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

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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

1. Courtwright AM, Lamattina AM, Takahashi M, et al.  Shorter telomere length following lung transplantation is associated with clinically significant leukopenia and decreased chronic lung allograft dysfunction-free survival. ERJ Open Res. 2020 Jun 15;6(2):00003-2020. [CrossRef] [PubMed]
2. Popescu I, Mannem H, Winters SA, et al. Impaired Cytomegalovirus Immunity in Idiopathic Pulmonary Fibrosis Lung Transplant Recipients with Short Telomeres. Am J Respir Crit Care Med. 2019 Feb 1;199(3):362-376. [CrossRef] [PubMed]
3. Duncan AJ, Dummer JS, Paradis IL, et al. Cytomegalovirus infection and survival in lung transplant recipients. J Heart Lung Transplant. 1991 Sep-Oct;10(5 Pt 1):638-44; discussion 645-6. [PubMed]
4. Bando K, Paradis IL, Komatsu K, et al. Analysis of time-dependent risks for infection, rejection, and death after pulmonary transplantation. J Thorac Cardiovasc Surg. 1995 Jan;109(1):49-57; discussion 57-9. [CrossRef] [PubMed]
5. Kotton CN, Kumar D, Caliendo AM, Huprikar S, Chou S, Danziger-Isakov L, Humar A; The Transplantation Society International CMV Consensus Group. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation. 2018 Jun;102(6):900-931. [CrossRef] [PubMed]
6. Preiksaitis JK, Hayden RT, Tong Y, et al. Are We There Yet? Impact of the First International Standard for Cytomegalovirus DNA on the Harmonization of Results Reported on Plasma Samples. Clin Infect Dis. 2016 Sep 1;63(5):583-9. [CrossRef] [PubMed]
7. Martin-Gandul C, Perez-Romero P, Sanchez M, et al. Determination, validation and standardization of a CMV DNA cut-off value in plasma for preemptive treatment of CMV infection in solid organ transplant recipients at lower risk for CMV infection. J Clin Virol. 2013 Jan;56(1):13-8. [CrossRef] [PubMed]
8. Martin-Gandul C, Perez-Romero P, Blanco-Lobo P, et al. Viral load, CMV-specific T-cell immune response and cytomegalovirus disease in solid organ transplant recipients at higher risk for cytomegalovirus infection during preemptive therapy. Transpl Int. 2014 Oct;27(10):1060-8. [CrossRef] [PubMed]
9. Boaretti M, Sorrentino A, Zantedeschi C, Forni A, Boschiero L, Fontana R. Quantification of cytomegalovirus DNA by a fully automated real-time PCR for early diagnosis and monitoring of active viral infection in solid organ transplant recipients. J Clin Virol. 2013 Feb;56(2):124-8. [CrossRef] [PubMed]
10. David-Neto E, Triboni AHK, Paula FJ, et al. A double-blinded, prospective study to define antigenemia and quantitative real-time polymerase chain reaction cutoffs to start preemptive therapy in low-risk, seropositive, renal transplanted recipients. Transplantation. 2014 Nov 27;98(10):1077-81. [CrossRef] [PubMed]
11. Weinberg A, Hodges TN, Li S, Cai G, Zamora MR. Comparison of PCR, antigenemia assay, and rapid blood culture for detection and prevention of cytomegalovirus disease after lung transplantation. J Clin Microbiol. 2000 Feb;38(2):768-72. [CrossRef] [PubMed]
12. Madi N, Al-Nakib W, Mustafa AS, Saeed T, Pacsa A, Nampoory MR. Detection and monitoring of cytomegalovirus infection in renal transplant patients by quantitative real-time PCR. Med Princ Pract. 2007;16(4):268-73. [CrossRef] [PubMed]
13. Guillamet MCV, Vazquez R, Noe J, Micek ST, Fraser VJ, Kollef MH. Impact of Baseline Characteristics on Future Episodes of Bloodstream Infections: Multistate Model in Septic Patients With Bloodstream Infections. Clin Infect Dis. 2020 Dec 15;71(12):3103-3109. [CrossRef] [PubMed]
14. Natori Y, Alghamdi A, Tazari M, et al. Use of Viral Load as a Surrogate Marker in Clinical Studies of Cytomegalovirus in Solid Organ Transplantation: A Systematic Review and Meta-analysis. Clin Infect Dis. 2018 Feb 1;66(4):617-631. [CrossRef] [PubMed]
15. Paya C, Humar A, Dominguez E, et al. Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant. 2004 Apr;4(4):611-20. [CrossRef] [PubMed]
16. Fleck-Derderian S, McClellan W, Wojcicki JM. The association between cytomegalovirus infection, obesity, and metabolic syndrome in U.S. adult females. Obesity (Silver Spring). 2017 Mar;25(3):626-633. [CrossRef] [PubMed]
17. Hamer M, Batty GD, Kivimäki M. Obesity, Metabolic Health, and History of Cytomegalovirus Infection in the General Population. J Clin Endocrinol Metab. 2016 Apr;101(4):1680-5. [CrossRef] [PubMed]
18. Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13512. [CrossRef] [PubMed]

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 

October 2022 Critical Care Case of the Month: A Middle-Aged Couple “Not Acting Right”

Richard A. Robbins, MD

Pulmonary and Critical Care Research and Education Foundation

Gilbert, AZ USA

History of Present Illness

A 62-year-old man and his 61-year-old wife were brought to Emergency Department by family who reported “they’re not acting right”. Both complain of headache, weakness, tiredness, trouble with daily activities and memory difficulties.

PMH, SH, and FH

• They live in a log cabin in a rural area near Payson.
• The man had a history of myocardial infarction and was post-op percutaneous intervention with stenting 3 years ago.
• There was no significant PMH in the woman.
• Both are retired. Neither drank alcohol to excess or smoked.

Meds (man only):

• Enteric-coated aspirin
• Metoprolol
• Atorvostatin

Physical Examination

• Vital signs in both are normal
• Both are oriented X 3 but sluggish and slow to answer.
• Physical examination is otherwise unremarkable in both.

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

1. CBC, BMP, ABGs
2. CXR
3. EKG
4. 1 and 3
5. All of the above

Cite as: Robbins RA. October 2022 Critical Care Case of the Month: A Middle-Aged Couple “Not Acting Right”. Southwest J Pulm Crit Care Sleep. 2022;25(4):43-46. doi: https://doi.org/10.13175/swjpccs042-22 PDF

Point-of-Care Ultrasound and Right Ventricular Strain: Utility in the Diagnosis of Pulmonary Embolism

Ramzi Ibrahim MD, João Paulo Ferreira MD

Department of Medicine, University of Arizona – Tucson and Banner University Medical Center

Tucson AZ USA

Abstract

Pulmonary emboli are associated with high morbidity and mortality, prompting early diagnostic and therapeutic considerations. Utilization of rapid point-of-care ultrasound (POCUS) to assess for signs of pulmonary emboli can provide valuable information to support immediate treatment. We present a case of suspected pulmonary embolism in the setting of pharmacological prophylaxis for venous thromboembolism with identification of right heart strain on bedside POCUS exam. Early treatment with anticoagulation was initiated considering the clinical presentation and POCUS findings. CT angiogram of the chest revealed bilateral pulmonary emboli, confirming our suspicion. Utilizing POCUS in a case of suspected pulmonary emboli can aid in clinical decision making.

Case Presentation

Our patient is a 50-year-old man with a history of morbid obesity, obstructive sleep apnea, and poorly controlled diabetes mellitus type 2 who was admitted to the hospital for sepsis secondary to left foot cellulitis and found to have left foot osteomyelitis with necrosis of the calcaneus. The patient was started on intravenous antimicrobials, underwent incision and debridement, and completed a partial calcanectomy of the left foot. During the hospital course, he remained on subcutaneous unfractionated heparin at 7,500 units three times a day for prevention of deep vein thrombosis. On post-operative day 12, he developed acute onset of dyspnea requiring 2 liters of supplemental oxygen and was slightly tachycardic in the low 100s. He complained of chest tightness without pain, however, he denied lower extremity discomfort, palpitations, orthopnea, or diaphoresis. Electrocardiogram was remarkable for sinus tachycardia without significant ST changes, T-wave inversions, conduction defects, or QTc prolongation. Rapid point-of-care ultrasound (POCUS) at bedside revealed interventricular septal bowing, hypokinesia of the mid free right ventricular wall, and increased right ventricle to left ventricle size ratio (>1:1 respectively) (Figures 1 and 2).

Figure 1. A: Static apical 4-chamber view showing interventricular bowing into the left ventricle (blue arrow), significantly enlarged right ventricle, and right ventricular free wall hypokinesia (green arrow). B: Video of apical 4-chamber view.

Figure 2. A: Static parasternal short axis view showing interventricular septal bowing in the left ventricle (green arrow). B: Video of parasternal short axis view.

With these findings, the patient was started on therapeutic anticoagulation. CT angiogram of the chest revealed a large burden of bilateral pulmonary emboli (PE). The pulmonary embolism severity index (PESI) score was 130 points which is associated with a 10%-24.5% mortality rate in the following 30 days. Formal echocardiogram showed a severely dilated right ventricle with reduced systolic function, paradoxical septal movement, and a D-shaped left ventricle. Patient remained hemodynamically stable and was discharged home after transition from heparin to rivaroxaban.

Discussion

Pulmonary emboli remain a commonly encountered pathological phenomenon in the hospital setting with a mortality rate ranging from <5% to 50% (1). Venous thromboembolism prophylaxis has been shown to reduce the risk of VTE in hospitalized patients, however, this does not eliminate the risk completely. Prompt diagnosis allows earlier treatment and improved outcomes however this is often challenging given the lack of specificity associated with its characteristic clinical symptoms (2). In the proper context, utilization of POCUS can aid the diagnosis of PE by assessing for signs of right ventricular strain. Characteristic findings seen on a cardiac-focused POCUS that represent right ventricular strain include McConnell’s sign (defined as right ventricular free wall akinesis/hypokinesis with sparing of the apex), septal flattening, right ventricular enlargement, tricuspid regurgitation, and tricuspid annular plane systolic excursion under 1.6 cm (3). Their respective sensitivities and specificities are highly dependent on the pre-test probability. For example, a prospective cohort study completed by Daley et al. (4) in 2019 showed that for patients with a clinical suspicion of PE, sensitivity of right ventricular strain was 100% for a PE in patients with a heart rate (HR) >110 beats per minute, and a sensitivity of 92% if HR >100 BPM. This study provides evidence to support the use of cardiac focused POCUS in ruling out pulmonary emboli in patients with signs of right ventricular strain and abnormal hemodynamic parameters such as tachycardia. Additionally, in settings where hemodynamic instability is present and the patient cannot be taken to the CT scanner for fear of decompensation, rapid POCUS assessment can be helpful. In our patient, given the acute need for supplemental oxygenation and dyspnea, along with his risk factors for a thromboembolic event, the use of POCUS aided in our clinical decision making. The yield of information that can be provided by POCUS is vital for early diagnostic and therapeutic decision making for patients with a clinical suspicion of pulmonary emboli.

References

1. Torbicki A, Perrier A, Konstantinides S, et al. Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J. 2008 Sep;29(18):2276-315. [CrossRef][PubMed]
2. Roy PM, Meyer G, Vielle B, et al. Appropriateness of diagnostic management and outcomes of suspected pulmonary embolism. Ann Intern Med. 2006 Feb 7;144(3):157-64. [CrossRef][PubMed]
3. Alerhand S, Sundaram T, Gottlieb M. What are the echocardiographic findings of acute right ventricular strain that suggest pulmonary embolism? Anaesth Crit Care Pain Med. 2021 Apr;40(2):100852. [CrossRef] [PubMed]
4. Daley JI, Dwyer KH, Grunwald Z, et al. Increased Sensitivity of Focused Cardiac Ultrasound for Pulmonary Embolism in Emergency Department Patients With Abnormal Vital Signs. Acad Emerg Med. 2019 Nov;26(11):1211-1220. [CrossRef][PubMed]

Cite as: Ibrahim R, Ferreira JP. Point-of-Care Ultrasound and Right Ventricular Strain: Utility in the Diagnosis of Pulmonary Embolism. Southwest J Pulm Crit Care Sleep. 2022;25(2):34-36. doi: https://doi.org/10.13175/swjpccs040-22 PDF