain injury

Unintended Consequence of Jesse’s Law in Arizona Critical Care Medicine

We present a composite but common case demonstrating an unfortunate result of Jesse's Law affecting intensivists and their patients who are at end of life. We follow with a short history and discussion of the ethical implications of the law.

Case Report: An 88 y/o widowed woman was admitted to an intensive care unit (ICU) in Arizona in respiratory failure after driving herself to the local emergency department. By the time her family was reached, she was intubated, on dialysis, and had a feeding tube placed for artificial nutrition and hydration (ANH). 

Over the next several days, she worsened and developed multi-organ failure. In conversations with the family, the intensivist elucidated that the patient lived alone and generally declined to complain or seek medical help. The family relayed she was a third-generation Arizonan who had grown up on the family ranch, where she still lived. She'd often told her family: "When my time comes, it comes; don't keep me alive on machines and tied to tubes. If I'm on my way out, just take me home and let me go." Like many patients, she lacked written advanced directives, but her extended family as her surrogates agreed "her time had come." They requested removal of all tubes and machines and discharge to the ranch with hospice services and family in attendance. As the orders were being written, the nurse asked the intensivist: "What about Jesse's law? We can't just take the feeding tube out and stop the feeding." The nurse was correct. This makes little sense for our patient.

How and why did Arizona get here?

In May of 2007, 36-year-old Jesse Ramirez and his wife were involved in a rollover car crash reportedly caused by a heated argument between the two. Jesse suffered a severe traumatic brain injury (TBI) and was in a coma. Ten days later, his wife, as his statutory surrogate, chose to move him to hospice and discontinue his ANH. Jesse's siblings filed suit, contending that his wife did not have his best interests at heart given their severe marital discord. The Arizona court ruled in favor of Jesse's siblings, and his tube feedings were continued. He moved from hospice to rehab and later regained some function including the ability to recognize and interact with his family (1). Jesse's law, prohibiting surrogates from discontinuing ANH, was passed in 2008 as a reaction to this unfortunate case.

Jesse's Law states: "There is a rebuttable presumption that a patient who does not have a valid living will, power of attorney or other health care directive has directed the patient's health care providers to provide the patient with food and fluid to the degree that is sufficient to sustain life, including, if necessary, through a medically invasive procedure… and … that provision is in the patient's best interests.”(2) The law, therefore, allows only a legally appointed medical power of attorney or a court-appointed guardian but not a statutory surrogate to discontinue ANH for non-medical reasons. The law listed no exceptions, which meant the critical care team could not discontinue our patient’s feeding tube unless her surrogate decision makers (SDMs) obtained permission from a court.

How does Jesse’s law align with the national evolution of patient rights at end-of-life? It doesn’t.

Those rights, including withdrawing and withholding life-sustaining treatment (LST), date to 1976 with the Karen Ann Quinlan case (3). Karen Ann suffered an anoxic brain injury following a respiratory arrest and was subsequently determined to be in a persistent vegetative state (PVS). When months passed without improvement, her family requested the discontinuation of her ventilator based on their belief that Karen Ann would not want her life prolonged in her current condition. The hospital and her treating physicians initially denied this request fearing accusations of murder. The case eventually reached the New Jersey Supreme Court, which allowed removal of the ventilator and set two groundbreaking precedents. First, the Court determined that families are appropriate SDMs for incapacitated patients. Second, the Court determined patients and SDMs do have the right to refuse LST (4).

The second major case, that of Nancy Cruzan, began in 1990. (3) This young woman's parents as her SDMs also requested withdrawal of LST, but in this case, the LST was her feeding tube. Nancy was also in a PVS after a car accident but did not need a ventilator; she had been kept alive through ANH alone. Nancy’s case was the first withdrawal of ANH to be heard by the US Supreme Court. Although the ruling was multifaceted, it did allow withdrawal of the feeding tube, and Nancy died eight years after her accident once her ANH was discontinued (5).

These landmark cases clearly established SDMs as appropriate medical decision-makers for incapacitated patients and empowered them to withhold or withdraw medical treatments, including ANH (3). Along with this power, SDMs have the obligation to make decisions according to accepted criteria, namely 1) the wishes of the patient 2) if patient wishes are unknown, then SDMs are to use substituted judgment, that is, to make the decision they believe the patient would make if she were able to speak for herself or 3) in the absence of the first two, SDMs are to act in the patient’s best interest (2,6).

Jesse’s law in Arizona creates an exception to these precedents. Although Arizona allows withholding or withdrawing other LST by SDMs (including ICU treatments), it does not allow for the withdrawal of ANH, even when the SDM has clear knowledge of the patient's wishes (2). Jesse's law specifically presumes that a patient receiving ANH who lacks advance directives wants – in all cases - to prolong life and continue ANH indefinitely without regard to prognosis, quality of life, or verbalized preferences as told to SDMs (2). This includes the patient described in our case, who clearly would not have wanted continued ANH as she was dying.

Jesse's law, with its lack of exceptions, therefore, causes undue harm at the end of life for dying Arizona patients because it makes assumptions about patient wishes and conflicts with patient autonomy. The law focuses on ANH when the real problem in Jesse’s case was an SDM who was clearly not acting in his best interests. Although young patients with brain injuries like Jesse may recover over time, our terminally ill patient could not; yet the law prohibited the ICU team from removing (withdrawing) her feeding tube.

Indeed, withholding and withdrawing LST have long been considered ethically equivalent. (3,7,8,9). McGee (7) reports stopping (withdrawing) ANH is akin to an omission (withholding). The accepted ethical premise is that omissions do not cause death; actions do. Therefore stopping ANH is no more a cause of death than not starting ANH would be. Similarly, Beauchamp and Childress (8), the founders of principles in modern medical ethics, assert no morally relevant difference between ANH and other types of LST types. They add the "right to refuse treatment should not be contingent on the type of treatment" offered. The American Academy of Neurology agrees and openly opposes legislation that presumes to know a patient's wishes regarding ANH and/or limits the ability of patients to declare their preferences, including through discussions with SDMs (9). Current ethical consensus supports an appropriately acting SDM (not the case with Jesse’s wife) to authorize withholding or withdrawing ANH as well as to make any other medical decision a surrogate would make.

Unfortunately, Jesse's law interferes with both autonomy and the informed consent process in Arizona for dying patients. Respect for autonomy allows patients (or their SDMs) to accept or reject recommended medical treatments that affect their bodies. "Every person being of adult years and sound mind has the right to determine what shall be done with his own body"(10). Respect for autonomy includes a requirement of informed consent. In Arizona, SDMs who consent to ANH do not then have the authority to withdraw consent unless they go to court to present "clear and convincing evidence" that the patient would refuse ANH (2). Few SDMs are aware of this when ANH is started, fewer still have the time or energy for a court appearance when faced with a dying loved one. And since informed consent requires the SDM to have "adequate and truthful information about the risk versus benefits and understand the treatment goals", we posit consent is often not obtained regarding ANH for patients such as ours (6).

An informed consent conversation for ANH includes at least three key points (6,11):

1) ANH is a medical treatment and not a basic intervention…for all patients;

2) ANH provides uncertain benefits for many diagnoses and has considerable risks and discomfort;

3) ANH is not a comfort measure since symptoms associated with not eating or drinking can be palliated and generally resolve within a short period of time.

We add that, in Arizona, the ANH informed consent conversation with surrogates ought to specify that permission for ANH cannot be withdrawn (without court intervention) once given. 

ANH is rarely indicated for patients with a terminal illness at end-of-life. It carries significant risks, including bleeding, infection, aspiration, and the use of physical or chemical restraints to prevent a patient from dislodging the required tubes. There is no evidence that ANH at the end of life leads to improved survival or quality of life; it is rarely beneficial and often harmful (7,11). And yet, Jesse's law makes no easy provisions for such patients.

Our patient wanted to die unencumbered by medical interventions including her feeding tube, but the ICU team could not accommodate that request under current Arizona law. So, what choices remain for our patient, her surrogates and the ICU team? The team can leave the feeding tube in place, or the surrogates can try and convince a court to allow its removal, spending time in court instead of with their loved one.

We assert that Jesse's law, with its lack of exceptions for patients such as ours, creates undue distress and barriers for intensivists and surrogates attempting to honor patient wishes and end ANH appropriately in dying patients. Jesse’s law should have addressed unreasonable surrogates instead of preventing all surrogates from taking an action that is often in the best interest of a loved one.

Conflict of Interest Statement: The authors have no conflict of interest and nothing to disclose. Both authors are employees of Banner Health.  

References

1. Grado G. (2011, October 8). Crash survivor's case spurs new state law. East Valley Tribune. Retrieved September 15, 2022, from https://www.eastvalleytribune.com/local/crash-survivor-s-case-spurs-new-state-law/article_486772f1-4bd0-59e3-b24f-073bbce7b543.html AZ HB2823.
2. AZ HB2823. Fifty-fifth Legislature 1st Regular. (2021, May 24). LegiScan. Retrieved November 07, 2022, from https://legiscan.com/AZ/bill/HB2823/2021
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4. In re Quinlan, 70 N.J. 10, 355 A.2d 647 (NJ 1976)
5. Cruzan v. Director, Missouri Department of Health, 110 S. Ct. 2841 (1990), 19 Fla. St. U. L. Rev. 209 (1991).
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7. McGee A. Does withdrawing life-sustaining treatment cause death or allow the patient to die? Med Law Rev. 2014 Winter;22(1):26-47. [CrossRef] [PubMed]
8. Beauchamp TL, Childress JF, Principles of Biomedical Ethics. 8th ed. New York, NY: Oxford University Press; 2019: 165-166.
9. Bacon D, Williams MA, Gordon J. Position statement on laws and regulations concerning life-sustaining treatment, including artificial nutrition and hydration, for patients lacking decision-making capacity. Neurology. 2007 Apr 3;68(14):1097-100. [CrossRef] [PubMed]
10. Schloendorff v. New York Hospital, 211 N.Y. 125, 105 N.E. 92 (N.Y. 1914).
11. Casarett D, Kapo J, Caplan A. Appropriate use of artificial nutrition and hydration--fundamental principles and recommendations. N Engl J Med. 2005 Dec 15;353(24):2607-12. [CrossRef] [PubMed]

Cite as: Jones-Adamczyk AL, Mayer PA. Unintended Consequence of Jesse’s Law in Arizona Critical Care Medicine. Southwest J Pulm Crit Care Sleep. 2022;25(5):83-87. doi: https://doi.org/10.13175/swjpccs051-22 PDF

Impact of Cytomegalovirus DNAemia Below the Lower Limit of Quantification: Multistate Model in Lung Transplant Recipients

Spenser E. January, PharmD¹ 

Daniel Britt, PharmD¹ 

April A. Pottebaum^, PharmD¹ 

Tamara T. Krekel, PharmD¹ 

Ramsey R. Hachem, MD²

Rodrigo Vazquez-Guillamet, MD²

¹Department of Pharmacy, Barnes-Jewish Hospital, Saint Louis, MO, USA

²Division of Pulmonary and Critical Care, Washington University in Saint Louis, Saint Louis, MO, USA

Abstract

Background 
Cytomegalovirus (CMV) infections following transplantation lead to significant morbidity. Identification of CMV DNAemia continually improves and now viral loads below the lower limit of quantification (LLOQ) are detectable. However, the clinical course of positive CMV qPCR <LLOQ is unknown.

Methods

This retrospective study included lung transplant recipients experiencing their first episode of positive CMV qPCR <LLOQ with all qPCR assays conducted using COBAS® AmpliPrep/COBAS® TaqMan®. A Markov-like multistate model was utilized to describe the course of CMV DNAemia <LLOQ. A multivariable model was employed to identify predictors of transitioning to a positive, quantifiable state.

Results 

100 patients with a CMV <LLOQ result were included, encompassing 1,248 transitions in the six months following first episode of CMV qPCR <LLOQ. There was an 97.8% probability of remaining <LLOQ or undetectable and a 2.2% probability of transitioning to a positive, quantifiable qPCR state. The multivariable regression model identified treatment for rejection, increasing body mass index, valganciclovir therapy, and increasing CMV qPCR viral load as being predictive of transitioning from CMV qPCR undetectable or <LLOQ into a positive, quantifiable CMV qPCR state.

Conclusions

Most patients did not transition into a positive, quantifiable CMV qPCR state following a first episode of positive CMV qPCR <LLOQ in this cohort of lung transplant recipients.

Article Abbreviations:

• <LLOQ: below the lower limit of quantification
• BMI: body mass index; CMV: cytomegalovirus
• IgG: immunoglobulin G
• IUnit: international units
• qPCR: quantitative polymerase chain reaction

Introduction 

Even with recent advancements in its diagnosis and treatment, cytomegalovirus (CMV) infection continues to be one of the most common complications after transplantation causing significant morbidity and contributing to mortality. Lung transplant recipients are especially afflicted; shorter telomere length has been associated with increased risk of CMV DNAemia, especially in patients with idiopathic pulmonary fibrosis (1,2). Compared to other solid organ transplants, previously uninfected lung recipients have the highest rate of CMV donor derived infections (3). Once infected with CMV, patients are at risk of disease related to virus replication but also to adverse outcomes via indirect pathways leading to acute or chronic rejection and superinfections with other pathogens (4).

To prevent these adverse outcomes, the current standard of care is to implement primary prevention strategies including universal prophylaxis and pre-emptive therapy. In the universal prophylaxis

strategy, every patient at high risk for CMV (e.g., recipient previously unexposed to CMV [CMV seronegative] receiving an organ from a CMV seropositive donor) is treated with valganciclovir, an oral antiviral highly active against CMV, for a period varying from 3 months to 1 year, followed by continued monitoring. In pre-emptive therapy, CMV quantitative polymerase chain reaction (qPCR) in whole blood or plasma is performed every week and active treatment is initiated if a pre-specified level of quantification is reached. This threshold is program and test dependent due to continued variability in reagents, amplification, and extraction techniques (5,6).  

Contemporary assays for the quantification of CMV in the blood are increasingly sensitive. Previous solid organ transplant studies have attempted to establish a threshold viral load to initiate treatment, which has ranged from a plasma cutoff of 1,500 IUnit/mL (7-10) to 5,087 copies/mL (11) and a whole blood cutoff of 800 copies/mL (12), but these studies did not include lung transplant recipients (7-10,12), did not include patients over one year from transplant (7-11), did not include all CMV serostatus groups (7,8,10) or were performed prior to the development of highly sensitive CMV qPCR assays (11). As a result, there is no consensus on when to initiate treatment in lung transplant recipients with asymptomatic DNAemia. Most experts will treat asymptomatic DNAemia with antivirals with the intent of preventing CMV related morbidity. However, with ever-increasing sensitivities of the assays, the probability of detection of clinically insignificant levels of DNAemia increases along with the risk of unnecessary exposure to treatment toxicities to the patient.

CMV remains in the host for life in one of three possible states: 1. CMV latent infection, when it can’t be detected in blood 2. CMV infection, when it is detected in blood but there are no symptoms of disease, and 3. CMV disease when signs of infection and clinical disease are present. Since CMV remains in the host, outcomes cannot be thought of as dichotomously cured or not cured; thus, the decision to treat or observe should consider the probabilities of transitioning between these states. We evaluated the probability of disease progression and spontaneous resolution for patients with CMV qPCR levels below the lower limit of quantification (<LLOQ). We hypothesize that a great majority of patients with positive qPCR <LLOQ will not progress to CMV infection or disease without treatment and that treatment might only be warranted in patients at especially high risk for progression.

Materials and Methods

This was a single-center retrospective cohort study conducted at Barnes-Jewish Hospital and Washington University in Saint Louis, Missouri. At our institution, the CMV qPCR assay in use since April 1, 2017 is the COBAS® AmpliPrep/COBAS® TaqMan® CMV assay which uses plasma specimens and had a quantifiable limit of ≥137 IUnits/mL during the study period. Adult lung transplant recipients were included in this study if they were transplanted between April 1, 2009 and April 1, 2019 and had a plasma CMV qPCR sample with CMV detected but <LLOQ (<137 IUnits/mL) between April 1, 2017 and July 1, 2019. All patients were followed for a duration of six months following their CMV <LLOQ result. Patients were excluded if they obtained any CMV qPCR during the study period at an outside laboratory, if they had no subsequent CMV qPCR or routine laboratory monitoring performed in the six months following the episode of positive CMV qPCR <LLOQ, if they had an episode of quantifiable CMV DNAemia without clearance (defined as two consecutive undetectable CMV qPCR results) prior to the positive CMV qPCR <LLOQ result, or if they were on valganciclovir at the time of CMV qPCR <LLOQ result.  We did not consider CMV bronchoalveolar lavage samples as tissue invasive disease and they were not included in the analysis. At Barnes-Jewish Hospital, the institutional protocol for lung transplant recipients is to administer valganciclovir prophylaxis for six months after transplant (followed by acyclovir for life) if the donor is CMV IgG seropositive and the recipient is CMV IgG seronegative; if the patient is CMV IgG seropositive or both donor and recipient are CMV IgG seronegative at the time of transplant they are given acyclovir for life. CMV qPCRs are monitored weekly during the first 3 months after transplant, then monthly for the remainder of the first year. The decision to initiate a CMV-active antiviral following a result of positive CMV qPCR <LLOQ is at the discretion of the treating physician; there is no institutional standard viral load at which to initiate antiviral therapy. CMV IVIg is not routinely used for prophylaxis or treatment at our institution. Induction immunosuppression for lung transplant recipients at Barnes-Jewish Hospital is typically intra-operative methylprednisolone 500 mg in conjunction with basiliximab 20 mg on post-operative day 0 and post-operative day 4; maintenance immunosuppression includes tacrolimus with a goal trough of 7-10 ng/mL for the first post-transplant year and 4-7 ng/mL thereafter, mycophenolate mofetil 1,000 mg twice daily, and prednisone tapered to 5 mg daily by six months post-transplant. In the instance of a CMV qPCR <LLOQ result, institutional practice is to not decrease maintenance immunosuppression unless another compelling indication to do so is present (e.g., leukopenia). If maintenance immunosuppression was decreased, the rationale behind the decrease was collected.

Statistical Analysis

Continuous data are presented as mean and standard deviations and compared using Student’s T test, categorical data as percentages and compared using Chi square or Fisher’s exact test as appropriate.

Markov like model: In Markov analysis, individuals can be in one of several “states”. The unit of analysis is a transition and not individuals. A transition is defined as moving from one state to another or staying in the same state. Transitions are further classified as favorable if the patient remained in the healthy <LLOQ state, transitioned from CMV infection to healthy <LLOQ or from CMV disease to CMV infection or healthy <LLOQ state. All other transitions were considered adverse. An advantage of this type of analysis is the possibility of providing patients and physicians not only with the probability of progression of their disease but also the probability of getting better and reversion to a healthy state. Markov analysis has been previously utilized to evaluate bacteremia states in patients with sepsis.¹³ To perform the analysis, all patients need to be evaluated at fixed time intervals, referred to as the Markov cycle. The mean interval between CMV testing was 13 days with median and interquartile range of 7 (7-14), based on these information and previous knowledge of response time for CMV viral load the Markov cycle was set at 14 days. Like most medical processes, transitions were not completely independent of the previous state so the strict definition of Markov modeling is unmet; therefore, a Markov-like model was implemented for transition analysis. Since the use of Markov modeling performed in this study is purely descriptive, and we did not project it into the future over multiple cycles, this is still appropriate.

Markov-model states: a priori we considered three states. A healthy state LLOQ was defined if the patient had either unquantifiable CMV or <LLOQ and no evidence of tissue invasive CMV disease. CMV infection was defined as CMV above LLOQ but without clinical symptoms or signs of invasive disease and lastly, CMV disease was defined as CMV quantifiable in blood and symptoms (fever for >2 days or malaise) or tissue invasive disease was present.

Patients lost to follow up before the six-month mark were censored at that point. Missing qPCRs were imputed as the mean from the previous and posterior state, when more than one consecutive qPCR was missing the transition was coded as missing. Transition probabilities are presented as percentages.

Multivariable logistic regression with adverse transition as an outcome was performed; factors considered for inclusion into the model were based on variables associated with progression of CMV DNAemia on univariable analysis at a P value of <0.10 and physiological plausibility to affect progression. Predictors were transition specific (e.g., valganciclovir, immunosuppression changes were accounted for only if given in the prior state). SPSS version 25 and Stata SE 15.1 (Stata-Corp, LLC) were used for statistical analysis with significance defined as a P value ≤ 0.05. This study was approved by the institutional review board with a waiver of consent given the retrospective nature of the study.

Results

Cohort characteristics

A total of 100 lung transplant recipients met inclusion criteria (Figure 1).

Figure 1. Study enrollment. To view an Figure 1 in an enlarged, separate window click here.

There were 50 (50%) females, recipients were mostly white and 86% of patients were on three-drug maintenance immunosuppression at the time of CMV PCR <LLOQ episode (mainly tacrolimus, mycophenolate mofetil, and prednisone); only one patient was maintained on a mechanistic target of rapamycin inhibitor. For induction, 95% received basiliximab in addition to methylprednisolone, two patients received equine antithymocyte globulin, two patients received rabbit antithymocyte globulin, and one patient received monotherapy induction with methylprednisolone. Seventy-three patients had their CMV qPCR <LLOQ within the first post-transplant year. Baseline characteristics are detailed in Table 1.

Table 1. Baseline characteristics.

To view Table 1 in an enlarged, separate window click here.

None of the patients who had a positive CMV qPCR <LLOQ episode were seronegative recipients of seronegative donors. Following the initial positive CMV qPCR <LLOQ, CMV qPCR was rechecked a median of 10 times per patient in the six months of follow-up. The median time from transplant to first positive qPCR was 73 (interquartile range 19 - 531) days. The median peak DNAemia was 535 (interquartile range 243 – 1249) IUnit/mL. Following the first episode of CMV PCR <LLOQ, 70 patients were monitored, 9 patients were placed on prophylactic antiviral dosing, and 21 patients were placed on treatment antiviral dosing. Valganciclovir was ultimately prescribed in 64 patients (four patients were prescribed ganciclovir before transitioning to valganciclovir). Thirty-two patients received intravenous immunoglobulins in the six-month follow-up period (none received CMV IVIg), mainly for donor specific antibodies or hypogammaglobulinemia. No patient required the use of cidofovir or foscarnet, and there were no cases of ganciclovir resistance.

During the follow up period, maintenance immunosuppression was de-escalated in 25% of patients. Of the 25 patients classified as de-escalation, all were related to antimetabolite being dose reduced, held, or both. The most common cause for de-escalation was leukopenia (56%), followed by CMV infection itself (24%), and two patients each had their antimetabolite held for diarrhea and cancer. Maintenance immunosuppression was intensified in 25% of patients. Intensification of immunosuppression occurred due to treatment for rejection, donor-specific antibodies, chronic lung allograft dysfunction, or a combination thereof. Therapies received included rabbit antithymocyte globulin (n=10), rituximab (n=6), methylprednisolone (n=3), carfilzomib (n=2), cyclophosphamide (n=1), and tocilizumab (n=1). The antimetabolite (mycophenolate or azathioprine) was resumed in four patients, and one patient was initiated on everolimus.

Transition analysis

The total number of transitions in the six months of follow-up was 1,248. Adverse transitions occurred 76 times (6.1% of all transitions). Of these adverse transitions, 26 (2.1%) were from healthy <LLOQ to CMV infection and 50 (4%) from CMV infection remained in the CMV infection state. Favorable transitions occurred 1174 times; 24 (1.9%) from CMV infection to healthy LLOQ and 1148 (92%) from healthy <LLOQ remained in the healthy <LLOQ state. There were 0 (0%) transitions to or from CMV disease. Transition probabilities between states are depicted in figure 2; from a state of healthy <LLOQ, the probability of remaining in this state on the subsequent Markov cycle (14 days later) was 97.8% and the probability of transitioning into the adverse CMV infection state was 2.2%.

Figure 2. Markov-like model of transition probabilities between healthy state <LLOQ, CMV infection, and CMV disease. The arrow thickness and bubble size are proportional to the number of transitions between states. Percentages reflect the probability of transitioning between states from one Markov cycle to the next. To view Figure 2 in an enlarged, separate window click here.

A multivariable logistic regression analysis was used to identify risk factors for adverse transitions to the CMV infection state.  A higher body mass index (BMI), recent intensification of immunosuppression, prescription of valganciclovir (after CMV pPCR <LLOQ result) and having higher CMV qPCR values in subsequent Markov cycles following initial CMV <LLOQ were predictive of transitioning into, or staying in, the CMV infection state (Table 2).

Table 2. Multivariable regression analysis of predictors adverse transitions: transitioning into, or staying in the state of, positive, quantifiable CMV DNAemia.

To view Table 2 in an enlarged, separate window click here.

To understand the increased risk of detrimental transitions while on treatment with valganciclovir we performed a logistic regression model with treatment with valganciclovir as the outcome. Induction with thymoglobulin (OR= 4.4; 95%CI: 2.6 , 7.6; p<0.001), transplant from a CMV seropositive donor to a seronegative recipient (OR= 2.5; 1.9, 3.3; p<0.001), number of immunosuppressive drugs (OR=1.1; 95% CI: 1.03, 1.16; p=0.002) were predictors in this model. Additionally, intensification of treatment with rabbit antithymocyte globulin was a perfect predictor of treatment with valganciclovir (10/10).

Discussion

Although previous solid organ transplant studies have sought to define a CMV viral load at which to initiate antiviral therapy, there remains no consensus on this threshold which is likely due to the heterogeneity in transplant populations studied and inter-assay variability (6-11, 14). Since no definitive quantity of CMV detected in the bloodstream has been established, this study evaluated the probability of transitioning from an undetectable or <LLOQ qPCR for CMV into a state of positive, quantifiable viral load (CMV infection) in lung transplant recipients to guide the use of antiviral treatment. Our results support a monitoring strategy in patients with CMV qPCR < LLOQ given the small probability of transitioning from qPCR <LLOQ to CMV infection and lack of further transition into CMV disease, which occurred in no patients. It should be noted that since routine invasive testing (e.g., biopsy of the GI tract) is not performed without cause at our institution, it is possible that patients could have had undiagnosed tissue invasive CMV. Valganciclovir is an effective treatment for CMV but has associated side effects such as leukopenia and neutropenia which have been reported in 13.5% and 8.2% of transplant patients, respectively (15). In the solid organ transplant population, these hematological abnormalities may be already present or exacerbated by baseline immunosuppression or short telomeres specifically in the lung transplant population (1). It is important to establish the patient population where the benefit of antiviral treatment outweighs the potential additive medication toxicities of valganciclovir when a result of positive CMV qPCR <LLOQ is encountered. Initiation of treatment might be warranted in patients undergoing intensification of immunosuppression and special attention should be given to patients with higher BMI as these were predictive of transitioning to CMV infection in the multivariable adjustment model.

The role of immunosuppression in the development of CMV infection and disease is well known, with risk factors for CMV including donor positive/recipient negative serostatus, short prophylaxis courses following transplantation, higher intensity immunosuppression, and rejection (5). The multivariable model in this study identified higher intensity immunosuppression as being an independent risk factor for progression from CMV qPCR <LLOQ to CMV infection. This study also found BMI to be a predictor of adverse transitions. Based on previous evidence, BMI is likely to be functioning as a proxy for the presence of metabolic syndrome. In the general population, the presence of metabolic syndrome independent of obesity is a risk factor for continued shedding of CMV in urine of infected individuals as well as for higher levels of DNAemia (16,17). Alternatively, patients with higher BMIs may be relatively underdosed when treated using fixed-dose oral valganciclovir.

Thirty percent of patients were placed on valganciclovir following their first episode of CMV <LLOQ; however, ultimately, 64% of this cohort was placed on valganciclovir during the six months of follow-up. The non-uniform time of valganciclovir initiation is a limitation of the current study. In the transitional analysis, treatment with valganciclovir was strongly associated with detrimental transitions (e.g., going from <LLOQ to CMV infection or remaining in CMV infection state). This finding should be understood as an association and not causation. Risk of treatment with valganciclovir was predicted by enhanced immunosuppression and belonging to the high-risk group of seropositive donor to seronegative recipient, suggesting confounding by prognosis. Patients at higher risk of progression and patients with DNAemia were more likely to be on treatment. Patients remaining in CMV infection are more likely to be on treatment with valganciclovir. The effectiveness of oral valganciclovir for the treatment of CMV DNAemia has been clearly demonstrated in randomized clinical trials and retrospective cohorts. In clinical practice, physicians are more likely to initiate treatment for <LLOQ CMV qPCR in patients they think are at a high risk of progressing to CMV infection or disease. For example, there likely is a lower threshold to initiate treatment for <LLOQ CMV in patients who are going to be treated for acute rejection. In this case valganciclovir treatment may reflect the perceived risk of CMV infection or disease by the treating clinician.

This study is limited by its retrospective nature; the duration and frequency of CMV qPCR monitoring were not uniform once patients were discharged from the hospital, use of CMV-active antivirals was determined via review of the electronic health record, and variables potentially associated with transitioning to a positive, quantifiable CMV DNAemia state could not be exhaustively evaluated. Large changes of immunosuppression, such as starting or stopping an immunosuppressant, was captured but smaller changes such as changes in tacrolimus goal troughs were not assessable. Additionally, our center utilizes a pre-emptive strategy for intermediate risk CMV patients (recipient CMV IgG positive) which differs from guideline recommendations and may limit generalizability to other institutions.¹⁸ It is unknown whether CMV <LLOQ and an undetectable CMV PCR result have the same impact on long-term allograft outcomes. In order to rigorously evaluate CMV PCR values it was necessary to restrict to one specific assay given inter-assay variability; this could have introduced bias by excluding patients who do not follow as closely at Barnes-Jewish Hospital. At Barnes-Jewish Hospital, lung transplant patients are placed on a CMV-active antiviral following a result of positive CMV qPCR <LLOQ at the discretion of the treating physician based on a variety of patient-specific factors. Since there is no protocol on how to manage an episode of positive CMV qPCR <LLOQ, selection bias played a role in the treatment of the patients in this cohort. Basiliximab is the induction agent of choice at Barnes-Jewish Hospital, which may limit the generalizability of these results for patients treated with antithymocyte globulin at other centers. Six months was chosen as the follow-up period to isolate the effect of chosen study variables on transitioning out of CMV undetectable or <LLOQ state. Longer studies may be helpful to determine the effects of a positive CMV qPCR <LLOQ episode that may extend past six months, and prospective studies will be beneficial to isolate and fully elucidate the effect of antiviral therapy on the course of CMV following a positive qPCR <LLOQ result.

In conclusion, there was a low risk of transitioning to a higher CMV viral load following an initial CMV qPCR result of <LLOQ, and risk factors for progression include intensification of immunosuppression (such as treatment for rejection) and higher BMI. Higher CMV viral loads were also associated with an increased risk of transitioning back into or staying in the state of positive, quantifiable CMV DNAemia. In the absence of the specific risk factors, it may be reasonable to serially monitor CMV qPCR as opposed to initiating antiviral therapy which may lead to toxicity. Larger, prospective studies are needed to fully determine the effect of CMV-active antivirals on low level CMV DNAemia.

Acknowledgements

The authors wish to acknowledge Karen Bennett Bain and Anne Thorndyke for their contributions to study design.
Funding: the authors received no sources of funding for this research.
Disclosures: none

References

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Cite as: January SE, Britt D, Pottebaum AA, Krekel TT, Hachem RR, Vazquez-Guillamet R. Impact of Cytomegalovirus DNAemia Below the Lower Limit of Quantification: Multistate Model in Lung Transplant Recipients. Southwest J Pulm, Crit Care Sleep. 2022;25(5):73-82. doi: https://doi.org/10.13175/swjpccs045-22 PDF