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Reclaiming patient-centered care from the grip of COVID-19
Over a year has passed since the first case of COVID-19 was reported in the United States, with over 114 million cases now reported worldwide, and over 2.5 million deaths at the time of this writing (Dong E, et al. Lancet Infect Dis. doi: 10.1016/S1473-3099[20]30120-1). While our vaccination efforts here in the United States have provided a much-needed glimmer of hope, it has been bittersweet, as we recently surpassed the grim milestone of 500,000 COVID-19-related deaths.
The infectious nature of SARS-CoV-2, coupled with the lack of adequate PPE early in the pandemic, led to radical changes in most hospital visitor policies. Rather than welcoming families into the care setting as we have been accustomed, we were forced to restrict access. While well-intentioned, the impact of this on patients, their families – and as we later learned, ourselves – has been devastating. Patients found themselves alone in an unfamiliar environment, infected with a disease there was no effective treatment for, hearing dismal news regarding inpatient and ICU mortality rates on news networks, and families could not see for themselves how their loved ones were progressing in their hospital course.
The impact on patient-centered care
The impact of this pandemic on patients and health care providers alike cannot be overstated. Arguably, one of the greatest challenges created by COVID-19 has been its direct assault on the core values of patient-centered care that we have spent decades striving to promote and embody.
Since its identification as a quality gap by the Institute of Medicine in 2001, the definition of patient-centered care has been tweaked over the past 20 years (Institute of Medicine (IOM). Crossing the Quality Chasm: A New Health System for the 21st Century. Washington, D.C: National Academy Press; 2001). Most frameworks include the active participation of patients and their families as part of the health care team, encouraging and facilitating the presence of family members in the care setting, and focusing on patients’ physical comfort and emotional well-being as fundamental tenets of patient centeredness (NEJM Catalyst: What is Patient-Centered Care? Explore the definition, benefits, and examples of patient-centered care. How does patient-centered care translate to new delivery models? January 1,2017).
Families, the “F” in the ABCDEF Bundle, have been recognized as an integral part of care in the ICU setting (Ely EW. Crit Care Med. 2017;45[2]:321). While engagement of family members began with our recognition of their role in emotionally supporting patients and efforts to improve communication, we have also seen the impact of family participation on reducing ICU delirium through frequent re-orientation and encouragement of early mobility (McKenzie J, et al. Australas J Ageing. 2020;39:21). In fact, a recent study has suggested that family members could play an even more active role in detecting and assessing ICU delirium using objective assessment tools (Fiest K, et al. Crit Care Med. 2020;48[7]:954). Post-ICU PTSD has been well described in both ICU survivors as well as in their family members, with evidence that family participation in care of patients during their ICU stay leads to its reduction (Amass TH, et al. Crit Care Med. 2020[Feb];48[2]:176).
The emotional toll
Comforting patients and families in times of distress and suffering is something that comes naturally to many in critical care, and our training further improves our ability to do this effectively. No amount of training, however, could have prepared us for the degree and volume of suffering we bore witness to this past year and the resulting moral injury many are still dealing with. We were present for families’ most intimate moments, holding phones and tablets up to patients so their families could say their goodbyes, listening to the “I love yous,” “I’ll miss yous,” “I’m sorrys,” and “Please don’t gos.” Nurses held patients’ hands as they took their last breaths so they wouldn’t die alone and worked to move husbands and wives into the same room so they could be together in their final moments. Entrenched in each of our identities is the role of healer, and we found ourselves questioning our effectiveness in rising to meet suffering on a scale we had never seen before. Little did we understand that while our paradigms were reinforcing the benefits of patient-centered care for patients and their families, that framework was also serving to facilitate our role as healers – that without it, we all suffer.
Rising to the challenge
These unprecedented circumstances led to creative efforts to bridge some of these barriers. Health systems created photo lanyards that providers wore over their PPE so patients could identify their health care team and connect with them on a more human level. Video conferencing technology was brought to the patient bedside using smartphones and tablets to assist them in communicating with their families. Doctors and nurses coordinated multiple calls throughout the day to ensure families felt included in the care plans and were always abreast of any new developments.
All these initiatives were our way of attempting to alleviate some of the suffering we were witnessing, and in some ways felt complicit in. It is in hindsight that we can look back and question if we could have done things differently. We treated family as visitors, when in fact, they are fundamental members of the care team who play an active and critical role in patient care. This was, in part, driven by national unpreparedness when it came to PPE supplies, in addition to misinformation and inconsistent messaging early in the pandemic with regards to the mechanism of transmission of disease from various health organizations. While we did our best given the circumstances, we must not allow this experience to lead us away from the tenets we know to be essential to patient, family, and health care provider well-being.
All in health care met the call to action – nurses, physicians, advanced practice providers, respiratory therapists, nutritionists, pharmacists, physical therapists, patient transporters, environmental service workers, and all others who kept our hospitals and patient care facilities open through this pandemic and embarked on what amounted to a collective, global, ongoing “code-blue alert,” resuscitating patient after patient, hotspot after hotspot, region after region, and country after country. We expanded hospital bed capacities, created ICU beds where there were none, developed novel process protocols, and learned in real time what seemed to help (or not) in treating this novel disease, all while participating in incredible international scientific collaboration and information sharing that has contributed in getting the collective “us” through this first year of the pandemic. We did what we were trained and called to do.
Preparing for the future
There will inevitably be another public health crisis, and we must advocate for better preparedness next time, insisting on overall stronger public health systems and pandemic preparedness. We must address our PPE stores and supply chains. We must have disaster preparedness plans that go beyond the scope of mass casualty events and bioterrorism. Beyond physical recovery, we must tend to the factors that impact patients’ long-term recovery, with attention to emotional and psychological well-being. We must advocate for all of this now, while the memories are fresh and before the impact of this collective suffering begins to fade. It can never again be acceptable to exclude families from the health care setting. We must advocate for our patients and for the resources, systems, processes, and support that will allow us to do better.
Dr. Hegab is Associate Director, Pulmonary Hypertension Program, Medical Director, Pulmonary Embolism Response Team, Division of Pulmonary and Critical Care Medicine, Henry Ford Hospital; and Assistant Professor, Wayne State University School of Medicine, Detroit.
Over a year has passed since the first case of COVID-19 was reported in the United States, with over 114 million cases now reported worldwide, and over 2.5 million deaths at the time of this writing (Dong E, et al. Lancet Infect Dis. doi: 10.1016/S1473-3099[20]30120-1). While our vaccination efforts here in the United States have provided a much-needed glimmer of hope, it has been bittersweet, as we recently surpassed the grim milestone of 500,000 COVID-19-related deaths.
The infectious nature of SARS-CoV-2, coupled with the lack of adequate PPE early in the pandemic, led to radical changes in most hospital visitor policies. Rather than welcoming families into the care setting as we have been accustomed, we were forced to restrict access. While well-intentioned, the impact of this on patients, their families – and as we later learned, ourselves – has been devastating. Patients found themselves alone in an unfamiliar environment, infected with a disease there was no effective treatment for, hearing dismal news regarding inpatient and ICU mortality rates on news networks, and families could not see for themselves how their loved ones were progressing in their hospital course.
The impact on patient-centered care
The impact of this pandemic on patients and health care providers alike cannot be overstated. Arguably, one of the greatest challenges created by COVID-19 has been its direct assault on the core values of patient-centered care that we have spent decades striving to promote and embody.
Since its identification as a quality gap by the Institute of Medicine in 2001, the definition of patient-centered care has been tweaked over the past 20 years (Institute of Medicine (IOM). Crossing the Quality Chasm: A New Health System for the 21st Century. Washington, D.C: National Academy Press; 2001). Most frameworks include the active participation of patients and their families as part of the health care team, encouraging and facilitating the presence of family members in the care setting, and focusing on patients’ physical comfort and emotional well-being as fundamental tenets of patient centeredness (NEJM Catalyst: What is Patient-Centered Care? Explore the definition, benefits, and examples of patient-centered care. How does patient-centered care translate to new delivery models? January 1,2017).
Families, the “F” in the ABCDEF Bundle, have been recognized as an integral part of care in the ICU setting (Ely EW. Crit Care Med. 2017;45[2]:321). While engagement of family members began with our recognition of their role in emotionally supporting patients and efforts to improve communication, we have also seen the impact of family participation on reducing ICU delirium through frequent re-orientation and encouragement of early mobility (McKenzie J, et al. Australas J Ageing. 2020;39:21). In fact, a recent study has suggested that family members could play an even more active role in detecting and assessing ICU delirium using objective assessment tools (Fiest K, et al. Crit Care Med. 2020;48[7]:954). Post-ICU PTSD has been well described in both ICU survivors as well as in their family members, with evidence that family participation in care of patients during their ICU stay leads to its reduction (Amass TH, et al. Crit Care Med. 2020[Feb];48[2]:176).
The emotional toll
Comforting patients and families in times of distress and suffering is something that comes naturally to many in critical care, and our training further improves our ability to do this effectively. No amount of training, however, could have prepared us for the degree and volume of suffering we bore witness to this past year and the resulting moral injury many are still dealing with. We were present for families’ most intimate moments, holding phones and tablets up to patients so their families could say their goodbyes, listening to the “I love yous,” “I’ll miss yous,” “I’m sorrys,” and “Please don’t gos.” Nurses held patients’ hands as they took their last breaths so they wouldn’t die alone and worked to move husbands and wives into the same room so they could be together in their final moments. Entrenched in each of our identities is the role of healer, and we found ourselves questioning our effectiveness in rising to meet suffering on a scale we had never seen before. Little did we understand that while our paradigms were reinforcing the benefits of patient-centered care for patients and their families, that framework was also serving to facilitate our role as healers – that without it, we all suffer.
Rising to the challenge
These unprecedented circumstances led to creative efforts to bridge some of these barriers. Health systems created photo lanyards that providers wore over their PPE so patients could identify their health care team and connect with them on a more human level. Video conferencing technology was brought to the patient bedside using smartphones and tablets to assist them in communicating with their families. Doctors and nurses coordinated multiple calls throughout the day to ensure families felt included in the care plans and were always abreast of any new developments.
All these initiatives were our way of attempting to alleviate some of the suffering we were witnessing, and in some ways felt complicit in. It is in hindsight that we can look back and question if we could have done things differently. We treated family as visitors, when in fact, they are fundamental members of the care team who play an active and critical role in patient care. This was, in part, driven by national unpreparedness when it came to PPE supplies, in addition to misinformation and inconsistent messaging early in the pandemic with regards to the mechanism of transmission of disease from various health organizations. While we did our best given the circumstances, we must not allow this experience to lead us away from the tenets we know to be essential to patient, family, and health care provider well-being.
All in health care met the call to action – nurses, physicians, advanced practice providers, respiratory therapists, nutritionists, pharmacists, physical therapists, patient transporters, environmental service workers, and all others who kept our hospitals and patient care facilities open through this pandemic and embarked on what amounted to a collective, global, ongoing “code-blue alert,” resuscitating patient after patient, hotspot after hotspot, region after region, and country after country. We expanded hospital bed capacities, created ICU beds where there were none, developed novel process protocols, and learned in real time what seemed to help (or not) in treating this novel disease, all while participating in incredible international scientific collaboration and information sharing that has contributed in getting the collective “us” through this first year of the pandemic. We did what we were trained and called to do.
Preparing for the future
There will inevitably be another public health crisis, and we must advocate for better preparedness next time, insisting on overall stronger public health systems and pandemic preparedness. We must address our PPE stores and supply chains. We must have disaster preparedness plans that go beyond the scope of mass casualty events and bioterrorism. Beyond physical recovery, we must tend to the factors that impact patients’ long-term recovery, with attention to emotional and psychological well-being. We must advocate for all of this now, while the memories are fresh and before the impact of this collective suffering begins to fade. It can never again be acceptable to exclude families from the health care setting. We must advocate for our patients and for the resources, systems, processes, and support that will allow us to do better.
Dr. Hegab is Associate Director, Pulmonary Hypertension Program, Medical Director, Pulmonary Embolism Response Team, Division of Pulmonary and Critical Care Medicine, Henry Ford Hospital; and Assistant Professor, Wayne State University School of Medicine, Detroit.
Over a year has passed since the first case of COVID-19 was reported in the United States, with over 114 million cases now reported worldwide, and over 2.5 million deaths at the time of this writing (Dong E, et al. Lancet Infect Dis. doi: 10.1016/S1473-3099[20]30120-1). While our vaccination efforts here in the United States have provided a much-needed glimmer of hope, it has been bittersweet, as we recently surpassed the grim milestone of 500,000 COVID-19-related deaths.
The infectious nature of SARS-CoV-2, coupled with the lack of adequate PPE early in the pandemic, led to radical changes in most hospital visitor policies. Rather than welcoming families into the care setting as we have been accustomed, we were forced to restrict access. While well-intentioned, the impact of this on patients, their families – and as we later learned, ourselves – has been devastating. Patients found themselves alone in an unfamiliar environment, infected with a disease there was no effective treatment for, hearing dismal news regarding inpatient and ICU mortality rates on news networks, and families could not see for themselves how their loved ones were progressing in their hospital course.
The impact on patient-centered care
The impact of this pandemic on patients and health care providers alike cannot be overstated. Arguably, one of the greatest challenges created by COVID-19 has been its direct assault on the core values of patient-centered care that we have spent decades striving to promote and embody.
Since its identification as a quality gap by the Institute of Medicine in 2001, the definition of patient-centered care has been tweaked over the past 20 years (Institute of Medicine (IOM). Crossing the Quality Chasm: A New Health System for the 21st Century. Washington, D.C: National Academy Press; 2001). Most frameworks include the active participation of patients and their families as part of the health care team, encouraging and facilitating the presence of family members in the care setting, and focusing on patients’ physical comfort and emotional well-being as fundamental tenets of patient centeredness (NEJM Catalyst: What is Patient-Centered Care? Explore the definition, benefits, and examples of patient-centered care. How does patient-centered care translate to new delivery models? January 1,2017).
Families, the “F” in the ABCDEF Bundle, have been recognized as an integral part of care in the ICU setting (Ely EW. Crit Care Med. 2017;45[2]:321). While engagement of family members began with our recognition of their role in emotionally supporting patients and efforts to improve communication, we have also seen the impact of family participation on reducing ICU delirium through frequent re-orientation and encouragement of early mobility (McKenzie J, et al. Australas J Ageing. 2020;39:21). In fact, a recent study has suggested that family members could play an even more active role in detecting and assessing ICU delirium using objective assessment tools (Fiest K, et al. Crit Care Med. 2020;48[7]:954). Post-ICU PTSD has been well described in both ICU survivors as well as in their family members, with evidence that family participation in care of patients during their ICU stay leads to its reduction (Amass TH, et al. Crit Care Med. 2020[Feb];48[2]:176).
The emotional toll
Comforting patients and families in times of distress and suffering is something that comes naturally to many in critical care, and our training further improves our ability to do this effectively. No amount of training, however, could have prepared us for the degree and volume of suffering we bore witness to this past year and the resulting moral injury many are still dealing with. We were present for families’ most intimate moments, holding phones and tablets up to patients so their families could say their goodbyes, listening to the “I love yous,” “I’ll miss yous,” “I’m sorrys,” and “Please don’t gos.” Nurses held patients’ hands as they took their last breaths so they wouldn’t die alone and worked to move husbands and wives into the same room so they could be together in their final moments. Entrenched in each of our identities is the role of healer, and we found ourselves questioning our effectiveness in rising to meet suffering on a scale we had never seen before. Little did we understand that while our paradigms were reinforcing the benefits of patient-centered care for patients and their families, that framework was also serving to facilitate our role as healers – that without it, we all suffer.
Rising to the challenge
These unprecedented circumstances led to creative efforts to bridge some of these barriers. Health systems created photo lanyards that providers wore over their PPE so patients could identify their health care team and connect with them on a more human level. Video conferencing technology was brought to the patient bedside using smartphones and tablets to assist them in communicating with their families. Doctors and nurses coordinated multiple calls throughout the day to ensure families felt included in the care plans and were always abreast of any new developments.
All these initiatives were our way of attempting to alleviate some of the suffering we were witnessing, and in some ways felt complicit in. It is in hindsight that we can look back and question if we could have done things differently. We treated family as visitors, when in fact, they are fundamental members of the care team who play an active and critical role in patient care. This was, in part, driven by national unpreparedness when it came to PPE supplies, in addition to misinformation and inconsistent messaging early in the pandemic with regards to the mechanism of transmission of disease from various health organizations. While we did our best given the circumstances, we must not allow this experience to lead us away from the tenets we know to be essential to patient, family, and health care provider well-being.
All in health care met the call to action – nurses, physicians, advanced practice providers, respiratory therapists, nutritionists, pharmacists, physical therapists, patient transporters, environmental service workers, and all others who kept our hospitals and patient care facilities open through this pandemic and embarked on what amounted to a collective, global, ongoing “code-blue alert,” resuscitating patient after patient, hotspot after hotspot, region after region, and country after country. We expanded hospital bed capacities, created ICU beds where there were none, developed novel process protocols, and learned in real time what seemed to help (or not) in treating this novel disease, all while participating in incredible international scientific collaboration and information sharing that has contributed in getting the collective “us” through this first year of the pandemic. We did what we were trained and called to do.
Preparing for the future
There will inevitably be another public health crisis, and we must advocate for better preparedness next time, insisting on overall stronger public health systems and pandemic preparedness. We must address our PPE stores and supply chains. We must have disaster preparedness plans that go beyond the scope of mass casualty events and bioterrorism. Beyond physical recovery, we must tend to the factors that impact patients’ long-term recovery, with attention to emotional and psychological well-being. We must advocate for all of this now, while the memories are fresh and before the impact of this collective suffering begins to fade. It can never again be acceptable to exclude families from the health care setting. We must advocate for our patients and for the resources, systems, processes, and support that will allow us to do better.
Dr. Hegab is Associate Director, Pulmonary Hypertension Program, Medical Director, Pulmonary Embolism Response Team, Division of Pulmonary and Critical Care Medicine, Henry Ford Hospital; and Assistant Professor, Wayne State University School of Medicine, Detroit.
COVID-19: Choosing the proper treatment at the proper time
Coronavirus disease 2019 (COVID-19), the disease caused by the highly contagious virus SARS-CoV-2, has affected over 45 million people worldwide and caused over 1.2 million deaths. Preventative strategies, including social distancing and facial coverings, have proven to be effective to decrease the risk of transmission. Unfortunately, despite these measures, a large number of individuals continue to get infected throughout the world. While most patients typically stay asymptomatic or develop mild forms of the disease, a fraction of them will progress to more severe forms that would necessitate hospital care. Since this is a novel virus, we do not have an effective antimicrobial agent and the care we provide is mostly supportive, aiming to prevent and treat the systemic complications produced by the virus and the inflammatory response that ensues.
The phases of COVID 19
COVID-19 can be clinically divided into three phases (Mason RJ, et al. Eur Respir J. 2020 Apr;55[4]).
The asymptomatic phase: Also known as incubation period. During this stage, the SARS-CoV-2 virus binds to the epithelial cells of the upper respiratory tract and starts replicating.
The viral phase: Associated with the classic constitutional symptoms such as fever, chills, headache, cough, fatigue, and diarrhea. This phase typically begins 4-6 days after exposure to SARS-CoV-2 and is characterized by high levels of viral replication and migration to the conducting airways, triggering the innate immune response.
The pulmonary phase: Characterized by hypoxia and ground glass infiltrates on computed tomography of the chest. By now, the virus has reached the respiratory bronchioles and the alveoli. During this phase (about 8-10 days after exposure) the virus begins to die, and the host immune response ensues. By now the number of viral units is very small, but the host immune reaction against the virus has begun to mount.
The virus is actively replicating during the asymptomatic and at the beginning of the viral phase. The severity of symptoms varies according to the viral load and patient comorbidities [mild-moderate (81%), severe (14%), and critical (5%)]. The disease course is characterized by dysregulated immunity, profound inflammatory response, and dysregulated coagulation. By distinguishing these phases, clinicians can start interventions that would aim at the main cause of the derangement at each specific phase. For example, antiviral agents seem more appropriate in the early phases of the disease, while anti-inflammatory medications could target the inflammatory response that occurs in the pulmonary phase (Figure 1).
The tools in our toolbox: Timing is paramount
Remdesivir
The preliminary results from a recent trial that compared remdesivir with placebo, given 6-12 days from the onset of symptoms, revealed a shorter time to recovery with Remdesivir (Beigel JH, et al. N Engl J Med. 2020 Oct;8. NEJMoa2007764). The patients who received remdesivir within 10 days of the onset of symptoms had a shorter recovery time compared with those who received it after 10 days from the onset of symptoms. Moreover, remdesivir did not alter the disease course in patients who received the drug after the onset of hypoxia. These results are consistent with those of Wang and colleagues who reported no effect in time to clinical improvement in most patients who received the drug 10 days after the onset of symptoms (Wang Y, et al. Lancet. 2020 May;395[10236]:1569-78). In most antiviral trials, the agent was potentially given when the immune response had already begun, stage in which the number of viral units is not as large as in the earlier phases, possibly explaining the lack effect in time of clinical improvement or mortality.
Convalescent plasma
Piechotta and colleagues recently showed that convalescent plasma, when given to patients more than 14 days from the onset of symptoms, provided no benefit in time to clinical improvement or 28-day mortality. At 14 days or later, the pulmonary phase (characterized by systemic inflammation) had started in nearly all patients. As it seems apparent, any intervention not targeted to modulate the inflammatory response is unlikely to make a difference in this stage. (Piechotta V, et al. Cochrane Database Syst Rev. 2020 Jul;7[7]:CD013600).
The negative results of these studies (antivirals and convalescent plasma) highlight the importance of timing. In most of these trials, the intervention was started at the end of the viral phase or in the pulmonary phase, when the virus was nearly or completely dead, but the host immune response has begun to mount.
Corticosteroids
Corticosteroids (methylprednisolone and dexamethasone) have shown positive effects when given at the proper time (beginning of the pulmonary phase). A recent study revealed a lower 28-day mortality when compared with placebo in hospitalized patients with COVID-19. However, a prespecified subgroup analysis showed no benefit and a signal of possible harm among those who received dexamethasone in the absence of hypoxia (viral phase) (Lim WS, et al. N Engl J Med. 2020 Jul;[NEJMoa2021436]). A meta-analysis of seven randomized trials that used different doses and types of corticosteroids (dexamethasone, methylprednisolone, and hydrocortisone) reported a lower 28-day mortality in the corticosteroids group. The benefit was more pronounced when the corticosteroids was used in critically ill patients who were not receiving invasive mechanical ventilation.
Self-proning
Self-proning is also thought to be beneficial during the pulmonary phase. Prone positioning for at least 3 hours improved oxygenation but the result was not sustained (Coppo A, et al. Lancet Respir Med. 2020 Aug;8[8]:765-74). A retrospective analysis of 199 patients with COVID-19 in the pulmonary phase who were being supported by high-flow nasal cannula showed that awake proning for more than 16 hours had no effect in the risk of intubation or mortality (Ferrando C, et al. reduce the use of critical care resources, and improve survival. We aimed to examine whether the combination of high-flow nasal oxygen therapy (HFNOCrit Care. 2020 [Oct];24[1]:597). There is concern that this intervention might produce a delay in intubation in patients who have worsening oxygenation; this is especially important as delayed intubation can be associated with worse outcomes. Despite the conflicting data, awake self-proning is a reasonable intervention that should be considered provided that it does not interfere with treatments that have been proven beneficial. As prospective evidence becomes available, recommendations may possibly change.
What about thromboembolic events?
Data on arterial and venous thromboembolic events (VTE) in the disease course of COVID-19 are largely variable. The prevalence of VTE in COVID-19 seems to be higher than other in causes of sepsis especially in critically ill patients. (Bilaloglu S, et al. JAMA. 2020 Aug;324(8):799-801). Despite the use of pharmacological prophylaxis, VTE was seen in 13.6% of critically ill patients and 3.6% of medical ward patients and associated with a higher mortality. Therefore, more trials are needed to understand the most effective way to prevent VTE. At the current time, clinicians need to be vigilant to detect VTE as early as possible. Some options to consider include performing a daily evaluation of the possible risks (emphasizing prevention), routine bedside point of care ultrasound, early diagnostic imaging studies for clinically suspected VTE, early mobilization and delirium prevention. Prophylactic doses of LMWH or UH for all hospitalized patients with no or low risk of bleeding or non-hospitalized patient with high risk for VTE can be entertained (Bikdeli B, et al. J Am Coll Cardiol 2020 Apr;75[23]:2950-73). Therapeutic dose anticoagulation should be only used in confirmed VTE or in highly suspected VTE with difficulties to obtain standard confirmatory imaging. A therapeutic approach based solely on D-dimer should be avoided, because the evidence is insufficient and the risk of bleeding in critically ill patients is not insignificant.
The available evidence is helpful but not definitive making it difficult to have a clear pathway to effectively treat the systemic effects of COVID-19. One should consider remdesivir and convalescent plasma during the viral phase before hypoxia ensue. Anti-inflammatory interventions (dexamethasone or methylprednisolone) should be given as soon as the pulmonary manifestations start (hypoxia). The type, optimal dose, and duration of corticosteroids vary from trial to trial and no evidence suggests that higher doses are associated with more benefit. It is not only important to choose the right treatment but also the phase when such treatment is most likely to be effective!
Dr. Megri is a Pulmonary and Critical Care Fellow at the University of Kentucky. Dr. Coz is Associate Professor of Medicine, University of Kentucky.
Coronavirus disease 2019 (COVID-19), the disease caused by the highly contagious virus SARS-CoV-2, has affected over 45 million people worldwide and caused over 1.2 million deaths. Preventative strategies, including social distancing and facial coverings, have proven to be effective to decrease the risk of transmission. Unfortunately, despite these measures, a large number of individuals continue to get infected throughout the world. While most patients typically stay asymptomatic or develop mild forms of the disease, a fraction of them will progress to more severe forms that would necessitate hospital care. Since this is a novel virus, we do not have an effective antimicrobial agent and the care we provide is mostly supportive, aiming to prevent and treat the systemic complications produced by the virus and the inflammatory response that ensues.
The phases of COVID 19
COVID-19 can be clinically divided into three phases (Mason RJ, et al. Eur Respir J. 2020 Apr;55[4]).
The asymptomatic phase: Also known as incubation period. During this stage, the SARS-CoV-2 virus binds to the epithelial cells of the upper respiratory tract and starts replicating.
The viral phase: Associated with the classic constitutional symptoms such as fever, chills, headache, cough, fatigue, and diarrhea. This phase typically begins 4-6 days after exposure to SARS-CoV-2 and is characterized by high levels of viral replication and migration to the conducting airways, triggering the innate immune response.
The pulmonary phase: Characterized by hypoxia and ground glass infiltrates on computed tomography of the chest. By now, the virus has reached the respiratory bronchioles and the alveoli. During this phase (about 8-10 days after exposure) the virus begins to die, and the host immune response ensues. By now the number of viral units is very small, but the host immune reaction against the virus has begun to mount.
The virus is actively replicating during the asymptomatic and at the beginning of the viral phase. The severity of symptoms varies according to the viral load and patient comorbidities [mild-moderate (81%), severe (14%), and critical (5%)]. The disease course is characterized by dysregulated immunity, profound inflammatory response, and dysregulated coagulation. By distinguishing these phases, clinicians can start interventions that would aim at the main cause of the derangement at each specific phase. For example, antiviral agents seem more appropriate in the early phases of the disease, while anti-inflammatory medications could target the inflammatory response that occurs in the pulmonary phase (Figure 1).
The tools in our toolbox: Timing is paramount
Remdesivir
The preliminary results from a recent trial that compared remdesivir with placebo, given 6-12 days from the onset of symptoms, revealed a shorter time to recovery with Remdesivir (Beigel JH, et al. N Engl J Med. 2020 Oct;8. NEJMoa2007764). The patients who received remdesivir within 10 days of the onset of symptoms had a shorter recovery time compared with those who received it after 10 days from the onset of symptoms. Moreover, remdesivir did not alter the disease course in patients who received the drug after the onset of hypoxia. These results are consistent with those of Wang and colleagues who reported no effect in time to clinical improvement in most patients who received the drug 10 days after the onset of symptoms (Wang Y, et al. Lancet. 2020 May;395[10236]:1569-78). In most antiviral trials, the agent was potentially given when the immune response had already begun, stage in which the number of viral units is not as large as in the earlier phases, possibly explaining the lack effect in time of clinical improvement or mortality.
Convalescent plasma
Piechotta and colleagues recently showed that convalescent plasma, when given to patients more than 14 days from the onset of symptoms, provided no benefit in time to clinical improvement or 28-day mortality. At 14 days or later, the pulmonary phase (characterized by systemic inflammation) had started in nearly all patients. As it seems apparent, any intervention not targeted to modulate the inflammatory response is unlikely to make a difference in this stage. (Piechotta V, et al. Cochrane Database Syst Rev. 2020 Jul;7[7]:CD013600).
The negative results of these studies (antivirals and convalescent plasma) highlight the importance of timing. In most of these trials, the intervention was started at the end of the viral phase or in the pulmonary phase, when the virus was nearly or completely dead, but the host immune response has begun to mount.
Corticosteroids
Corticosteroids (methylprednisolone and dexamethasone) have shown positive effects when given at the proper time (beginning of the pulmonary phase). A recent study revealed a lower 28-day mortality when compared with placebo in hospitalized patients with COVID-19. However, a prespecified subgroup analysis showed no benefit and a signal of possible harm among those who received dexamethasone in the absence of hypoxia (viral phase) (Lim WS, et al. N Engl J Med. 2020 Jul;[NEJMoa2021436]). A meta-analysis of seven randomized trials that used different doses and types of corticosteroids (dexamethasone, methylprednisolone, and hydrocortisone) reported a lower 28-day mortality in the corticosteroids group. The benefit was more pronounced when the corticosteroids was used in critically ill patients who were not receiving invasive mechanical ventilation.
Self-proning
Self-proning is also thought to be beneficial during the pulmonary phase. Prone positioning for at least 3 hours improved oxygenation but the result was not sustained (Coppo A, et al. Lancet Respir Med. 2020 Aug;8[8]:765-74). A retrospective analysis of 199 patients with COVID-19 in the pulmonary phase who were being supported by high-flow nasal cannula showed that awake proning for more than 16 hours had no effect in the risk of intubation or mortality (Ferrando C, et al. reduce the use of critical care resources, and improve survival. We aimed to examine whether the combination of high-flow nasal oxygen therapy (HFNOCrit Care. 2020 [Oct];24[1]:597). There is concern that this intervention might produce a delay in intubation in patients who have worsening oxygenation; this is especially important as delayed intubation can be associated with worse outcomes. Despite the conflicting data, awake self-proning is a reasonable intervention that should be considered provided that it does not interfere with treatments that have been proven beneficial. As prospective evidence becomes available, recommendations may possibly change.
What about thromboembolic events?
Data on arterial and venous thromboembolic events (VTE) in the disease course of COVID-19 are largely variable. The prevalence of VTE in COVID-19 seems to be higher than other in causes of sepsis especially in critically ill patients. (Bilaloglu S, et al. JAMA. 2020 Aug;324(8):799-801). Despite the use of pharmacological prophylaxis, VTE was seen in 13.6% of critically ill patients and 3.6% of medical ward patients and associated with a higher mortality. Therefore, more trials are needed to understand the most effective way to prevent VTE. At the current time, clinicians need to be vigilant to detect VTE as early as possible. Some options to consider include performing a daily evaluation of the possible risks (emphasizing prevention), routine bedside point of care ultrasound, early diagnostic imaging studies for clinically suspected VTE, early mobilization and delirium prevention. Prophylactic doses of LMWH or UH for all hospitalized patients with no or low risk of bleeding or non-hospitalized patient with high risk for VTE can be entertained (Bikdeli B, et al. J Am Coll Cardiol 2020 Apr;75[23]:2950-73). Therapeutic dose anticoagulation should be only used in confirmed VTE or in highly suspected VTE with difficulties to obtain standard confirmatory imaging. A therapeutic approach based solely on D-dimer should be avoided, because the evidence is insufficient and the risk of bleeding in critically ill patients is not insignificant.
The available evidence is helpful but not definitive making it difficult to have a clear pathway to effectively treat the systemic effects of COVID-19. One should consider remdesivir and convalescent plasma during the viral phase before hypoxia ensue. Anti-inflammatory interventions (dexamethasone or methylprednisolone) should be given as soon as the pulmonary manifestations start (hypoxia). The type, optimal dose, and duration of corticosteroids vary from trial to trial and no evidence suggests that higher doses are associated with more benefit. It is not only important to choose the right treatment but also the phase when such treatment is most likely to be effective!
Dr. Megri is a Pulmonary and Critical Care Fellow at the University of Kentucky. Dr. Coz is Associate Professor of Medicine, University of Kentucky.
Coronavirus disease 2019 (COVID-19), the disease caused by the highly contagious virus SARS-CoV-2, has affected over 45 million people worldwide and caused over 1.2 million deaths. Preventative strategies, including social distancing and facial coverings, have proven to be effective to decrease the risk of transmission. Unfortunately, despite these measures, a large number of individuals continue to get infected throughout the world. While most patients typically stay asymptomatic or develop mild forms of the disease, a fraction of them will progress to more severe forms that would necessitate hospital care. Since this is a novel virus, we do not have an effective antimicrobial agent and the care we provide is mostly supportive, aiming to prevent and treat the systemic complications produced by the virus and the inflammatory response that ensues.
The phases of COVID 19
COVID-19 can be clinically divided into three phases (Mason RJ, et al. Eur Respir J. 2020 Apr;55[4]).
The asymptomatic phase: Also known as incubation period. During this stage, the SARS-CoV-2 virus binds to the epithelial cells of the upper respiratory tract and starts replicating.
The viral phase: Associated with the classic constitutional symptoms such as fever, chills, headache, cough, fatigue, and diarrhea. This phase typically begins 4-6 days after exposure to SARS-CoV-2 and is characterized by high levels of viral replication and migration to the conducting airways, triggering the innate immune response.
The pulmonary phase: Characterized by hypoxia and ground glass infiltrates on computed tomography of the chest. By now, the virus has reached the respiratory bronchioles and the alveoli. During this phase (about 8-10 days after exposure) the virus begins to die, and the host immune response ensues. By now the number of viral units is very small, but the host immune reaction against the virus has begun to mount.
The virus is actively replicating during the asymptomatic and at the beginning of the viral phase. The severity of symptoms varies according to the viral load and patient comorbidities [mild-moderate (81%), severe (14%), and critical (5%)]. The disease course is characterized by dysregulated immunity, profound inflammatory response, and dysregulated coagulation. By distinguishing these phases, clinicians can start interventions that would aim at the main cause of the derangement at each specific phase. For example, antiviral agents seem more appropriate in the early phases of the disease, while anti-inflammatory medications could target the inflammatory response that occurs in the pulmonary phase (Figure 1).
The tools in our toolbox: Timing is paramount
Remdesivir
The preliminary results from a recent trial that compared remdesivir with placebo, given 6-12 days from the onset of symptoms, revealed a shorter time to recovery with Remdesivir (Beigel JH, et al. N Engl J Med. 2020 Oct;8. NEJMoa2007764). The patients who received remdesivir within 10 days of the onset of symptoms had a shorter recovery time compared with those who received it after 10 days from the onset of symptoms. Moreover, remdesivir did not alter the disease course in patients who received the drug after the onset of hypoxia. These results are consistent with those of Wang and colleagues who reported no effect in time to clinical improvement in most patients who received the drug 10 days after the onset of symptoms (Wang Y, et al. Lancet. 2020 May;395[10236]:1569-78). In most antiviral trials, the agent was potentially given when the immune response had already begun, stage in which the number of viral units is not as large as in the earlier phases, possibly explaining the lack effect in time of clinical improvement or mortality.
Convalescent plasma
Piechotta and colleagues recently showed that convalescent plasma, when given to patients more than 14 days from the onset of symptoms, provided no benefit in time to clinical improvement or 28-day mortality. At 14 days or later, the pulmonary phase (characterized by systemic inflammation) had started in nearly all patients. As it seems apparent, any intervention not targeted to modulate the inflammatory response is unlikely to make a difference in this stage. (Piechotta V, et al. Cochrane Database Syst Rev. 2020 Jul;7[7]:CD013600).
The negative results of these studies (antivirals and convalescent plasma) highlight the importance of timing. In most of these trials, the intervention was started at the end of the viral phase or in the pulmonary phase, when the virus was nearly or completely dead, but the host immune response has begun to mount.
Corticosteroids
Corticosteroids (methylprednisolone and dexamethasone) have shown positive effects when given at the proper time (beginning of the pulmonary phase). A recent study revealed a lower 28-day mortality when compared with placebo in hospitalized patients with COVID-19. However, a prespecified subgroup analysis showed no benefit and a signal of possible harm among those who received dexamethasone in the absence of hypoxia (viral phase) (Lim WS, et al. N Engl J Med. 2020 Jul;[NEJMoa2021436]). A meta-analysis of seven randomized trials that used different doses and types of corticosteroids (dexamethasone, methylprednisolone, and hydrocortisone) reported a lower 28-day mortality in the corticosteroids group. The benefit was more pronounced when the corticosteroids was used in critically ill patients who were not receiving invasive mechanical ventilation.
Self-proning
Self-proning is also thought to be beneficial during the pulmonary phase. Prone positioning for at least 3 hours improved oxygenation but the result was not sustained (Coppo A, et al. Lancet Respir Med. 2020 Aug;8[8]:765-74). A retrospective analysis of 199 patients with COVID-19 in the pulmonary phase who were being supported by high-flow nasal cannula showed that awake proning for more than 16 hours had no effect in the risk of intubation or mortality (Ferrando C, et al. reduce the use of critical care resources, and improve survival. We aimed to examine whether the combination of high-flow nasal oxygen therapy (HFNOCrit Care. 2020 [Oct];24[1]:597). There is concern that this intervention might produce a delay in intubation in patients who have worsening oxygenation; this is especially important as delayed intubation can be associated with worse outcomes. Despite the conflicting data, awake self-proning is a reasonable intervention that should be considered provided that it does not interfere with treatments that have been proven beneficial. As prospective evidence becomes available, recommendations may possibly change.
What about thromboembolic events?
Data on arterial and venous thromboembolic events (VTE) in the disease course of COVID-19 are largely variable. The prevalence of VTE in COVID-19 seems to be higher than other in causes of sepsis especially in critically ill patients. (Bilaloglu S, et al. JAMA. 2020 Aug;324(8):799-801). Despite the use of pharmacological prophylaxis, VTE was seen in 13.6% of critically ill patients and 3.6% of medical ward patients and associated with a higher mortality. Therefore, more trials are needed to understand the most effective way to prevent VTE. At the current time, clinicians need to be vigilant to detect VTE as early as possible. Some options to consider include performing a daily evaluation of the possible risks (emphasizing prevention), routine bedside point of care ultrasound, early diagnostic imaging studies for clinically suspected VTE, early mobilization and delirium prevention. Prophylactic doses of LMWH or UH for all hospitalized patients with no or low risk of bleeding or non-hospitalized patient with high risk for VTE can be entertained (Bikdeli B, et al. J Am Coll Cardiol 2020 Apr;75[23]:2950-73). Therapeutic dose anticoagulation should be only used in confirmed VTE or in highly suspected VTE with difficulties to obtain standard confirmatory imaging. A therapeutic approach based solely on D-dimer should be avoided, because the evidence is insufficient and the risk of bleeding in critically ill patients is not insignificant.
The available evidence is helpful but not definitive making it difficult to have a clear pathway to effectively treat the systemic effects of COVID-19. One should consider remdesivir and convalescent plasma during the viral phase before hypoxia ensue. Anti-inflammatory interventions (dexamethasone or methylprednisolone) should be given as soon as the pulmonary manifestations start (hypoxia). The type, optimal dose, and duration of corticosteroids vary from trial to trial and no evidence suggests that higher doses are associated with more benefit. It is not only important to choose the right treatment but also the phase when such treatment is most likely to be effective!
Dr. Megri is a Pulmonary and Critical Care Fellow at the University of Kentucky. Dr. Coz is Associate Professor of Medicine, University of Kentucky.
What will be the future of American medicine?
For at least the last 6 months, and what seems like much longer, the United States has been in a period of great upheaval unseen for decades. Thanks in part to a novel coronavirus that quickly spread globally, along with social and racial tensions reaching a boiling point after nationwide economic uncertainty and the deaths of George Floyd and Breonna Taylor at the hands of law enforcement. In the year of a presidential election, leaders both elected and running are looking for solutions. Medicine has also been scrambling for answers as hospitals deal with ever growing censuses and dwindling resources, which have placed a strain on budgets, employees, and communities. Through these difficult times, there appears to be a resolve to investigate how we arrived here, where do we want to go, and what will take us there. As industries look to foster more inclusive and diverse environments, health care also looks to lead this philosophical shift toward a more equitable system. In the meantime, minorities, particularly African Americans, are dying at alarming rates.
With state government shutdowns, school closures, and a transition to work from home, Americans have been increasingly cognizant of issues that are more likely to be drowned out by the routine of previously “normal” life. As the staggering coronavirus infection numbers and deaths began to be published, undeniable trends were laid bare for the country to see. While the pandemic has been a deadly scare for the entire nation, the risk of serious complications or death for others was undeniable or even likely. For many Americans of underrepresented groups, but for Black people in general, 2020 has been another checkpoint in a long straight path, as centuries of systemic injustices and racist policies enacted through legislation, health policy have left these communities far behind and incredibly unprepared for this latest challenge.
For millions of Black Americans, although there is never acceptance of it, living with inequality has become a way of life. Much is known about the eventually desegregated lunch counters and public transportation but health care also facilitated disparities that have manifested themselves in the disparate outcomes we see today. Although Brown v Board of Education eliminated the legal precedent of segregated public spaces, enforcement was not immediately unanimous. In the paper The Politics of Racial Disparities, author David Smith describes the segregation in the state hospital in the state capital of Mississippi. Accounts detailed the dismay of white patients who traveled in the same elevators as Black patients, separate floors new and expectant Black mothers were admitted to, and even policies that discouraged Black and White children from utilizing play areas at the same time. All of these policies and the resistance to change were occurring in the 1960s as the larger national appetite toward overt discrimination began to sour. Although the deep south has historically held the reputation of outdated values, this was not solely a regional problem.
Nationwide, African Americans, as well as other minorities, are very aware of the health pitfalls that await them once leaving the hospital as newborns. According to CDC data, they are more likely than White non-Hispanic White adults to be diagnosed with diabetes and hypertension. Eighty percent of African American women are overweight or obese compared with 65% of non-Hispanic White women. These comorbidities have been especially telling this year as they account for a large proportion of comorbid conditions listed on deceased COVID-19 patients’ death certificates.
Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, and member of the White House coronavirus task force, is particularly concerned about these trends. He stated in a recent interview that the virus is, “shedding another bright light on a systemic problem that has been with us for a very long period of time.” While he does not explicitly state what the systemic problem is, you could assume it relates to racial injustice. He also goes on to say, “…social determinants of health put people of color in a position-because of employment, socioeconomic status, availability of jobs-that makes it more likely for them to be in contact with an infected person and not be able to separate themselves.”
When these statistics are quoted, discussions of personal responsibility are often discussed; however, these arguments do not stand up against the long documented, intentional exclusion of minorities, in particular Black people, from the health systems and economic opportunities the country has to offer. Lacking any significant economic power, these communities have no buffer against a pandemic, no option but to show up for work. Additionally, these jobs cannot be done in the comfort of one’s living room. Large cities, such as New York City, served as a harbinger to what could happen when masks and social distancing was ignored, as well as a tendency to blame overcrowding. More investigation unearths that the true culprit in major metropolitan areas is not the size but its effects on resident social habits. Dr. Mary Bassett explains in The New York Times, “The answer is simple: the high cost of housing.” Multigenerational households are more prevalent among minority communities, explaining the rapid spread through these epicenters.
The historical legacy of redlining and other laws that were exclusionary and hostile to racial equality have made systems much more difficult to change, even when the parties involved are willing to take a more active role in change. The question is will it be enough to have merely stopped these practices or will a more active role in reversal of policies and their intended effects be needed?
Medicine is grappling with its role in the larger context of how to provide better access and better care. The Affordable Care Act, signed into law by President Barack Obama in 2010, aimed to begin that journey. When the mandate for individual states to opt in was struck down in 2012, state legislators were able to decide whether to opt into a Medicaid agreement with the government, providing basic care to all citizens of their state. Twelve states currently have not opted into the Medicaid expansion, leaving a significant portion of their residents uninsured. Of those states, a majority have minority populations represented at levels greater than the national average.
Medicine should use this opportunity to position itself as an ally in the fight for equality. The American dream story has always been structured around innovation and discovery. The medical field shares in this delight when coincidence, discovery, and problem solving intersect. This country prides itself on its abilities to problem solve and has sold this branding to the rest of the world. America loves winning, our current President repeatedly says so. What greater win would equal care and elimination of racial disparities in chronic diseases. As our health leaders assemble solutions for a multifactorial problem, the public must become more engaged to assist in creating solutions, maintain dedication and focus on the goals, and continue to hold leaders and elected officials accountable.
Increased diversity in health-care spaces both on the ground and in leadership will help ensure less represented voices are heard. We must invest in our education system to broaden the representation of minority physicians who often do not represent their population’s share. Changes must also go beyond direct patient care and population health measures but must also address the social determinants of health, such as a livable wage, fair and affordable housing, and wealth inequality.
With federal support for biomedical research becoming more difficult, the path for the next big innovation becomes increasingly expensive and never guaranteed. We hope to create a safe and effective COVID-19 vaccine. The elimination of race as an indirect determinant of health is a worthwhile goal that, if achieved, would be near the top of the list of this country’s achievements. With 1.2 trillion spent on health care in 2019 (Brookings institute), we cannot afford not to.
Dr. Williams is Affiliate Professor, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Mississippi; and the G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi.
For at least the last 6 months, and what seems like much longer, the United States has been in a period of great upheaval unseen for decades. Thanks in part to a novel coronavirus that quickly spread globally, along with social and racial tensions reaching a boiling point after nationwide economic uncertainty and the deaths of George Floyd and Breonna Taylor at the hands of law enforcement. In the year of a presidential election, leaders both elected and running are looking for solutions. Medicine has also been scrambling for answers as hospitals deal with ever growing censuses and dwindling resources, which have placed a strain on budgets, employees, and communities. Through these difficult times, there appears to be a resolve to investigate how we arrived here, where do we want to go, and what will take us there. As industries look to foster more inclusive and diverse environments, health care also looks to lead this philosophical shift toward a more equitable system. In the meantime, minorities, particularly African Americans, are dying at alarming rates.
With state government shutdowns, school closures, and a transition to work from home, Americans have been increasingly cognizant of issues that are more likely to be drowned out by the routine of previously “normal” life. As the staggering coronavirus infection numbers and deaths began to be published, undeniable trends were laid bare for the country to see. While the pandemic has been a deadly scare for the entire nation, the risk of serious complications or death for others was undeniable or even likely. For many Americans of underrepresented groups, but for Black people in general, 2020 has been another checkpoint in a long straight path, as centuries of systemic injustices and racist policies enacted through legislation, health policy have left these communities far behind and incredibly unprepared for this latest challenge.
For millions of Black Americans, although there is never acceptance of it, living with inequality has become a way of life. Much is known about the eventually desegregated lunch counters and public transportation but health care also facilitated disparities that have manifested themselves in the disparate outcomes we see today. Although Brown v Board of Education eliminated the legal precedent of segregated public spaces, enforcement was not immediately unanimous. In the paper The Politics of Racial Disparities, author David Smith describes the segregation in the state hospital in the state capital of Mississippi. Accounts detailed the dismay of white patients who traveled in the same elevators as Black patients, separate floors new and expectant Black mothers were admitted to, and even policies that discouraged Black and White children from utilizing play areas at the same time. All of these policies and the resistance to change were occurring in the 1960s as the larger national appetite toward overt discrimination began to sour. Although the deep south has historically held the reputation of outdated values, this was not solely a regional problem.
Nationwide, African Americans, as well as other minorities, are very aware of the health pitfalls that await them once leaving the hospital as newborns. According to CDC data, they are more likely than White non-Hispanic White adults to be diagnosed with diabetes and hypertension. Eighty percent of African American women are overweight or obese compared with 65% of non-Hispanic White women. These comorbidities have been especially telling this year as they account for a large proportion of comorbid conditions listed on deceased COVID-19 patients’ death certificates.
Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, and member of the White House coronavirus task force, is particularly concerned about these trends. He stated in a recent interview that the virus is, “shedding another bright light on a systemic problem that has been with us for a very long period of time.” While he does not explicitly state what the systemic problem is, you could assume it relates to racial injustice. He also goes on to say, “…social determinants of health put people of color in a position-because of employment, socioeconomic status, availability of jobs-that makes it more likely for them to be in contact with an infected person and not be able to separate themselves.”
When these statistics are quoted, discussions of personal responsibility are often discussed; however, these arguments do not stand up against the long documented, intentional exclusion of minorities, in particular Black people, from the health systems and economic opportunities the country has to offer. Lacking any significant economic power, these communities have no buffer against a pandemic, no option but to show up for work. Additionally, these jobs cannot be done in the comfort of one’s living room. Large cities, such as New York City, served as a harbinger to what could happen when masks and social distancing was ignored, as well as a tendency to blame overcrowding. More investigation unearths that the true culprit in major metropolitan areas is not the size but its effects on resident social habits. Dr. Mary Bassett explains in The New York Times, “The answer is simple: the high cost of housing.” Multigenerational households are more prevalent among minority communities, explaining the rapid spread through these epicenters.
The historical legacy of redlining and other laws that were exclusionary and hostile to racial equality have made systems much more difficult to change, even when the parties involved are willing to take a more active role in change. The question is will it be enough to have merely stopped these practices or will a more active role in reversal of policies and their intended effects be needed?
Medicine is grappling with its role in the larger context of how to provide better access and better care. The Affordable Care Act, signed into law by President Barack Obama in 2010, aimed to begin that journey. When the mandate for individual states to opt in was struck down in 2012, state legislators were able to decide whether to opt into a Medicaid agreement with the government, providing basic care to all citizens of their state. Twelve states currently have not opted into the Medicaid expansion, leaving a significant portion of their residents uninsured. Of those states, a majority have minority populations represented at levels greater than the national average.
Medicine should use this opportunity to position itself as an ally in the fight for equality. The American dream story has always been structured around innovation and discovery. The medical field shares in this delight when coincidence, discovery, and problem solving intersect. This country prides itself on its abilities to problem solve and has sold this branding to the rest of the world. America loves winning, our current President repeatedly says so. What greater win would equal care and elimination of racial disparities in chronic diseases. As our health leaders assemble solutions for a multifactorial problem, the public must become more engaged to assist in creating solutions, maintain dedication and focus on the goals, and continue to hold leaders and elected officials accountable.
Increased diversity in health-care spaces both on the ground and in leadership will help ensure less represented voices are heard. We must invest in our education system to broaden the representation of minority physicians who often do not represent their population’s share. Changes must also go beyond direct patient care and population health measures but must also address the social determinants of health, such as a livable wage, fair and affordable housing, and wealth inequality.
With federal support for biomedical research becoming more difficult, the path for the next big innovation becomes increasingly expensive and never guaranteed. We hope to create a safe and effective COVID-19 vaccine. The elimination of race as an indirect determinant of health is a worthwhile goal that, if achieved, would be near the top of the list of this country’s achievements. With 1.2 trillion spent on health care in 2019 (Brookings institute), we cannot afford not to.
Dr. Williams is Affiliate Professor, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Mississippi; and the G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi.
For at least the last 6 months, and what seems like much longer, the United States has been in a period of great upheaval unseen for decades. Thanks in part to a novel coronavirus that quickly spread globally, along with social and racial tensions reaching a boiling point after nationwide economic uncertainty and the deaths of George Floyd and Breonna Taylor at the hands of law enforcement. In the year of a presidential election, leaders both elected and running are looking for solutions. Medicine has also been scrambling for answers as hospitals deal with ever growing censuses and dwindling resources, which have placed a strain on budgets, employees, and communities. Through these difficult times, there appears to be a resolve to investigate how we arrived here, where do we want to go, and what will take us there. As industries look to foster more inclusive and diverse environments, health care also looks to lead this philosophical shift toward a more equitable system. In the meantime, minorities, particularly African Americans, are dying at alarming rates.
With state government shutdowns, school closures, and a transition to work from home, Americans have been increasingly cognizant of issues that are more likely to be drowned out by the routine of previously “normal” life. As the staggering coronavirus infection numbers and deaths began to be published, undeniable trends were laid bare for the country to see. While the pandemic has been a deadly scare for the entire nation, the risk of serious complications or death for others was undeniable or even likely. For many Americans of underrepresented groups, but for Black people in general, 2020 has been another checkpoint in a long straight path, as centuries of systemic injustices and racist policies enacted through legislation, health policy have left these communities far behind and incredibly unprepared for this latest challenge.
For millions of Black Americans, although there is never acceptance of it, living with inequality has become a way of life. Much is known about the eventually desegregated lunch counters and public transportation but health care also facilitated disparities that have manifested themselves in the disparate outcomes we see today. Although Brown v Board of Education eliminated the legal precedent of segregated public spaces, enforcement was not immediately unanimous. In the paper The Politics of Racial Disparities, author David Smith describes the segregation in the state hospital in the state capital of Mississippi. Accounts detailed the dismay of white patients who traveled in the same elevators as Black patients, separate floors new and expectant Black mothers were admitted to, and even policies that discouraged Black and White children from utilizing play areas at the same time. All of these policies and the resistance to change were occurring in the 1960s as the larger national appetite toward overt discrimination began to sour. Although the deep south has historically held the reputation of outdated values, this was not solely a regional problem.
Nationwide, African Americans, as well as other minorities, are very aware of the health pitfalls that await them once leaving the hospital as newborns. According to CDC data, they are more likely than White non-Hispanic White adults to be diagnosed with diabetes and hypertension. Eighty percent of African American women are overweight or obese compared with 65% of non-Hispanic White women. These comorbidities have been especially telling this year as they account for a large proportion of comorbid conditions listed on deceased COVID-19 patients’ death certificates.
Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, and member of the White House coronavirus task force, is particularly concerned about these trends. He stated in a recent interview that the virus is, “shedding another bright light on a systemic problem that has been with us for a very long period of time.” While he does not explicitly state what the systemic problem is, you could assume it relates to racial injustice. He also goes on to say, “…social determinants of health put people of color in a position-because of employment, socioeconomic status, availability of jobs-that makes it more likely for them to be in contact with an infected person and not be able to separate themselves.”
When these statistics are quoted, discussions of personal responsibility are often discussed; however, these arguments do not stand up against the long documented, intentional exclusion of minorities, in particular Black people, from the health systems and economic opportunities the country has to offer. Lacking any significant economic power, these communities have no buffer against a pandemic, no option but to show up for work. Additionally, these jobs cannot be done in the comfort of one’s living room. Large cities, such as New York City, served as a harbinger to what could happen when masks and social distancing was ignored, as well as a tendency to blame overcrowding. More investigation unearths that the true culprit in major metropolitan areas is not the size but its effects on resident social habits. Dr. Mary Bassett explains in The New York Times, “The answer is simple: the high cost of housing.” Multigenerational households are more prevalent among minority communities, explaining the rapid spread through these epicenters.
The historical legacy of redlining and other laws that were exclusionary and hostile to racial equality have made systems much more difficult to change, even when the parties involved are willing to take a more active role in change. The question is will it be enough to have merely stopped these practices or will a more active role in reversal of policies and their intended effects be needed?
Medicine is grappling with its role in the larger context of how to provide better access and better care. The Affordable Care Act, signed into law by President Barack Obama in 2010, aimed to begin that journey. When the mandate for individual states to opt in was struck down in 2012, state legislators were able to decide whether to opt into a Medicaid agreement with the government, providing basic care to all citizens of their state. Twelve states currently have not opted into the Medicaid expansion, leaving a significant portion of their residents uninsured. Of those states, a majority have minority populations represented at levels greater than the national average.
Medicine should use this opportunity to position itself as an ally in the fight for equality. The American dream story has always been structured around innovation and discovery. The medical field shares in this delight when coincidence, discovery, and problem solving intersect. This country prides itself on its abilities to problem solve and has sold this branding to the rest of the world. America loves winning, our current President repeatedly says so. What greater win would equal care and elimination of racial disparities in chronic diseases. As our health leaders assemble solutions for a multifactorial problem, the public must become more engaged to assist in creating solutions, maintain dedication and focus on the goals, and continue to hold leaders and elected officials accountable.
Increased diversity in health-care spaces both on the ground and in leadership will help ensure less represented voices are heard. We must invest in our education system to broaden the representation of minority physicians who often do not represent their population’s share. Changes must also go beyond direct patient care and population health measures but must also address the social determinants of health, such as a livable wage, fair and affordable housing, and wealth inequality.
With federal support for biomedical research becoming more difficult, the path for the next big innovation becomes increasingly expensive and never guaranteed. We hope to create a safe and effective COVID-19 vaccine. The elimination of race as an indirect determinant of health is a worthwhile goal that, if achieved, would be near the top of the list of this country’s achievements. With 1.2 trillion spent on health care in 2019 (Brookings institute), we cannot afford not to.
Dr. Williams is Affiliate Professor, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Mississippi; and the G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi.
Management of EVALI in the ICU
Since 2019, more than 2,700 individuals have been hospitalized with electronic cigarette- (e-cigarette), or vaping-associated lung injury (EVALI). This entity first reached clinical attention after a series of otherwise healthy young adults presented with dyspnea, severe hypoxia, and diffuse pulmonary infiltrates in the Midwest (Layden J, et al. N Engl J Med. 2020;382[10]:903). Investigation of these cases revealed an association with the use of e-cigarettes, or vaping. As cases continued to mount, the link between vaping and acute lung injury became increasingly apparent.
How it presents
EVALI can present in variable ways, ranging from mild cough or dyspnea without hypoxia to severe acute respiratory distress syndrome (ARDS), requiring advanced life support. Although challenging in the ICU setting, obtaining a detailed history of vaping is crucial to make the diagnosis. Collateral history can be helpful, but if unrevealing, it should not be considered sufficient to exclude vaping as potential etiology, particularly in adolescent e-cigarette users, where parental awareness of substance use history may be limited. If a vaping history is obtained, it is important to assess the substance(s) vaped, how these substances were obtained, and methods of inhalation. While e-cigarettes are the most commonly recognized method of vaping, alternate methods such as “dabbing” and “dripping,” are increasingly popular among vape users, often utilizing modified e-liquid components that may not be reported by patients unless specifically queried.
About 82% of patients hospitalized with EVALI reported vaping tetrahydrocannabinol- (THC) containing fluid. This is important because, unlike nicotine based e-liquids that are primarily purchased over the counter, more than 70% of THC-containing e-liquids are reportedly obtained through informal sources, including illegal distributors. In contrast, only 14% of patients hospitalized with EVALI reported vaping of commercial nicotine products alone. Nicotine-based e-liquids can also be modified, and informal purchasing sources remain a concern, particularly among younger users.
The onset of respiratory symptoms in EVALI is often preceded by several days of a systemic prodrome, including low-grade fevers, myalgia, gastrointestinal complaints, and fatigue (MacMurdo M, et al. Chest. 2020;157[6]:e181). The diagnosis of EVALI is made clinically, and alternative etiologies of lung injury (eg, infections) should be excluded. As there is significant overlap between the presenting symptoms of EVALI and COVID-19 infection, patients should be tested for COVID-19 before a diagnosis of EVALI can be made.
Imaging patterns of EVALI include diffuse alveolar damage (the most common), comprising of diffuse ground-glass opacities, septal thickening, and heterogeneous consolidation (MacMurdo M, et al. Chest. 2020;157[6]:e181). Bilateral ground glass opacities suggestive of organizing pneumonia have also been described. Atypical patterns of nodularity suggestive of hypersensitivity pneumonitis are significantly less common. Given the variety of imaging patterns, EVALI should be considered as a differential diagnosis in all patients presenting with new bilateral pulmonary infiltrates and severe hypoxia.
Early evaluation of these patients revealed lipid-laden macrophages in the bronchoalveolar lavage (BAL) fluid of these patients, raising concern for exogenous lipid inhalation resulting in the development of lipoid pneumonia (Maddock SD, et al. N Engl J Med. 2019;381[15]:1488). Analysis of BAL fluid revealed the presence of vitamin E acetate, a diluent utilized to cut, or dilute, e-liquid (Blount BC, et al. MMWR. 2019;68[45]:1040). This supported the hypothesis that the outbreak of EVALI was being driven, at least in part, by contaminated or self-modified e-liquid. Evaluation of lung biopsies revealed different pathologic patterns of acute lung injury, including diffuse alveolar damage and organizing pneumonia. Importantly, while lipid-laden macrophages were detected, other characteristics of lipoid pneumonia were absent (Mukhopadhyay S, et al. Am J Clin Path. 2019;153[1]30).
How to manage EVALI
Approximately half of patients hospitalized with EVALI required ICU admission. However, there is likely a substantial portion of patients with mild disease who may not be represented in the current registry since they did not require hospitalization. The management is primarily supportive and, in patients who require mechanical ventilation, following lung-protective ventilator strategies is of paramount importance. Steroids have been used in some case series, particularly for patients presenting with more severe disease, but data on benefit, optimal dose, and duration are limited.
Vaping cessation is crucial and should be aggressively encouraged. Newer generations of e-cigarettes contain comparatively higher nicotine concentrations, and likely have high potential for nicotine addiction. Treatment for nicotine dependence, including pharmacologic therapy, needs to be considered in all patients following recovery from EVALI.
With supportive care and removal of ongoing exposure, recovery is anticipated in most patients. Long-term outcomes in patients who develop EVALI remain unclear. Although early fibrosis was present in some patients who had transbronchial biopsies, the long-term effects on pulmonary function that may be seen in patients with a history of EVALI are yet to be determined.
What about policy?
New regulations related to e-cigarette use have been proposed in response to the increasing prevalence of vaping and the EVALI outbreak. These regulations center primarily on limiting adolescent e-cigarette usage. Tobacco 21, federal legislation passed in 2019, makes it illegal to sell tobacco products to those under the age of 21. The FDA also issued an enforcement policy on unauthorized flavored e-cigarette products. However, this has been criticized for not being comprehensive enough. For example, tobacco and menthol flavors were not included in the ban. Furthermore, THC-containing e-liquid remains largely unregulated at the federal level, and state-level regulation varies significantly by marijuana legalization status.
Policy initiatives that restrict sales without also addressing drivers of e-cigarette use, such as nicotine dependence and aggressive marketing campaigns, are of particular concern and are likely to disproportionately impact younger users. Another unintended effect of e-cigarette sales restrictions may result in a new wave of illegal product distribution and e-liquid modification. Supporting this hypothesis was the finding that the risk of EVALI was higher in states without legalized recreational marijuana, suggesting that users who obtained e-liquid through these informal sources were at greater risk of exposure to contaminated product (Wing C, et al. JAMA Netw Open. 2020;3[4]:e202187). While the CDC is no longer actively tracking EVALI cases, they continue to be reported, and vape use remains common (Armatas C, et al. MMWR. 69[25]:801). As long as e-cigarettes remain in use, another EVALI outbreak remains possible.
It remains important for the intensivist to be familiar with the full spectrum of vaping methods, and to report suspected cases when they arise. While treatable, much remains unknown about the long-term effects on this patient population. Further research is needed to better understand the long-term outcomes in patients with EVALI, in addition to the treatment of nicotine dependence and substance use associated with vaping. Finally, comprehensive regulation to curb e-cigarette usage is needed, particularly among adolescents. However, legislation that is too narrow in scope runs the risk of channeling adolescent e-cigarette users to obtain product through informal sources, further increasing their risk for EVALI. As clinicians, we cannot afford to drop our guard!
Dr. Macmurdo and Dr. Choi are with Cleveland Clinic, Respiratory Institute, Cleveland, Ohio.
Since 2019, more than 2,700 individuals have been hospitalized with electronic cigarette- (e-cigarette), or vaping-associated lung injury (EVALI). This entity first reached clinical attention after a series of otherwise healthy young adults presented with dyspnea, severe hypoxia, and diffuse pulmonary infiltrates in the Midwest (Layden J, et al. N Engl J Med. 2020;382[10]:903). Investigation of these cases revealed an association with the use of e-cigarettes, or vaping. As cases continued to mount, the link between vaping and acute lung injury became increasingly apparent.
How it presents
EVALI can present in variable ways, ranging from mild cough or dyspnea without hypoxia to severe acute respiratory distress syndrome (ARDS), requiring advanced life support. Although challenging in the ICU setting, obtaining a detailed history of vaping is crucial to make the diagnosis. Collateral history can be helpful, but if unrevealing, it should not be considered sufficient to exclude vaping as potential etiology, particularly in adolescent e-cigarette users, where parental awareness of substance use history may be limited. If a vaping history is obtained, it is important to assess the substance(s) vaped, how these substances were obtained, and methods of inhalation. While e-cigarettes are the most commonly recognized method of vaping, alternate methods such as “dabbing” and “dripping,” are increasingly popular among vape users, often utilizing modified e-liquid components that may not be reported by patients unless specifically queried.
About 82% of patients hospitalized with EVALI reported vaping tetrahydrocannabinol- (THC) containing fluid. This is important because, unlike nicotine based e-liquids that are primarily purchased over the counter, more than 70% of THC-containing e-liquids are reportedly obtained through informal sources, including illegal distributors. In contrast, only 14% of patients hospitalized with EVALI reported vaping of commercial nicotine products alone. Nicotine-based e-liquids can also be modified, and informal purchasing sources remain a concern, particularly among younger users.
The onset of respiratory symptoms in EVALI is often preceded by several days of a systemic prodrome, including low-grade fevers, myalgia, gastrointestinal complaints, and fatigue (MacMurdo M, et al. Chest. 2020;157[6]:e181). The diagnosis of EVALI is made clinically, and alternative etiologies of lung injury (eg, infections) should be excluded. As there is significant overlap between the presenting symptoms of EVALI and COVID-19 infection, patients should be tested for COVID-19 before a diagnosis of EVALI can be made.
Imaging patterns of EVALI include diffuse alveolar damage (the most common), comprising of diffuse ground-glass opacities, septal thickening, and heterogeneous consolidation (MacMurdo M, et al. Chest. 2020;157[6]:e181). Bilateral ground glass opacities suggestive of organizing pneumonia have also been described. Atypical patterns of nodularity suggestive of hypersensitivity pneumonitis are significantly less common. Given the variety of imaging patterns, EVALI should be considered as a differential diagnosis in all patients presenting with new bilateral pulmonary infiltrates and severe hypoxia.
Early evaluation of these patients revealed lipid-laden macrophages in the bronchoalveolar lavage (BAL) fluid of these patients, raising concern for exogenous lipid inhalation resulting in the development of lipoid pneumonia (Maddock SD, et al. N Engl J Med. 2019;381[15]:1488). Analysis of BAL fluid revealed the presence of vitamin E acetate, a diluent utilized to cut, or dilute, e-liquid (Blount BC, et al. MMWR. 2019;68[45]:1040). This supported the hypothesis that the outbreak of EVALI was being driven, at least in part, by contaminated or self-modified e-liquid. Evaluation of lung biopsies revealed different pathologic patterns of acute lung injury, including diffuse alveolar damage and organizing pneumonia. Importantly, while lipid-laden macrophages were detected, other characteristics of lipoid pneumonia were absent (Mukhopadhyay S, et al. Am J Clin Path. 2019;153[1]30).
How to manage EVALI
Approximately half of patients hospitalized with EVALI required ICU admission. However, there is likely a substantial portion of patients with mild disease who may not be represented in the current registry since they did not require hospitalization. The management is primarily supportive and, in patients who require mechanical ventilation, following lung-protective ventilator strategies is of paramount importance. Steroids have been used in some case series, particularly for patients presenting with more severe disease, but data on benefit, optimal dose, and duration are limited.
Vaping cessation is crucial and should be aggressively encouraged. Newer generations of e-cigarettes contain comparatively higher nicotine concentrations, and likely have high potential for nicotine addiction. Treatment for nicotine dependence, including pharmacologic therapy, needs to be considered in all patients following recovery from EVALI.
With supportive care and removal of ongoing exposure, recovery is anticipated in most patients. Long-term outcomes in patients who develop EVALI remain unclear. Although early fibrosis was present in some patients who had transbronchial biopsies, the long-term effects on pulmonary function that may be seen in patients with a history of EVALI are yet to be determined.
What about policy?
New regulations related to e-cigarette use have been proposed in response to the increasing prevalence of vaping and the EVALI outbreak. These regulations center primarily on limiting adolescent e-cigarette usage. Tobacco 21, federal legislation passed in 2019, makes it illegal to sell tobacco products to those under the age of 21. The FDA also issued an enforcement policy on unauthorized flavored e-cigarette products. However, this has been criticized for not being comprehensive enough. For example, tobacco and menthol flavors were not included in the ban. Furthermore, THC-containing e-liquid remains largely unregulated at the federal level, and state-level regulation varies significantly by marijuana legalization status.
Policy initiatives that restrict sales without also addressing drivers of e-cigarette use, such as nicotine dependence and aggressive marketing campaigns, are of particular concern and are likely to disproportionately impact younger users. Another unintended effect of e-cigarette sales restrictions may result in a new wave of illegal product distribution and e-liquid modification. Supporting this hypothesis was the finding that the risk of EVALI was higher in states without legalized recreational marijuana, suggesting that users who obtained e-liquid through these informal sources were at greater risk of exposure to contaminated product (Wing C, et al. JAMA Netw Open. 2020;3[4]:e202187). While the CDC is no longer actively tracking EVALI cases, they continue to be reported, and vape use remains common (Armatas C, et al. MMWR. 69[25]:801). As long as e-cigarettes remain in use, another EVALI outbreak remains possible.
It remains important for the intensivist to be familiar with the full spectrum of vaping methods, and to report suspected cases when they arise. While treatable, much remains unknown about the long-term effects on this patient population. Further research is needed to better understand the long-term outcomes in patients with EVALI, in addition to the treatment of nicotine dependence and substance use associated with vaping. Finally, comprehensive regulation to curb e-cigarette usage is needed, particularly among adolescents. However, legislation that is too narrow in scope runs the risk of channeling adolescent e-cigarette users to obtain product through informal sources, further increasing their risk for EVALI. As clinicians, we cannot afford to drop our guard!
Dr. Macmurdo and Dr. Choi are with Cleveland Clinic, Respiratory Institute, Cleveland, Ohio.
Since 2019, more than 2,700 individuals have been hospitalized with electronic cigarette- (e-cigarette), or vaping-associated lung injury (EVALI). This entity first reached clinical attention after a series of otherwise healthy young adults presented with dyspnea, severe hypoxia, and diffuse pulmonary infiltrates in the Midwest (Layden J, et al. N Engl J Med. 2020;382[10]:903). Investigation of these cases revealed an association with the use of e-cigarettes, or vaping. As cases continued to mount, the link between vaping and acute lung injury became increasingly apparent.
How it presents
EVALI can present in variable ways, ranging from mild cough or dyspnea without hypoxia to severe acute respiratory distress syndrome (ARDS), requiring advanced life support. Although challenging in the ICU setting, obtaining a detailed history of vaping is crucial to make the diagnosis. Collateral history can be helpful, but if unrevealing, it should not be considered sufficient to exclude vaping as potential etiology, particularly in adolescent e-cigarette users, where parental awareness of substance use history may be limited. If a vaping history is obtained, it is important to assess the substance(s) vaped, how these substances were obtained, and methods of inhalation. While e-cigarettes are the most commonly recognized method of vaping, alternate methods such as “dabbing” and “dripping,” are increasingly popular among vape users, often utilizing modified e-liquid components that may not be reported by patients unless specifically queried.
About 82% of patients hospitalized with EVALI reported vaping tetrahydrocannabinol- (THC) containing fluid. This is important because, unlike nicotine based e-liquids that are primarily purchased over the counter, more than 70% of THC-containing e-liquids are reportedly obtained through informal sources, including illegal distributors. In contrast, only 14% of patients hospitalized with EVALI reported vaping of commercial nicotine products alone. Nicotine-based e-liquids can also be modified, and informal purchasing sources remain a concern, particularly among younger users.
The onset of respiratory symptoms in EVALI is often preceded by several days of a systemic prodrome, including low-grade fevers, myalgia, gastrointestinal complaints, and fatigue (MacMurdo M, et al. Chest. 2020;157[6]:e181). The diagnosis of EVALI is made clinically, and alternative etiologies of lung injury (eg, infections) should be excluded. As there is significant overlap between the presenting symptoms of EVALI and COVID-19 infection, patients should be tested for COVID-19 before a diagnosis of EVALI can be made.
Imaging patterns of EVALI include diffuse alveolar damage (the most common), comprising of diffuse ground-glass opacities, septal thickening, and heterogeneous consolidation (MacMurdo M, et al. Chest. 2020;157[6]:e181). Bilateral ground glass opacities suggestive of organizing pneumonia have also been described. Atypical patterns of nodularity suggestive of hypersensitivity pneumonitis are significantly less common. Given the variety of imaging patterns, EVALI should be considered as a differential diagnosis in all patients presenting with new bilateral pulmonary infiltrates and severe hypoxia.
Early evaluation of these patients revealed lipid-laden macrophages in the bronchoalveolar lavage (BAL) fluid of these patients, raising concern for exogenous lipid inhalation resulting in the development of lipoid pneumonia (Maddock SD, et al. N Engl J Med. 2019;381[15]:1488). Analysis of BAL fluid revealed the presence of vitamin E acetate, a diluent utilized to cut, or dilute, e-liquid (Blount BC, et al. MMWR. 2019;68[45]:1040). This supported the hypothesis that the outbreak of EVALI was being driven, at least in part, by contaminated or self-modified e-liquid. Evaluation of lung biopsies revealed different pathologic patterns of acute lung injury, including diffuse alveolar damage and organizing pneumonia. Importantly, while lipid-laden macrophages were detected, other characteristics of lipoid pneumonia were absent (Mukhopadhyay S, et al. Am J Clin Path. 2019;153[1]30).
How to manage EVALI
Approximately half of patients hospitalized with EVALI required ICU admission. However, there is likely a substantial portion of patients with mild disease who may not be represented in the current registry since they did not require hospitalization. The management is primarily supportive and, in patients who require mechanical ventilation, following lung-protective ventilator strategies is of paramount importance. Steroids have been used in some case series, particularly for patients presenting with more severe disease, but data on benefit, optimal dose, and duration are limited.
Vaping cessation is crucial and should be aggressively encouraged. Newer generations of e-cigarettes contain comparatively higher nicotine concentrations, and likely have high potential for nicotine addiction. Treatment for nicotine dependence, including pharmacologic therapy, needs to be considered in all patients following recovery from EVALI.
With supportive care and removal of ongoing exposure, recovery is anticipated in most patients. Long-term outcomes in patients who develop EVALI remain unclear. Although early fibrosis was present in some patients who had transbronchial biopsies, the long-term effects on pulmonary function that may be seen in patients with a history of EVALI are yet to be determined.
What about policy?
New regulations related to e-cigarette use have been proposed in response to the increasing prevalence of vaping and the EVALI outbreak. These regulations center primarily on limiting adolescent e-cigarette usage. Tobacco 21, federal legislation passed in 2019, makes it illegal to sell tobacco products to those under the age of 21. The FDA also issued an enforcement policy on unauthorized flavored e-cigarette products. However, this has been criticized for not being comprehensive enough. For example, tobacco and menthol flavors were not included in the ban. Furthermore, THC-containing e-liquid remains largely unregulated at the federal level, and state-level regulation varies significantly by marijuana legalization status.
Policy initiatives that restrict sales without also addressing drivers of e-cigarette use, such as nicotine dependence and aggressive marketing campaigns, are of particular concern and are likely to disproportionately impact younger users. Another unintended effect of e-cigarette sales restrictions may result in a new wave of illegal product distribution and e-liquid modification. Supporting this hypothesis was the finding that the risk of EVALI was higher in states without legalized recreational marijuana, suggesting that users who obtained e-liquid through these informal sources were at greater risk of exposure to contaminated product (Wing C, et al. JAMA Netw Open. 2020;3[4]:e202187). While the CDC is no longer actively tracking EVALI cases, they continue to be reported, and vape use remains common (Armatas C, et al. MMWR. 69[25]:801). As long as e-cigarettes remain in use, another EVALI outbreak remains possible.
It remains important for the intensivist to be familiar with the full spectrum of vaping methods, and to report suspected cases when they arise. While treatable, much remains unknown about the long-term effects on this patient population. Further research is needed to better understand the long-term outcomes in patients with EVALI, in addition to the treatment of nicotine dependence and substance use associated with vaping. Finally, comprehensive regulation to curb e-cigarette usage is needed, particularly among adolescents. However, legislation that is too narrow in scope runs the risk of channeling adolescent e-cigarette users to obtain product through informal sources, further increasing their risk for EVALI. As clinicians, we cannot afford to drop our guard!
Dr. Macmurdo and Dr. Choi are with Cleveland Clinic, Respiratory Institute, Cleveland, Ohio.
COVID-19: Just a virus, right?
My first exposure to the notion of scarce resources was in medical school. I had to discuss the ethical principles behind the allocation of organs for transplantation, specifically livers and the required abstinence from alcohol ... but this was just an exercise, right?
A few years later, during residency, I heard the anecdotes from one of my internal medicine attendings about the time he spent in Europe as a visiting geriatrics fellow in the 1970s. The health-care districts in the region would be allotted an annual budget, and it was up to those districts how to best allocate those resources to meet, to the best of their abilities, the health-care needs of their population. He vividly recalled that a patient he cared for, an individual over 65 in need of renal replacement therapy for a reversible condition, who was not offered such therapy despite the clear benefit. There was a finite amount of resources, and those resources were thought to be better spent on public health measures like vaccination ... but that was on another continent and in another era, right?
I remember when I first heard of an outbreak of viral pneumonia in China in January of this year. As someone prone to anxiety, my first strategy was to put my head in the sand and wait it out. This strategy didn’t last very long – within a couple of weeks, there were confirmed cases in the United States. It was now apparent that this virus was not going to be contained. In an impressively short amount of time, SARS-CoV 2 has infected over 3.5 million individuals and killed almost a quarter million people worldwide. In the United States, we have seen almost 1.2 million cases and lost over 68 thousand lives. This pandemic has managed to devastate multiple countries, health care systems, and economies. It has also challenged every physician’s ideas of beneficence and justice ... but it’s just a virus, right?
Beneficence, the principle of medical ethics regarding acting in the patient’s best interest, had always seemed to me to be a no-brainer. Not like autonomy, which can get sticky, or justice, which I really had not had to consider much prior to 2020. Of course, I would always do what was best for my patient, I thought, why wouldn’t I?
Justice, the principle that deals with the distribution of scarce health-care resources, is the wrench that has been thrown into the beneficence works in the age of COVID-19. In a country and an era in which I had not dreamed we would ever have to think about how to support multiple people with one ventilator, we have had to do just that (“Joint Statement on Multiple Patients per Ventilator,” CHEST News, Mar 27, 2020). Things that I have taken for granted through all of my training are now worth their weight in gold—from sedative drips and inhalers down to videolaryngoscopy blades and face masks. I can’t just do what is best for my patient because sometimes what is best for my patient is not what is best for my next patient, what is best for my team, or even what is best for me and for my family. COVID-19 has reminded us of the uncomfortable truth that when contemplating justice, the patient in front of us is not the only person we have to consider.
Early on, before things in the United States had surged, I asked the twitter community what I thought would be a hypothetical question: “An employee needs to urgently help a COVID-19 patient. There is no appropriate PPE available due to shortage. What should happen?”
Like the idea of splitting ventilators, it was a thought I had never considered pre-COVID-19. Our instinct as physicians, especially as critical care physicians, is to intervene in emergency situations as quickly as possible. The extensive PPE required to manage COVID-19 patients has slowed that process, but, as many institutions are reaching the ends of their PPE stores, our safety is now placed at odds with that of our patient’s. To stay back violates what we feel is our duty to our patients, to go in violates our duty to ourselves, to our families, and to the rest of our patients. To care adequately for your patient is to put yourself at risk (and vice-versa), and this is a problem that I don’t think we have an answer for.
COVID-19 threatens many good and noble things, and what is worse, it directly puts them at odds with one another. They are paired sliding scales, where more of one means less of the other. If I have enough masks, it means my colleague probably doesn’t. If we have enough ventilators, it means another city doesn’t. If I get a break to be with my family, it means someone else is having to leave theirs to tend to patients who are sicker, lonelier, and more numerous than in any other time in recent memory.
And if these situations and resource limitations don’t provide enough moral injury for health-care workers, there are some specifics of humanity’s response to the pandemic that are exceptionally hurtful.
We as a country had notice, which was squandered. Instead of caution and preparation, we saw the powers that be make light of the serious situation most scientists and clinicians warned was coming. Instead of efforts to find or create PPE, we saw accusations against us of misuse and waste (“Trump comments about hospital mask thefts spark backlash from doctors,” Newsweek, March 30, 2020). Instead of support, we saw our altruism taken advantage of and used against us in unsafe and unfair situations. We have seen physicians in training and full-fledged attendings alike treated unfairly by their supervisors, instead of protected. Every instance of anti-science opinion or action from our friends and families that we once tolerated now feels like a personal affront, as these directly increase our risk and our immediate family’s risk of contracting the illness. We are being touted as heroes and angels, but really, we’re afraid—afraid of our patients, afraid of illness, afraid for our families, and afraid of jobs that we used to love. We don’t want to be praised; we just want to work our regular jobs safely and with adequate support.
I don’t know what health care looks like at the end of all of this. Relationships between physicians and health-care administrations were strained before the pandemic, to say the least. How can health-care workers just go back to business as usual, working for entities that were so ill-prepared, and, in many cases, calloused toward the concerns of their employees?
COVID-19 has revealed the fragility of our health-care system, our public health capabilities, and our economy. The pandemic has forced us to finally acknowledge something that has been true all along—our resources are finite, and tension exists between what is right and what is profitable, and between what is just and what is easy.
But it’s just a virus, right?
Dr. Fridenmaker is a Pulmonary and Critical Care Fellow at the University of Kentucky, Lexington.
My first exposure to the notion of scarce resources was in medical school. I had to discuss the ethical principles behind the allocation of organs for transplantation, specifically livers and the required abstinence from alcohol ... but this was just an exercise, right?
A few years later, during residency, I heard the anecdotes from one of my internal medicine attendings about the time he spent in Europe as a visiting geriatrics fellow in the 1970s. The health-care districts in the region would be allotted an annual budget, and it was up to those districts how to best allocate those resources to meet, to the best of their abilities, the health-care needs of their population. He vividly recalled that a patient he cared for, an individual over 65 in need of renal replacement therapy for a reversible condition, who was not offered such therapy despite the clear benefit. There was a finite amount of resources, and those resources were thought to be better spent on public health measures like vaccination ... but that was on another continent and in another era, right?
I remember when I first heard of an outbreak of viral pneumonia in China in January of this year. As someone prone to anxiety, my first strategy was to put my head in the sand and wait it out. This strategy didn’t last very long – within a couple of weeks, there were confirmed cases in the United States. It was now apparent that this virus was not going to be contained. In an impressively short amount of time, SARS-CoV 2 has infected over 3.5 million individuals and killed almost a quarter million people worldwide. In the United States, we have seen almost 1.2 million cases and lost over 68 thousand lives. This pandemic has managed to devastate multiple countries, health care systems, and economies. It has also challenged every physician’s ideas of beneficence and justice ... but it’s just a virus, right?
Beneficence, the principle of medical ethics regarding acting in the patient’s best interest, had always seemed to me to be a no-brainer. Not like autonomy, which can get sticky, or justice, which I really had not had to consider much prior to 2020. Of course, I would always do what was best for my patient, I thought, why wouldn’t I?
Justice, the principle that deals with the distribution of scarce health-care resources, is the wrench that has been thrown into the beneficence works in the age of COVID-19. In a country and an era in which I had not dreamed we would ever have to think about how to support multiple people with one ventilator, we have had to do just that (“Joint Statement on Multiple Patients per Ventilator,” CHEST News, Mar 27, 2020). Things that I have taken for granted through all of my training are now worth their weight in gold—from sedative drips and inhalers down to videolaryngoscopy blades and face masks. I can’t just do what is best for my patient because sometimes what is best for my patient is not what is best for my next patient, what is best for my team, or even what is best for me and for my family. COVID-19 has reminded us of the uncomfortable truth that when contemplating justice, the patient in front of us is not the only person we have to consider.
Early on, before things in the United States had surged, I asked the twitter community what I thought would be a hypothetical question: “An employee needs to urgently help a COVID-19 patient. There is no appropriate PPE available due to shortage. What should happen?”
Like the idea of splitting ventilators, it was a thought I had never considered pre-COVID-19. Our instinct as physicians, especially as critical care physicians, is to intervene in emergency situations as quickly as possible. The extensive PPE required to manage COVID-19 patients has slowed that process, but, as many institutions are reaching the ends of their PPE stores, our safety is now placed at odds with that of our patient’s. To stay back violates what we feel is our duty to our patients, to go in violates our duty to ourselves, to our families, and to the rest of our patients. To care adequately for your patient is to put yourself at risk (and vice-versa), and this is a problem that I don’t think we have an answer for.
COVID-19 threatens many good and noble things, and what is worse, it directly puts them at odds with one another. They are paired sliding scales, where more of one means less of the other. If I have enough masks, it means my colleague probably doesn’t. If we have enough ventilators, it means another city doesn’t. If I get a break to be with my family, it means someone else is having to leave theirs to tend to patients who are sicker, lonelier, and more numerous than in any other time in recent memory.
And if these situations and resource limitations don’t provide enough moral injury for health-care workers, there are some specifics of humanity’s response to the pandemic that are exceptionally hurtful.
We as a country had notice, which was squandered. Instead of caution and preparation, we saw the powers that be make light of the serious situation most scientists and clinicians warned was coming. Instead of efforts to find or create PPE, we saw accusations against us of misuse and waste (“Trump comments about hospital mask thefts spark backlash from doctors,” Newsweek, March 30, 2020). Instead of support, we saw our altruism taken advantage of and used against us in unsafe and unfair situations. We have seen physicians in training and full-fledged attendings alike treated unfairly by their supervisors, instead of protected. Every instance of anti-science opinion or action from our friends and families that we once tolerated now feels like a personal affront, as these directly increase our risk and our immediate family’s risk of contracting the illness. We are being touted as heroes and angels, but really, we’re afraid—afraid of our patients, afraid of illness, afraid for our families, and afraid of jobs that we used to love. We don’t want to be praised; we just want to work our regular jobs safely and with adequate support.
I don’t know what health care looks like at the end of all of this. Relationships between physicians and health-care administrations were strained before the pandemic, to say the least. How can health-care workers just go back to business as usual, working for entities that were so ill-prepared, and, in many cases, calloused toward the concerns of their employees?
COVID-19 has revealed the fragility of our health-care system, our public health capabilities, and our economy. The pandemic has forced us to finally acknowledge something that has been true all along—our resources are finite, and tension exists between what is right and what is profitable, and between what is just and what is easy.
But it’s just a virus, right?
Dr. Fridenmaker is a Pulmonary and Critical Care Fellow at the University of Kentucky, Lexington.
My first exposure to the notion of scarce resources was in medical school. I had to discuss the ethical principles behind the allocation of organs for transplantation, specifically livers and the required abstinence from alcohol ... but this was just an exercise, right?
A few years later, during residency, I heard the anecdotes from one of my internal medicine attendings about the time he spent in Europe as a visiting geriatrics fellow in the 1970s. The health-care districts in the region would be allotted an annual budget, and it was up to those districts how to best allocate those resources to meet, to the best of their abilities, the health-care needs of their population. He vividly recalled that a patient he cared for, an individual over 65 in need of renal replacement therapy for a reversible condition, who was not offered such therapy despite the clear benefit. There was a finite amount of resources, and those resources were thought to be better spent on public health measures like vaccination ... but that was on another continent and in another era, right?
I remember when I first heard of an outbreak of viral pneumonia in China in January of this year. As someone prone to anxiety, my first strategy was to put my head in the sand and wait it out. This strategy didn’t last very long – within a couple of weeks, there were confirmed cases in the United States. It was now apparent that this virus was not going to be contained. In an impressively short amount of time, SARS-CoV 2 has infected over 3.5 million individuals and killed almost a quarter million people worldwide. In the United States, we have seen almost 1.2 million cases and lost over 68 thousand lives. This pandemic has managed to devastate multiple countries, health care systems, and economies. It has also challenged every physician’s ideas of beneficence and justice ... but it’s just a virus, right?
Beneficence, the principle of medical ethics regarding acting in the patient’s best interest, had always seemed to me to be a no-brainer. Not like autonomy, which can get sticky, or justice, which I really had not had to consider much prior to 2020. Of course, I would always do what was best for my patient, I thought, why wouldn’t I?
Justice, the principle that deals with the distribution of scarce health-care resources, is the wrench that has been thrown into the beneficence works in the age of COVID-19. In a country and an era in which I had not dreamed we would ever have to think about how to support multiple people with one ventilator, we have had to do just that (“Joint Statement on Multiple Patients per Ventilator,” CHEST News, Mar 27, 2020). Things that I have taken for granted through all of my training are now worth their weight in gold—from sedative drips and inhalers down to videolaryngoscopy blades and face masks. I can’t just do what is best for my patient because sometimes what is best for my patient is not what is best for my next patient, what is best for my team, or even what is best for me and for my family. COVID-19 has reminded us of the uncomfortable truth that when contemplating justice, the patient in front of us is not the only person we have to consider.
Early on, before things in the United States had surged, I asked the twitter community what I thought would be a hypothetical question: “An employee needs to urgently help a COVID-19 patient. There is no appropriate PPE available due to shortage. What should happen?”
Like the idea of splitting ventilators, it was a thought I had never considered pre-COVID-19. Our instinct as physicians, especially as critical care physicians, is to intervene in emergency situations as quickly as possible. The extensive PPE required to manage COVID-19 patients has slowed that process, but, as many institutions are reaching the ends of their PPE stores, our safety is now placed at odds with that of our patient’s. To stay back violates what we feel is our duty to our patients, to go in violates our duty to ourselves, to our families, and to the rest of our patients. To care adequately for your patient is to put yourself at risk (and vice-versa), and this is a problem that I don’t think we have an answer for.
COVID-19 threatens many good and noble things, and what is worse, it directly puts them at odds with one another. They are paired sliding scales, where more of one means less of the other. If I have enough masks, it means my colleague probably doesn’t. If we have enough ventilators, it means another city doesn’t. If I get a break to be with my family, it means someone else is having to leave theirs to tend to patients who are sicker, lonelier, and more numerous than in any other time in recent memory.
And if these situations and resource limitations don’t provide enough moral injury for health-care workers, there are some specifics of humanity’s response to the pandemic that are exceptionally hurtful.
We as a country had notice, which was squandered. Instead of caution and preparation, we saw the powers that be make light of the serious situation most scientists and clinicians warned was coming. Instead of efforts to find or create PPE, we saw accusations against us of misuse and waste (“Trump comments about hospital mask thefts spark backlash from doctors,” Newsweek, March 30, 2020). Instead of support, we saw our altruism taken advantage of and used against us in unsafe and unfair situations. We have seen physicians in training and full-fledged attendings alike treated unfairly by their supervisors, instead of protected. Every instance of anti-science opinion or action from our friends and families that we once tolerated now feels like a personal affront, as these directly increase our risk and our immediate family’s risk of contracting the illness. We are being touted as heroes and angels, but really, we’re afraid—afraid of our patients, afraid of illness, afraid for our families, and afraid of jobs that we used to love. We don’t want to be praised; we just want to work our regular jobs safely and with adequate support.
I don’t know what health care looks like at the end of all of this. Relationships between physicians and health-care administrations were strained before the pandemic, to say the least. How can health-care workers just go back to business as usual, working for entities that were so ill-prepared, and, in many cases, calloused toward the concerns of their employees?
COVID-19 has revealed the fragility of our health-care system, our public health capabilities, and our economy. The pandemic has forced us to finally acknowledge something that has been true all along—our resources are finite, and tension exists between what is right and what is profitable, and between what is just and what is easy.
But it’s just a virus, right?
Dr. Fridenmaker is a Pulmonary and Critical Care Fellow at the University of Kentucky, Lexington.
Consider COVID-19–associated multisystem hyperinflammatory syndrome
A 21-year-old young adult presented to the ED with a 1-week history of high fever, vomiting, diarrhea, and abdominal pain. His mother was SARS-CoV-2 positive by polymerase chain reaction approximately 3 weeks prior; his PCR was negative for SARS-CoV-2.
Following admission, he became hypotensive and tachycardic with evidence of myocarditis. His chest x-ray was normal and his O2 saturation was 100% on room air. His clinical presentation was initially suggestive of toxic shock syndrome without a rash, but despite aggressive fluid resuscitation and broad-spectrum antibiotics, he continued to clinically deteriorate with persistent high fever and increasing cardiac stress. Echocardiography revealed biventricular dysfunction. His laboratory abnormalities included rising inflammatory markers and troponin I and B-type natriuretic peptide (BNP). A repeat PCR for SARS-CoV-2 was negative on day 2 of illness. He was diagnosed as likely having macrophage-activation syndrome (MAS) despite the atypical features (myocarditis), and he received Anakinra with no apparent response. He also was given intravenous immunoglobulin (IVIg) for his myocarditis and subsequently high-dose steroids. He became afebrile, his blood pressure stabilized, his inflammatory markers declined, and over several days he returned to normal. His COVID-19 antibody test IgG was positive on day 4 of illness.
This case challenged us for several reasons. First, the PCR from his nasopharynx was negative on two occasions, which raises the issue of how sensitive and accurate these PCR tests are for SARS-CoV-2 or are patients with COVID-19–associated hyperinflammatory syndrome still PCR positive? Second, although we have seen many adult cases with a cytokine storm picture similar to this patient, nearly all of the prior cases had chest x-ray abnormalities and hypoxia. Third, the severity of the myocardial dysfunction and rising troponin and BNP also was unusual in our experience with COVID-19 infection. Lastly, the use of antibody detection to SARS-CoV-2 enabled us to confirm recent COIVD-19 disease and see his illness as part of the likely spectrum of clinical syndromes seen with this virus.
The Lancet reported eight children, aged 4-14 years, with a hyperinflammatory shock-like syndrome in early May.1 The cases had features similar to atypical Kawasaki disease, KD shock syndrome, and toxic shock syndrome. Each case had high fever for multiple days; diarrhea and abdominal pain was present in even children; elevated ferritin, C-reactive protein, d-dimer, increased troponins, and ventricular dysfunction also was present in seven. Most patients had no pulmonary involvement, and most tested negative for SARS-CoV-2 despite four of the eight having direct contact with a COVID-positive family member. All received IVIg and antibiotics; six received aspirin. Seven of the eight made a full recovery; one child died from a large cerebrovascular infarct.
Also in early May, the New York Times described a “mysterious” hyperinflammatory syndrome in children thought to be linked to COVID-19. A total of 76 suspected cases in children had been reported in New York state, three of whom died. The syndrome has been given the name pediatric multisystem inflammatory syndrome. The syndrome can resemble KD shock syndrome with rash; fever; conjunctivitis; hypotension; and redness in the lips, tongue and mucous membranes . It also can resemble toxic shock syndrome with abdominal pain, vomiting, and diarrhea. However, the degree of cardiac inflammation and dysfunction is substantial in many cases and usually beyond that seen in KD or toxic shock.
The syndrome is not limited to the United States. The Royal College of Pediatrics and Child Health has created a case definition:2
- A child presenting with persistent fever, inflammation (elevated C-reactive protein, neutrophilia, and lymphopenia) and evidence of single or multiorgan dysfunction (shock, cardiac, respiratory, renal, gastrointestinal, or neurologic) with additional features.
- Exclusion of any other microbial causes such as bacterial sepsis or staphylococcal or streptococcal shock syndromes, infections known to be associated with myocarditis (such as enterovirus).
- SARS-CoV-2 testing may or may not be positive.
As with our young adult, treatment is supportive, nonspecific, and aimed at quieting the inflammatory response. The current thinking is the syndrome is seen as antibody to SARS-CoV-2 appears and frequently the nasopharyngeal PCR is negative. It is hypothesized that the syndrome occurs in genetically predisposed hosts and potentially is a late-onset inflammatory process or potentially an antibody-triggered inflammatory process. The negative PCR from nasopharyngeal specimens reflects that the onset is later in the course of disease; whether fecal samples would be COVID positive is unknown. As with our case, antibody testing for IgG against SARS-CoV-2 is appropriate to confirm COVID-19 disease and may be positive as early as day 7.
The approach needs to be team oriented and include cardiology, rheumatology, infectious diseases, and intensive care specialists working collaboratively. Such cases should be considered COVID positive despite negative PCR tests, and full personal protective equipment should be used as we do not as yet know if live virus could be found in stool. We initiated treatment with Anakinra (an interleukin-1 type-1 receptor inhibitor) as part of our treatment protocol for MAS; we did not appreciate a response. He then received IVIg and high-dose steroids, and he recovered over several days with improved cardiac function and stable blood pressure.
What is the pathogenesis? Is SARS-CoV-2 causative or just an associated finding? Who are the at-risk children, adolescents, and adults? Is there a genetic predisposition? What therapies work best? The eight cases described in London all received IVIg, as did our case, and all but one improved and survived. In adults we have seen substantial inflammation with elevated C-reactive protein (often as high as 300), ferritin, lactate dehydrogenase, triglycerides, fibrinogen, and d-dimers, but nearly all have extensive pulmonary disease, hypoxia, and are SARS-CoV-2 positive by PCR. Influenza is also associated with a cytokine storm syndrome in adolescents and young adults.3 The mechanisms influenza virus uses to initiate a cytokine storm and strategies for immunomodulatory treatment may provide insights into COVID-19–associated multisystem hyperinflammatory syndrome.
Dr. Pelton is professor of pediatrics and epidemiology at Boston University and public health and senior attending physician in pediatric infectious diseases at Boston Medical Center. Dr. Camelo is a senior fellow in pediatric infectious diseases at Boston Medical Center. They have no relevant financial disclosures. Email them at [email protected].
References
1. Riphagen S et al. Lancet. 2020 May 6. doi: 10.1016/S0140-6736(20)31094-1.
2. Royal College of Paediatrics and Child Health Guidance: Paediatric multisystem inflammatory syndrome temporally associated with COVID-19.
3. Liu Q et al.Cell Mol Immunol. 2016 Jan;13(1):3-10.
A 21-year-old young adult presented to the ED with a 1-week history of high fever, vomiting, diarrhea, and abdominal pain. His mother was SARS-CoV-2 positive by polymerase chain reaction approximately 3 weeks prior; his PCR was negative for SARS-CoV-2.
Following admission, he became hypotensive and tachycardic with evidence of myocarditis. His chest x-ray was normal and his O2 saturation was 100% on room air. His clinical presentation was initially suggestive of toxic shock syndrome without a rash, but despite aggressive fluid resuscitation and broad-spectrum antibiotics, he continued to clinically deteriorate with persistent high fever and increasing cardiac stress. Echocardiography revealed biventricular dysfunction. His laboratory abnormalities included rising inflammatory markers and troponin I and B-type natriuretic peptide (BNP). A repeat PCR for SARS-CoV-2 was negative on day 2 of illness. He was diagnosed as likely having macrophage-activation syndrome (MAS) despite the atypical features (myocarditis), and he received Anakinra with no apparent response. He also was given intravenous immunoglobulin (IVIg) for his myocarditis and subsequently high-dose steroids. He became afebrile, his blood pressure stabilized, his inflammatory markers declined, and over several days he returned to normal. His COVID-19 antibody test IgG was positive on day 4 of illness.
This case challenged us for several reasons. First, the PCR from his nasopharynx was negative on two occasions, which raises the issue of how sensitive and accurate these PCR tests are for SARS-CoV-2 or are patients with COVID-19–associated hyperinflammatory syndrome still PCR positive? Second, although we have seen many adult cases with a cytokine storm picture similar to this patient, nearly all of the prior cases had chest x-ray abnormalities and hypoxia. Third, the severity of the myocardial dysfunction and rising troponin and BNP also was unusual in our experience with COVID-19 infection. Lastly, the use of antibody detection to SARS-CoV-2 enabled us to confirm recent COIVD-19 disease and see his illness as part of the likely spectrum of clinical syndromes seen with this virus.
The Lancet reported eight children, aged 4-14 years, with a hyperinflammatory shock-like syndrome in early May.1 The cases had features similar to atypical Kawasaki disease, KD shock syndrome, and toxic shock syndrome. Each case had high fever for multiple days; diarrhea and abdominal pain was present in even children; elevated ferritin, C-reactive protein, d-dimer, increased troponins, and ventricular dysfunction also was present in seven. Most patients had no pulmonary involvement, and most tested negative for SARS-CoV-2 despite four of the eight having direct contact with a COVID-positive family member. All received IVIg and antibiotics; six received aspirin. Seven of the eight made a full recovery; one child died from a large cerebrovascular infarct.
Also in early May, the New York Times described a “mysterious” hyperinflammatory syndrome in children thought to be linked to COVID-19. A total of 76 suspected cases in children had been reported in New York state, three of whom died. The syndrome has been given the name pediatric multisystem inflammatory syndrome. The syndrome can resemble KD shock syndrome with rash; fever; conjunctivitis; hypotension; and redness in the lips, tongue and mucous membranes . It also can resemble toxic shock syndrome with abdominal pain, vomiting, and diarrhea. However, the degree of cardiac inflammation and dysfunction is substantial in many cases and usually beyond that seen in KD or toxic shock.
The syndrome is not limited to the United States. The Royal College of Pediatrics and Child Health has created a case definition:2
- A child presenting with persistent fever, inflammation (elevated C-reactive protein, neutrophilia, and lymphopenia) and evidence of single or multiorgan dysfunction (shock, cardiac, respiratory, renal, gastrointestinal, or neurologic) with additional features.
- Exclusion of any other microbial causes such as bacterial sepsis or staphylococcal or streptococcal shock syndromes, infections known to be associated with myocarditis (such as enterovirus).
- SARS-CoV-2 testing may or may not be positive.
As with our young adult, treatment is supportive, nonspecific, and aimed at quieting the inflammatory response. The current thinking is the syndrome is seen as antibody to SARS-CoV-2 appears and frequently the nasopharyngeal PCR is negative. It is hypothesized that the syndrome occurs in genetically predisposed hosts and potentially is a late-onset inflammatory process or potentially an antibody-triggered inflammatory process. The negative PCR from nasopharyngeal specimens reflects that the onset is later in the course of disease; whether fecal samples would be COVID positive is unknown. As with our case, antibody testing for IgG against SARS-CoV-2 is appropriate to confirm COVID-19 disease and may be positive as early as day 7.
The approach needs to be team oriented and include cardiology, rheumatology, infectious diseases, and intensive care specialists working collaboratively. Such cases should be considered COVID positive despite negative PCR tests, and full personal protective equipment should be used as we do not as yet know if live virus could be found in stool. We initiated treatment with Anakinra (an interleukin-1 type-1 receptor inhibitor) as part of our treatment protocol for MAS; we did not appreciate a response. He then received IVIg and high-dose steroids, and he recovered over several days with improved cardiac function and stable blood pressure.
What is the pathogenesis? Is SARS-CoV-2 causative or just an associated finding? Who are the at-risk children, adolescents, and adults? Is there a genetic predisposition? What therapies work best? The eight cases described in London all received IVIg, as did our case, and all but one improved and survived. In adults we have seen substantial inflammation with elevated C-reactive protein (often as high as 300), ferritin, lactate dehydrogenase, triglycerides, fibrinogen, and d-dimers, but nearly all have extensive pulmonary disease, hypoxia, and are SARS-CoV-2 positive by PCR. Influenza is also associated with a cytokine storm syndrome in adolescents and young adults.3 The mechanisms influenza virus uses to initiate a cytokine storm and strategies for immunomodulatory treatment may provide insights into COVID-19–associated multisystem hyperinflammatory syndrome.
Dr. Pelton is professor of pediatrics and epidemiology at Boston University and public health and senior attending physician in pediatric infectious diseases at Boston Medical Center. Dr. Camelo is a senior fellow in pediatric infectious diseases at Boston Medical Center. They have no relevant financial disclosures. Email them at [email protected].
References
1. Riphagen S et al. Lancet. 2020 May 6. doi: 10.1016/S0140-6736(20)31094-1.
2. Royal College of Paediatrics and Child Health Guidance: Paediatric multisystem inflammatory syndrome temporally associated with COVID-19.
3. Liu Q et al.Cell Mol Immunol. 2016 Jan;13(1):3-10.
A 21-year-old young adult presented to the ED with a 1-week history of high fever, vomiting, diarrhea, and abdominal pain. His mother was SARS-CoV-2 positive by polymerase chain reaction approximately 3 weeks prior; his PCR was negative for SARS-CoV-2.
Following admission, he became hypotensive and tachycardic with evidence of myocarditis. His chest x-ray was normal and his O2 saturation was 100% on room air. His clinical presentation was initially suggestive of toxic shock syndrome without a rash, but despite aggressive fluid resuscitation and broad-spectrum antibiotics, he continued to clinically deteriorate with persistent high fever and increasing cardiac stress. Echocardiography revealed biventricular dysfunction. His laboratory abnormalities included rising inflammatory markers and troponin I and B-type natriuretic peptide (BNP). A repeat PCR for SARS-CoV-2 was negative on day 2 of illness. He was diagnosed as likely having macrophage-activation syndrome (MAS) despite the atypical features (myocarditis), and he received Anakinra with no apparent response. He also was given intravenous immunoglobulin (IVIg) for his myocarditis and subsequently high-dose steroids. He became afebrile, his blood pressure stabilized, his inflammatory markers declined, and over several days he returned to normal. His COVID-19 antibody test IgG was positive on day 4 of illness.
This case challenged us for several reasons. First, the PCR from his nasopharynx was negative on two occasions, which raises the issue of how sensitive and accurate these PCR tests are for SARS-CoV-2 or are patients with COVID-19–associated hyperinflammatory syndrome still PCR positive? Second, although we have seen many adult cases with a cytokine storm picture similar to this patient, nearly all of the prior cases had chest x-ray abnormalities and hypoxia. Third, the severity of the myocardial dysfunction and rising troponin and BNP also was unusual in our experience with COVID-19 infection. Lastly, the use of antibody detection to SARS-CoV-2 enabled us to confirm recent COIVD-19 disease and see his illness as part of the likely spectrum of clinical syndromes seen with this virus.
The Lancet reported eight children, aged 4-14 years, with a hyperinflammatory shock-like syndrome in early May.1 The cases had features similar to atypical Kawasaki disease, KD shock syndrome, and toxic shock syndrome. Each case had high fever for multiple days; diarrhea and abdominal pain was present in even children; elevated ferritin, C-reactive protein, d-dimer, increased troponins, and ventricular dysfunction also was present in seven. Most patients had no pulmonary involvement, and most tested negative for SARS-CoV-2 despite four of the eight having direct contact with a COVID-positive family member. All received IVIg and antibiotics; six received aspirin. Seven of the eight made a full recovery; one child died from a large cerebrovascular infarct.
Also in early May, the New York Times described a “mysterious” hyperinflammatory syndrome in children thought to be linked to COVID-19. A total of 76 suspected cases in children had been reported in New York state, three of whom died. The syndrome has been given the name pediatric multisystem inflammatory syndrome. The syndrome can resemble KD shock syndrome with rash; fever; conjunctivitis; hypotension; and redness in the lips, tongue and mucous membranes . It also can resemble toxic shock syndrome with abdominal pain, vomiting, and diarrhea. However, the degree of cardiac inflammation and dysfunction is substantial in many cases and usually beyond that seen in KD or toxic shock.
The syndrome is not limited to the United States. The Royal College of Pediatrics and Child Health has created a case definition:2
- A child presenting with persistent fever, inflammation (elevated C-reactive protein, neutrophilia, and lymphopenia) and evidence of single or multiorgan dysfunction (shock, cardiac, respiratory, renal, gastrointestinal, or neurologic) with additional features.
- Exclusion of any other microbial causes such as bacterial sepsis or staphylococcal or streptococcal shock syndromes, infections known to be associated with myocarditis (such as enterovirus).
- SARS-CoV-2 testing may or may not be positive.
As with our young adult, treatment is supportive, nonspecific, and aimed at quieting the inflammatory response. The current thinking is the syndrome is seen as antibody to SARS-CoV-2 appears and frequently the nasopharyngeal PCR is negative. It is hypothesized that the syndrome occurs in genetically predisposed hosts and potentially is a late-onset inflammatory process or potentially an antibody-triggered inflammatory process. The negative PCR from nasopharyngeal specimens reflects that the onset is later in the course of disease; whether fecal samples would be COVID positive is unknown. As with our case, antibody testing for IgG against SARS-CoV-2 is appropriate to confirm COVID-19 disease and may be positive as early as day 7.
The approach needs to be team oriented and include cardiology, rheumatology, infectious diseases, and intensive care specialists working collaboratively. Such cases should be considered COVID positive despite negative PCR tests, and full personal protective equipment should be used as we do not as yet know if live virus could be found in stool. We initiated treatment with Anakinra (an interleukin-1 type-1 receptor inhibitor) as part of our treatment protocol for MAS; we did not appreciate a response. He then received IVIg and high-dose steroids, and he recovered over several days with improved cardiac function and stable blood pressure.
What is the pathogenesis? Is SARS-CoV-2 causative or just an associated finding? Who are the at-risk children, adolescents, and adults? Is there a genetic predisposition? What therapies work best? The eight cases described in London all received IVIg, as did our case, and all but one improved and survived. In adults we have seen substantial inflammation with elevated C-reactive protein (often as high as 300), ferritin, lactate dehydrogenase, triglycerides, fibrinogen, and d-dimers, but nearly all have extensive pulmonary disease, hypoxia, and are SARS-CoV-2 positive by PCR. Influenza is also associated with a cytokine storm syndrome in adolescents and young adults.3 The mechanisms influenza virus uses to initiate a cytokine storm and strategies for immunomodulatory treatment may provide insights into COVID-19–associated multisystem hyperinflammatory syndrome.
Dr. Pelton is professor of pediatrics and epidemiology at Boston University and public health and senior attending physician in pediatric infectious diseases at Boston Medical Center. Dr. Camelo is a senior fellow in pediatric infectious diseases at Boston Medical Center. They have no relevant financial disclosures. Email them at [email protected].
References
1. Riphagen S et al. Lancet. 2020 May 6. doi: 10.1016/S0140-6736(20)31094-1.
2. Royal College of Paediatrics and Child Health Guidance: Paediatric multisystem inflammatory syndrome temporally associated with COVID-19.
3. Liu Q et al.Cell Mol Immunol. 2016 Jan;13(1):3-10.
Hyperoxia in the ICU: Is less more?
“All things are poison and nothing is without poison, only the dose permits something not to be poisonous.” Paracelsus once said.
A bit of history
Oxygen was discovered in 1775 and was since noted to be both vital and poisonous. It was much later in 1899 that it was demonstrated that partial pressures of oxygen up to 75% led to both severe lung injury and death as compared with levels of 40% to 50%. While the administration of oxygen in hypoxic patients is beneficial, this intervention in healthy subjects leads to a reduction in heart rate, cardiac index, and an increase in mean arterial pressure, systemic vascular resistance, and large artery stiffness.
While oxygen itself is not toxic, the reactive oxygen species that form as a result of oxygen metabolism are. A study showed that supplementation of oxygen in patients with COPD, or in women undergoing C-section with the use of spinal anesthesia, leads to an increase in reactive oxygen species (Winslow RM. Transfusion. 2013;53[2]:424).
Hyperoxia has multiple clinical effects on lung physiology and gas exchange that include worsening hypoxemia secondary to absorptive atelectasis and damage to the airways and lung parenchyma (Sackner MA, et al. Ann Intern Med. 1975;82[1]:40).
High levels of inspired oxygen could also lead to accentuation of hypercapnia as explained by the Haldane effect; a reduction of the affinity for carbon dioxide leading to an increase in PaC02. High oxygen levels can also decrease the hypoxic drive for ventilation leading to worsening hypercapnia.
Hyperoxia is a situation routinely encountered in clinical practice, as well, often resulting from an overzealous attempt to prevent or reverse hypoxia. ICU physicians, though aware of potential threats of hyperoxia, often fail to translate such concerns in their clinical practice (Helmerhorst HJ, et al. Ann Intensive Care. 2014;4:23).
Effects of hyperoxia in CNS and cardiovascular disease
The last 2 decades have seen several studies looking into the effects of hyperoxia in specific clinical scenarios. Arterial hyperoxia was found to be independently associated with in-hospital death in ventilated stroke patients in the ICU, as compared with either arterial normoxia or hypoxia (Rincon F, et al. Crit Care Med. 2014;42[2]:387). The AVOID trial showed that supplemental oxygen therapy in patients with ST-elevation myocardial infarction, but without hypoxia, increased early myocardial injury with risk of larger myocardial infarct size at 6 months. (Stub D, et al. Circulation. 2015;131[24]:2143).
Hyperoxia in the ICU
Although the potential risks of hyperoxia in conditions such as stroke and cardiac arrest had been observed, the jury was still out on its effects on a critically ill, mixed population, as routinely encountered in the ICU. Oxygen-ICU, a single center trial published in 2016, was one of the first looking at a mixed ICU population, while assessing the effects of a conservative oxygen delivery strategy against a conventional one (Girardis M, et al. JAMA. 2016;316[15]:1583). The researchers noted a significant mortality difference favoring conservative oxygen therapy, particularly in intubated patients. The IOTA group’s systematic review and meta-analysis of 16,000 patients, showed an increased relative risk of death in-hospital with hyperoxia, that persisted over a prolonged period while conferring no obvious advantages (Chu DK, et al. Lancet. 2018;391[10131]:1693).
With the growing body of evidence, the need of the hour was an ICU-based randomized trial that may settle the debate. The 21 center, 1,000 patient ICU-ROX trial promised to deliver on that (Mackle D, et al. N Engl J Med. 2019 Oct 14. doi: 10.1056/NEJMoa1903297). The study design was more reflective of real-life clinical scenarios than some of its predecessors, with the control group exposed to usual-oxygen therapy instead of liberal hyperoxia. Both groups had a lower saturation threshold of 91% while the conservative-oxygen group had an upper limit of 97% along with a conscious effort made to drop the FIO2 to 21%. Though both groups had similar median PaO2 levels, the conservative group spent much greater time (median 29 hours) at 21% FIO2 than the usual group (median 1 hour). SpO2 targets also allowed frequent changes to oxygen delivery without the need for blood gases.
Presuming the primary effect of oxygen toxicity would be on the lungs, the study was powered for a primary outcome of ventilator-free-days, which showed no significant difference among the groups. No significant differences in mortality or other secondary outcomes were observed.
The ICU-ROX trial leaves us with a few questions, the most important are:
Are the detrimental effects of hyperoxia limited to certain disease-specific groups or generally applicable?
The evidence is substantial inpatients with cardiac arrest/myocardial injury. A prespecified subgroup analysis in ICU-ROX indicated a higher number of ventilator-free days with conservative oxygen therapy in patients with hypoxic ischemic encephalopathy. When asked, Dr. Paul Young, one of the investigators of the ICU-ROX group, states, “These are actually pretty small subgroups, and the number of mortality events is quite small. My belief is that these data are best viewed as hypothesis generating rather than practice changing”
Where do we stand?
While we look for further answers regarding the consequences of hyperoxia, it is established that conservative oxygen therapy aimed at reducing delivered FIO2 is a safe practice without any adverse outcomes. The conservative oxygen group in ICU-ROX allowed SpO2 levels as low as 91% with no serious hypoxic events. On the other hand, the IOTA group in their data analysis suggested a possible increase in mortality risk, which was dose-dependent on the magnitude of increase in SpO2, in the range of 94% to 96%. Based on the available evidence, it is reasonable to encourage targeting lowest FIO2 values needed to maintain SpO2 between 91% and 96% in our ICU patients. There would always be a small fraction of patients, such as those with ARDS or severe hypoxic respiratory failure, in whom this may not be achievable given fluctuating and unreliable SpO2 levels in the setting of profound hypoxia.
What lies ahead?
As the debate rages on, in an effort to answer this question for once and for all, the researchers of ICU-ROX are planning to conduct a multinational, multicenter RCT, the MEGA-ROX. An ICU trial of this size has not been attempted before and, given the sample size, Dr. Young feels the MEGA-ROX will be powered to detect an absolute mortality difference as low as 1.5%, if it does exist. There is a distinct possibility that conservative oxygen therapy will be best for patients with some diagnoses while liberal oxygen will be best for patients with other diagnoses. “We are conducting a number of parallel nested trials within the overall 40,000 participant trial sample. Each of these nested trials will evaluate a prespecified hypothesis in a specific cohort of critically ill patients and is accompanied by an appropriate power calculation. This will be able to address any heterogeneity of treatment effect among the different subgroups,” he concluded. As we eagerly await the results of MEGA-ROX, there may be a growing belief among intensivists that when it comes to oxygen in the ICU, less may be truly more.
Dr. Chaaban and Dr. Sen are with the University of Kentucky College of Medicine, Lexington, Kentucky.
Correction, 4/10/20: An earlier version of this article misstated Dr. Sen's name
“All things are poison and nothing is without poison, only the dose permits something not to be poisonous.” Paracelsus once said.
A bit of history
Oxygen was discovered in 1775 and was since noted to be both vital and poisonous. It was much later in 1899 that it was demonstrated that partial pressures of oxygen up to 75% led to both severe lung injury and death as compared with levels of 40% to 50%. While the administration of oxygen in hypoxic patients is beneficial, this intervention in healthy subjects leads to a reduction in heart rate, cardiac index, and an increase in mean arterial pressure, systemic vascular resistance, and large artery stiffness.
While oxygen itself is not toxic, the reactive oxygen species that form as a result of oxygen metabolism are. A study showed that supplementation of oxygen in patients with COPD, or in women undergoing C-section with the use of spinal anesthesia, leads to an increase in reactive oxygen species (Winslow RM. Transfusion. 2013;53[2]:424).
Hyperoxia has multiple clinical effects on lung physiology and gas exchange that include worsening hypoxemia secondary to absorptive atelectasis and damage to the airways and lung parenchyma (Sackner MA, et al. Ann Intern Med. 1975;82[1]:40).
High levels of inspired oxygen could also lead to accentuation of hypercapnia as explained by the Haldane effect; a reduction of the affinity for carbon dioxide leading to an increase in PaC02. High oxygen levels can also decrease the hypoxic drive for ventilation leading to worsening hypercapnia.
Hyperoxia is a situation routinely encountered in clinical practice, as well, often resulting from an overzealous attempt to prevent or reverse hypoxia. ICU physicians, though aware of potential threats of hyperoxia, often fail to translate such concerns in their clinical practice (Helmerhorst HJ, et al. Ann Intensive Care. 2014;4:23).
Effects of hyperoxia in CNS and cardiovascular disease
The last 2 decades have seen several studies looking into the effects of hyperoxia in specific clinical scenarios. Arterial hyperoxia was found to be independently associated with in-hospital death in ventilated stroke patients in the ICU, as compared with either arterial normoxia or hypoxia (Rincon F, et al. Crit Care Med. 2014;42[2]:387). The AVOID trial showed that supplemental oxygen therapy in patients with ST-elevation myocardial infarction, but without hypoxia, increased early myocardial injury with risk of larger myocardial infarct size at 6 months. (Stub D, et al. Circulation. 2015;131[24]:2143).
Hyperoxia in the ICU
Although the potential risks of hyperoxia in conditions such as stroke and cardiac arrest had been observed, the jury was still out on its effects on a critically ill, mixed population, as routinely encountered in the ICU. Oxygen-ICU, a single center trial published in 2016, was one of the first looking at a mixed ICU population, while assessing the effects of a conservative oxygen delivery strategy against a conventional one (Girardis M, et al. JAMA. 2016;316[15]:1583). The researchers noted a significant mortality difference favoring conservative oxygen therapy, particularly in intubated patients. The IOTA group’s systematic review and meta-analysis of 16,000 patients, showed an increased relative risk of death in-hospital with hyperoxia, that persisted over a prolonged period while conferring no obvious advantages (Chu DK, et al. Lancet. 2018;391[10131]:1693).
With the growing body of evidence, the need of the hour was an ICU-based randomized trial that may settle the debate. The 21 center, 1,000 patient ICU-ROX trial promised to deliver on that (Mackle D, et al. N Engl J Med. 2019 Oct 14. doi: 10.1056/NEJMoa1903297). The study design was more reflective of real-life clinical scenarios than some of its predecessors, with the control group exposed to usual-oxygen therapy instead of liberal hyperoxia. Both groups had a lower saturation threshold of 91% while the conservative-oxygen group had an upper limit of 97% along with a conscious effort made to drop the FIO2 to 21%. Though both groups had similar median PaO2 levels, the conservative group spent much greater time (median 29 hours) at 21% FIO2 than the usual group (median 1 hour). SpO2 targets also allowed frequent changes to oxygen delivery without the need for blood gases.
Presuming the primary effect of oxygen toxicity would be on the lungs, the study was powered for a primary outcome of ventilator-free-days, which showed no significant difference among the groups. No significant differences in mortality or other secondary outcomes were observed.
The ICU-ROX trial leaves us with a few questions, the most important are:
Are the detrimental effects of hyperoxia limited to certain disease-specific groups or generally applicable?
The evidence is substantial inpatients with cardiac arrest/myocardial injury. A prespecified subgroup analysis in ICU-ROX indicated a higher number of ventilator-free days with conservative oxygen therapy in patients with hypoxic ischemic encephalopathy. When asked, Dr. Paul Young, one of the investigators of the ICU-ROX group, states, “These are actually pretty small subgroups, and the number of mortality events is quite small. My belief is that these data are best viewed as hypothesis generating rather than practice changing”
Where do we stand?
While we look for further answers regarding the consequences of hyperoxia, it is established that conservative oxygen therapy aimed at reducing delivered FIO2 is a safe practice without any adverse outcomes. The conservative oxygen group in ICU-ROX allowed SpO2 levels as low as 91% with no serious hypoxic events. On the other hand, the IOTA group in their data analysis suggested a possible increase in mortality risk, which was dose-dependent on the magnitude of increase in SpO2, in the range of 94% to 96%. Based on the available evidence, it is reasonable to encourage targeting lowest FIO2 values needed to maintain SpO2 between 91% and 96% in our ICU patients. There would always be a small fraction of patients, such as those with ARDS or severe hypoxic respiratory failure, in whom this may not be achievable given fluctuating and unreliable SpO2 levels in the setting of profound hypoxia.
What lies ahead?
As the debate rages on, in an effort to answer this question for once and for all, the researchers of ICU-ROX are planning to conduct a multinational, multicenter RCT, the MEGA-ROX. An ICU trial of this size has not been attempted before and, given the sample size, Dr. Young feels the MEGA-ROX will be powered to detect an absolute mortality difference as low as 1.5%, if it does exist. There is a distinct possibility that conservative oxygen therapy will be best for patients with some diagnoses while liberal oxygen will be best for patients with other diagnoses. “We are conducting a number of parallel nested trials within the overall 40,000 participant trial sample. Each of these nested trials will evaluate a prespecified hypothesis in a specific cohort of critically ill patients and is accompanied by an appropriate power calculation. This will be able to address any heterogeneity of treatment effect among the different subgroups,” he concluded. As we eagerly await the results of MEGA-ROX, there may be a growing belief among intensivists that when it comes to oxygen in the ICU, less may be truly more.
Dr. Chaaban and Dr. Sen are with the University of Kentucky College of Medicine, Lexington, Kentucky.
Correction, 4/10/20: An earlier version of this article misstated Dr. Sen's name
“All things are poison and nothing is without poison, only the dose permits something not to be poisonous.” Paracelsus once said.
A bit of history
Oxygen was discovered in 1775 and was since noted to be both vital and poisonous. It was much later in 1899 that it was demonstrated that partial pressures of oxygen up to 75% led to both severe lung injury and death as compared with levels of 40% to 50%. While the administration of oxygen in hypoxic patients is beneficial, this intervention in healthy subjects leads to a reduction in heart rate, cardiac index, and an increase in mean arterial pressure, systemic vascular resistance, and large artery stiffness.
While oxygen itself is not toxic, the reactive oxygen species that form as a result of oxygen metabolism are. A study showed that supplementation of oxygen in patients with COPD, or in women undergoing C-section with the use of spinal anesthesia, leads to an increase in reactive oxygen species (Winslow RM. Transfusion. 2013;53[2]:424).
Hyperoxia has multiple clinical effects on lung physiology and gas exchange that include worsening hypoxemia secondary to absorptive atelectasis and damage to the airways and lung parenchyma (Sackner MA, et al. Ann Intern Med. 1975;82[1]:40).
High levels of inspired oxygen could also lead to accentuation of hypercapnia as explained by the Haldane effect; a reduction of the affinity for carbon dioxide leading to an increase in PaC02. High oxygen levels can also decrease the hypoxic drive for ventilation leading to worsening hypercapnia.
Hyperoxia is a situation routinely encountered in clinical practice, as well, often resulting from an overzealous attempt to prevent or reverse hypoxia. ICU physicians, though aware of potential threats of hyperoxia, often fail to translate such concerns in their clinical practice (Helmerhorst HJ, et al. Ann Intensive Care. 2014;4:23).
Effects of hyperoxia in CNS and cardiovascular disease
The last 2 decades have seen several studies looking into the effects of hyperoxia in specific clinical scenarios. Arterial hyperoxia was found to be independently associated with in-hospital death in ventilated stroke patients in the ICU, as compared with either arterial normoxia or hypoxia (Rincon F, et al. Crit Care Med. 2014;42[2]:387). The AVOID trial showed that supplemental oxygen therapy in patients with ST-elevation myocardial infarction, but without hypoxia, increased early myocardial injury with risk of larger myocardial infarct size at 6 months. (Stub D, et al. Circulation. 2015;131[24]:2143).
Hyperoxia in the ICU
Although the potential risks of hyperoxia in conditions such as stroke and cardiac arrest had been observed, the jury was still out on its effects on a critically ill, mixed population, as routinely encountered in the ICU. Oxygen-ICU, a single center trial published in 2016, was one of the first looking at a mixed ICU population, while assessing the effects of a conservative oxygen delivery strategy against a conventional one (Girardis M, et al. JAMA. 2016;316[15]:1583). The researchers noted a significant mortality difference favoring conservative oxygen therapy, particularly in intubated patients. The IOTA group’s systematic review and meta-analysis of 16,000 patients, showed an increased relative risk of death in-hospital with hyperoxia, that persisted over a prolonged period while conferring no obvious advantages (Chu DK, et al. Lancet. 2018;391[10131]:1693).
With the growing body of evidence, the need of the hour was an ICU-based randomized trial that may settle the debate. The 21 center, 1,000 patient ICU-ROX trial promised to deliver on that (Mackle D, et al. N Engl J Med. 2019 Oct 14. doi: 10.1056/NEJMoa1903297). The study design was more reflective of real-life clinical scenarios than some of its predecessors, with the control group exposed to usual-oxygen therapy instead of liberal hyperoxia. Both groups had a lower saturation threshold of 91% while the conservative-oxygen group had an upper limit of 97% along with a conscious effort made to drop the FIO2 to 21%. Though both groups had similar median PaO2 levels, the conservative group spent much greater time (median 29 hours) at 21% FIO2 than the usual group (median 1 hour). SpO2 targets also allowed frequent changes to oxygen delivery without the need for blood gases.
Presuming the primary effect of oxygen toxicity would be on the lungs, the study was powered for a primary outcome of ventilator-free-days, which showed no significant difference among the groups. No significant differences in mortality or other secondary outcomes were observed.
The ICU-ROX trial leaves us with a few questions, the most important are:
Are the detrimental effects of hyperoxia limited to certain disease-specific groups or generally applicable?
The evidence is substantial inpatients with cardiac arrest/myocardial injury. A prespecified subgroup analysis in ICU-ROX indicated a higher number of ventilator-free days with conservative oxygen therapy in patients with hypoxic ischemic encephalopathy. When asked, Dr. Paul Young, one of the investigators of the ICU-ROX group, states, “These are actually pretty small subgroups, and the number of mortality events is quite small. My belief is that these data are best viewed as hypothesis generating rather than practice changing”
Where do we stand?
While we look for further answers regarding the consequences of hyperoxia, it is established that conservative oxygen therapy aimed at reducing delivered FIO2 is a safe practice without any adverse outcomes. The conservative oxygen group in ICU-ROX allowed SpO2 levels as low as 91% with no serious hypoxic events. On the other hand, the IOTA group in their data analysis suggested a possible increase in mortality risk, which was dose-dependent on the magnitude of increase in SpO2, in the range of 94% to 96%. Based on the available evidence, it is reasonable to encourage targeting lowest FIO2 values needed to maintain SpO2 between 91% and 96% in our ICU patients. There would always be a small fraction of patients, such as those with ARDS or severe hypoxic respiratory failure, in whom this may not be achievable given fluctuating and unreliable SpO2 levels in the setting of profound hypoxia.
What lies ahead?
As the debate rages on, in an effort to answer this question for once and for all, the researchers of ICU-ROX are planning to conduct a multinational, multicenter RCT, the MEGA-ROX. An ICU trial of this size has not been attempted before and, given the sample size, Dr. Young feels the MEGA-ROX will be powered to detect an absolute mortality difference as low as 1.5%, if it does exist. There is a distinct possibility that conservative oxygen therapy will be best for patients with some diagnoses while liberal oxygen will be best for patients with other diagnoses. “We are conducting a number of parallel nested trials within the overall 40,000 participant trial sample. Each of these nested trials will evaluate a prespecified hypothesis in a specific cohort of critically ill patients and is accompanied by an appropriate power calculation. This will be able to address any heterogeneity of treatment effect among the different subgroups,” he concluded. As we eagerly await the results of MEGA-ROX, there may be a growing belief among intensivists that when it comes to oxygen in the ICU, less may be truly more.
Dr. Chaaban and Dr. Sen are with the University of Kentucky College of Medicine, Lexington, Kentucky.
Correction, 4/10/20: An earlier version of this article misstated Dr. Sen's name
Neuromuscular blockade for ARDS in the ICU
The ability to control the delivery of ventilation to patients having the acute respiratory distress syndrome (ARDS) without encountering patient respiratory effort via the administration of neuromuscular blocking drugs has been a potentially appealing therapeutic option for decades (Light RW, et al. Anesth Analg. 1975;54[2]:219). This practice had been common in the late 20th century in order to avoid excessive tachypnea and appearance of patient discomfort with the collateral benefit of improving oxygenation and decreasing the fraction of inspired oxygen (FiO2) (Hansen-Flaschen JH, et al. JAMA. 1991;26:2870). Following the publication by the NIH-sponsored ARDS Network of the landmark low tidal volume lung protective ventilation trial, whereupon study subjects had been allowed to breathe up to 35 times per minute (ARDS Network, N Engl J Med. 2000;342[18]:1301) and additional concerns that neuromuscular blockade could potentially be associated with neuromuscular weakness, this practice fell out of favor.
Although the validity of using lung protective ventilation in ARDS, with a plateau pressure of less than 30 cm/H2O via delivery of a low tidal volume, has withstood the test of time, subsequent attempts to utilize methods that would further protect the lung with additional “rescue” approaches to mechanical ventilation led to a partial renaissance of the neuromuscular blockade (NMB) approach. For example, high frequency oscillatory ventilation, with its idiosyncratic delivery of minute volumes of ventilator gas, requires NMB in order to be used. However, the publication of two negative trials, including one demonstrating an increased mortality, sidelined this approach (Ferguson ND, et al. N Engl J Med. 2013;368[9]:795).
More notably, the use of NMB in patients with ARDS has been advocated during conventional mechanical ventilation to avoid the generation of large tidal volumes via ventilator asynchrony occurring during patient-triggered breaths. Ostensibly, wiping out any patient effort via NMB eliminates manifestations of asynchrony, such as double triggering, which can generate areas of regional tidal hyperinflation in the injured lung and thereby worsen ventilator-induced lung injury. The utilization of NMB early in the course of ARDS (less than 48 hours) resulted in less lung inflammation (Forel JM, et al. Crit Care Med. 2006;34[11]:2749). Subsequently, the ACURASYS trial found that patients with moderately severe or severe ARDS treated with NMB had a mortality benefit comparable to that seen in the original ARDS low tidal volume trial (Papazian L, et al. N Engl J Med. 2010;369:980).
Several criticisms of ACURASYS led to the desire for a larger confirmatory trial be undertaken. The NIH-sponsored successor to the ARDS Network, the Prevention and Early Treatment of Acute Lung Injury (PETAL) Network, took this on straight away with its formation in 2014 (disclosure: the author is a Principal Investigator of one of the 13 PETAL Network Clinical Centers). This trial, called the Re-Evaluation of Systemic Early Neuromuscular Blockade, the ROSE trial, was published last year in the New England Journal of Medicine and failed to confirm a mortality benefit to NMB when used early in the course of ARDS, such as had been done earlier (Moss M, et al. N Engl J Med. 2019;380[21]:1997).
What then, should clinicians consider the proper use of NMB in ARDS to be?
There has been a recent spate of large negative trials of once-promising interventions in critical care medicine (Laffey. Lancet Respir Med. 2018;6[9]659). Among these were trials related to early mobility, vitamin D administration, transpulmonary pressure titrated positive end-expiratory pressure (PEEP), and of course, high frequency oscillatory ventilation, just to name a few disappointments. Recognition of heterogeneity of treatment effect (HTE), with some subgroups being more likely to respond to an intervention than others (Iwashyna. Am J Respir Crit Care Med. 2015;192[9]:1045), is cold comfort to the bedside clinician and all but the most dedicated health services researcher. At least to date, personalized medicine has fallen short of prospective validation in ARDS (Constantin et al. Lancet Respir Med. 2019;7[10]:870).
The failure of the ROSE trial to demonstrate a mortality benefit to ARDS patients with a P/F ratio of less than 150 on at least 8 cm H2O treated with early NMB means the routine use of this approach in all such patients isn’t warranted. In a prescient nod to HTE, “a foolish consistency,” as Emerson said, “is the hobgoblin of little minds.” Importantly, there were several subtle but not necessarily irrelevant differences between ACURASYS and ROSE. ROSE used a high PEEP algorithm to titrate PEEP to FiO2, rather than the conventional low PEEP approach used in the original ARDS Network and ACURASYS trials. Potentially, the benefits of NMB on the injured lung in ARDS may have been mitigated by using higher PEEP levels. ROSE also failed to demonstrate a decrease in barotrauma as had been reported earlier. That said, it is difficult to ascribe the lack of benefit of NMB mechanistically to less asynchrony induced regional tidal hyperinflation in the NMB group at high PEEP, especially given the lighter sedation targets employed in both the NMB and the placebo group. Meanwhile, ROSE did confirm patients were not harmed by NMB by resulting in more neuromuscular weakness upon recovery.
Among patients with Berlin severe ARDS (ie. P/F less than 100 on at least 5 cm H2O PEEP) evaluated between publication of ACURASYS and ROSE, clinicians were far more inclined to use NMB than other rescue modalities, including prone ventilation (Duan, Ann Am Thorac Soc. 2017;12:1818). It seems unlikely the publication of ROSE will alter this. As rescue modalities go, NMB is relatively inexpensive, widely available and easily performed (Co, I and Hyzy RC, Crit Care Med. 2019 Dec 18. doi: 10.1097/CCM.0000000000004198). Ultimately, though the question isn’t whether NMB will be used in ARDS patients with refractory hypoxemia early or even later, but whether prone ventilation should be simultaneously initiated at the time of, or even before the institution of NMB.
As in ACURASYS, patients in the landmark PROSEVA prone ventilation trial were treated with a low PEEP algorithm (Guérin C et al. N Engl J Med. 2013;368[23]:2159). Prone ventilation has many salutary physiologic benefits, not the least of which is recruitment of areas of collapsed lung. Patients who are recruitable with PEEP, i.e. whose PaO2 increases with increasing PEEP in the face of an unchanged or minimally changed plateau pressure, may also demonstrate a mortality benefit (Goligher, EC et al. Am J Respir Crit Care Med. 2014;190[1]:70). It remains unknown whether prone ventilation would remain of significant benefit should a high PEEP approach be employed.
Prone ventilation clearly has its adherents (Albert, RK, Ann Am Thorac Soc. 2020;17[1]:24), although underutilization remains prevalent perhaps due to its somewhat cumbersome nature. While it might have been interesting had ROSE performed a simultaneous assessment of prone ventilation along with NMB via a factorial trial design, clinicians remain at the crossroads of how to escalate ventilator support in the ARDS patient with worsening, if not refractory hypoxemia. The use of NMB with a high PEEP approach often allows for recruitment and a concomitant lowering of FiO2 to acceptable levels in advance of the utilization of prone ventilation. Although some clinicians are able to successfully utilize prone ventilation without NMB, many are not, and NMB use was widespread in PROSEVA.
With no evidence of harm, the employment of NMB in the setting of Berlin severe ARDS is entirely justifiable, whether occurring early or late in the clinical course, regardless of, or potentially with the concomitant employment of prone ventilation. These two rescue modalities remain first line and, despite evidence to the contrary (Li, et al. Am J Respir Crit Care Med. 2018;197[8]:991) should be employed in advance of others, most notably extracorporeal support.
Dr. Hyzy is with the Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor.
The ability to control the delivery of ventilation to patients having the acute respiratory distress syndrome (ARDS) without encountering patient respiratory effort via the administration of neuromuscular blocking drugs has been a potentially appealing therapeutic option for decades (Light RW, et al. Anesth Analg. 1975;54[2]:219). This practice had been common in the late 20th century in order to avoid excessive tachypnea and appearance of patient discomfort with the collateral benefit of improving oxygenation and decreasing the fraction of inspired oxygen (FiO2) (Hansen-Flaschen JH, et al. JAMA. 1991;26:2870). Following the publication by the NIH-sponsored ARDS Network of the landmark low tidal volume lung protective ventilation trial, whereupon study subjects had been allowed to breathe up to 35 times per minute (ARDS Network, N Engl J Med. 2000;342[18]:1301) and additional concerns that neuromuscular blockade could potentially be associated with neuromuscular weakness, this practice fell out of favor.
Although the validity of using lung protective ventilation in ARDS, with a plateau pressure of less than 30 cm/H2O via delivery of a low tidal volume, has withstood the test of time, subsequent attempts to utilize methods that would further protect the lung with additional “rescue” approaches to mechanical ventilation led to a partial renaissance of the neuromuscular blockade (NMB) approach. For example, high frequency oscillatory ventilation, with its idiosyncratic delivery of minute volumes of ventilator gas, requires NMB in order to be used. However, the publication of two negative trials, including one demonstrating an increased mortality, sidelined this approach (Ferguson ND, et al. N Engl J Med. 2013;368[9]:795).
More notably, the use of NMB in patients with ARDS has been advocated during conventional mechanical ventilation to avoid the generation of large tidal volumes via ventilator asynchrony occurring during patient-triggered breaths. Ostensibly, wiping out any patient effort via NMB eliminates manifestations of asynchrony, such as double triggering, which can generate areas of regional tidal hyperinflation in the injured lung and thereby worsen ventilator-induced lung injury. The utilization of NMB early in the course of ARDS (less than 48 hours) resulted in less lung inflammation (Forel JM, et al. Crit Care Med. 2006;34[11]:2749). Subsequently, the ACURASYS trial found that patients with moderately severe or severe ARDS treated with NMB had a mortality benefit comparable to that seen in the original ARDS low tidal volume trial (Papazian L, et al. N Engl J Med. 2010;369:980).
Several criticisms of ACURASYS led to the desire for a larger confirmatory trial be undertaken. The NIH-sponsored successor to the ARDS Network, the Prevention and Early Treatment of Acute Lung Injury (PETAL) Network, took this on straight away with its formation in 2014 (disclosure: the author is a Principal Investigator of one of the 13 PETAL Network Clinical Centers). This trial, called the Re-Evaluation of Systemic Early Neuromuscular Blockade, the ROSE trial, was published last year in the New England Journal of Medicine and failed to confirm a mortality benefit to NMB when used early in the course of ARDS, such as had been done earlier (Moss M, et al. N Engl J Med. 2019;380[21]:1997).
What then, should clinicians consider the proper use of NMB in ARDS to be?
There has been a recent spate of large negative trials of once-promising interventions in critical care medicine (Laffey. Lancet Respir Med. 2018;6[9]659). Among these were trials related to early mobility, vitamin D administration, transpulmonary pressure titrated positive end-expiratory pressure (PEEP), and of course, high frequency oscillatory ventilation, just to name a few disappointments. Recognition of heterogeneity of treatment effect (HTE), with some subgroups being more likely to respond to an intervention than others (Iwashyna. Am J Respir Crit Care Med. 2015;192[9]:1045), is cold comfort to the bedside clinician and all but the most dedicated health services researcher. At least to date, personalized medicine has fallen short of prospective validation in ARDS (Constantin et al. Lancet Respir Med. 2019;7[10]:870).
The failure of the ROSE trial to demonstrate a mortality benefit to ARDS patients with a P/F ratio of less than 150 on at least 8 cm H2O treated with early NMB means the routine use of this approach in all such patients isn’t warranted. In a prescient nod to HTE, “a foolish consistency,” as Emerson said, “is the hobgoblin of little minds.” Importantly, there were several subtle but not necessarily irrelevant differences between ACURASYS and ROSE. ROSE used a high PEEP algorithm to titrate PEEP to FiO2, rather than the conventional low PEEP approach used in the original ARDS Network and ACURASYS trials. Potentially, the benefits of NMB on the injured lung in ARDS may have been mitigated by using higher PEEP levels. ROSE also failed to demonstrate a decrease in barotrauma as had been reported earlier. That said, it is difficult to ascribe the lack of benefit of NMB mechanistically to less asynchrony induced regional tidal hyperinflation in the NMB group at high PEEP, especially given the lighter sedation targets employed in both the NMB and the placebo group. Meanwhile, ROSE did confirm patients were not harmed by NMB by resulting in more neuromuscular weakness upon recovery.
Among patients with Berlin severe ARDS (ie. P/F less than 100 on at least 5 cm H2O PEEP) evaluated between publication of ACURASYS and ROSE, clinicians were far more inclined to use NMB than other rescue modalities, including prone ventilation (Duan, Ann Am Thorac Soc. 2017;12:1818). It seems unlikely the publication of ROSE will alter this. As rescue modalities go, NMB is relatively inexpensive, widely available and easily performed (Co, I and Hyzy RC, Crit Care Med. 2019 Dec 18. doi: 10.1097/CCM.0000000000004198). Ultimately, though the question isn’t whether NMB will be used in ARDS patients with refractory hypoxemia early or even later, but whether prone ventilation should be simultaneously initiated at the time of, or even before the institution of NMB.
As in ACURASYS, patients in the landmark PROSEVA prone ventilation trial were treated with a low PEEP algorithm (Guérin C et al. N Engl J Med. 2013;368[23]:2159). Prone ventilation has many salutary physiologic benefits, not the least of which is recruitment of areas of collapsed lung. Patients who are recruitable with PEEP, i.e. whose PaO2 increases with increasing PEEP in the face of an unchanged or minimally changed plateau pressure, may also demonstrate a mortality benefit (Goligher, EC et al. Am J Respir Crit Care Med. 2014;190[1]:70). It remains unknown whether prone ventilation would remain of significant benefit should a high PEEP approach be employed.
Prone ventilation clearly has its adherents (Albert, RK, Ann Am Thorac Soc. 2020;17[1]:24), although underutilization remains prevalent perhaps due to its somewhat cumbersome nature. While it might have been interesting had ROSE performed a simultaneous assessment of prone ventilation along with NMB via a factorial trial design, clinicians remain at the crossroads of how to escalate ventilator support in the ARDS patient with worsening, if not refractory hypoxemia. The use of NMB with a high PEEP approach often allows for recruitment and a concomitant lowering of FiO2 to acceptable levels in advance of the utilization of prone ventilation. Although some clinicians are able to successfully utilize prone ventilation without NMB, many are not, and NMB use was widespread in PROSEVA.
With no evidence of harm, the employment of NMB in the setting of Berlin severe ARDS is entirely justifiable, whether occurring early or late in the clinical course, regardless of, or potentially with the concomitant employment of prone ventilation. These two rescue modalities remain first line and, despite evidence to the contrary (Li, et al. Am J Respir Crit Care Med. 2018;197[8]:991) should be employed in advance of others, most notably extracorporeal support.
Dr. Hyzy is with the Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor.
The ability to control the delivery of ventilation to patients having the acute respiratory distress syndrome (ARDS) without encountering patient respiratory effort via the administration of neuromuscular blocking drugs has been a potentially appealing therapeutic option for decades (Light RW, et al. Anesth Analg. 1975;54[2]:219). This practice had been common in the late 20th century in order to avoid excessive tachypnea and appearance of patient discomfort with the collateral benefit of improving oxygenation and decreasing the fraction of inspired oxygen (FiO2) (Hansen-Flaschen JH, et al. JAMA. 1991;26:2870). Following the publication by the NIH-sponsored ARDS Network of the landmark low tidal volume lung protective ventilation trial, whereupon study subjects had been allowed to breathe up to 35 times per minute (ARDS Network, N Engl J Med. 2000;342[18]:1301) and additional concerns that neuromuscular blockade could potentially be associated with neuromuscular weakness, this practice fell out of favor.
Although the validity of using lung protective ventilation in ARDS, with a plateau pressure of less than 30 cm/H2O via delivery of a low tidal volume, has withstood the test of time, subsequent attempts to utilize methods that would further protect the lung with additional “rescue” approaches to mechanical ventilation led to a partial renaissance of the neuromuscular blockade (NMB) approach. For example, high frequency oscillatory ventilation, with its idiosyncratic delivery of minute volumes of ventilator gas, requires NMB in order to be used. However, the publication of two negative trials, including one demonstrating an increased mortality, sidelined this approach (Ferguson ND, et al. N Engl J Med. 2013;368[9]:795).
More notably, the use of NMB in patients with ARDS has been advocated during conventional mechanical ventilation to avoid the generation of large tidal volumes via ventilator asynchrony occurring during patient-triggered breaths. Ostensibly, wiping out any patient effort via NMB eliminates manifestations of asynchrony, such as double triggering, which can generate areas of regional tidal hyperinflation in the injured lung and thereby worsen ventilator-induced lung injury. The utilization of NMB early in the course of ARDS (less than 48 hours) resulted in less lung inflammation (Forel JM, et al. Crit Care Med. 2006;34[11]:2749). Subsequently, the ACURASYS trial found that patients with moderately severe or severe ARDS treated with NMB had a mortality benefit comparable to that seen in the original ARDS low tidal volume trial (Papazian L, et al. N Engl J Med. 2010;369:980).
Several criticisms of ACURASYS led to the desire for a larger confirmatory trial be undertaken. The NIH-sponsored successor to the ARDS Network, the Prevention and Early Treatment of Acute Lung Injury (PETAL) Network, took this on straight away with its formation in 2014 (disclosure: the author is a Principal Investigator of one of the 13 PETAL Network Clinical Centers). This trial, called the Re-Evaluation of Systemic Early Neuromuscular Blockade, the ROSE trial, was published last year in the New England Journal of Medicine and failed to confirm a mortality benefit to NMB when used early in the course of ARDS, such as had been done earlier (Moss M, et al. N Engl J Med. 2019;380[21]:1997).
What then, should clinicians consider the proper use of NMB in ARDS to be?
There has been a recent spate of large negative trials of once-promising interventions in critical care medicine (Laffey. Lancet Respir Med. 2018;6[9]659). Among these were trials related to early mobility, vitamin D administration, transpulmonary pressure titrated positive end-expiratory pressure (PEEP), and of course, high frequency oscillatory ventilation, just to name a few disappointments. Recognition of heterogeneity of treatment effect (HTE), with some subgroups being more likely to respond to an intervention than others (Iwashyna. Am J Respir Crit Care Med. 2015;192[9]:1045), is cold comfort to the bedside clinician and all but the most dedicated health services researcher. At least to date, personalized medicine has fallen short of prospective validation in ARDS (Constantin et al. Lancet Respir Med. 2019;7[10]:870).
The failure of the ROSE trial to demonstrate a mortality benefit to ARDS patients with a P/F ratio of less than 150 on at least 8 cm H2O treated with early NMB means the routine use of this approach in all such patients isn’t warranted. In a prescient nod to HTE, “a foolish consistency,” as Emerson said, “is the hobgoblin of little minds.” Importantly, there were several subtle but not necessarily irrelevant differences between ACURASYS and ROSE. ROSE used a high PEEP algorithm to titrate PEEP to FiO2, rather than the conventional low PEEP approach used in the original ARDS Network and ACURASYS trials. Potentially, the benefits of NMB on the injured lung in ARDS may have been mitigated by using higher PEEP levels. ROSE also failed to demonstrate a decrease in barotrauma as had been reported earlier. That said, it is difficult to ascribe the lack of benefit of NMB mechanistically to less asynchrony induced regional tidal hyperinflation in the NMB group at high PEEP, especially given the lighter sedation targets employed in both the NMB and the placebo group. Meanwhile, ROSE did confirm patients were not harmed by NMB by resulting in more neuromuscular weakness upon recovery.
Among patients with Berlin severe ARDS (ie. P/F less than 100 on at least 5 cm H2O PEEP) evaluated between publication of ACURASYS and ROSE, clinicians were far more inclined to use NMB than other rescue modalities, including prone ventilation (Duan, Ann Am Thorac Soc. 2017;12:1818). It seems unlikely the publication of ROSE will alter this. As rescue modalities go, NMB is relatively inexpensive, widely available and easily performed (Co, I and Hyzy RC, Crit Care Med. 2019 Dec 18. doi: 10.1097/CCM.0000000000004198). Ultimately, though the question isn’t whether NMB will be used in ARDS patients with refractory hypoxemia early or even later, but whether prone ventilation should be simultaneously initiated at the time of, or even before the institution of NMB.
As in ACURASYS, patients in the landmark PROSEVA prone ventilation trial were treated with a low PEEP algorithm (Guérin C et al. N Engl J Med. 2013;368[23]:2159). Prone ventilation has many salutary physiologic benefits, not the least of which is recruitment of areas of collapsed lung. Patients who are recruitable with PEEP, i.e. whose PaO2 increases with increasing PEEP in the face of an unchanged or minimally changed plateau pressure, may also demonstrate a mortality benefit (Goligher, EC et al. Am J Respir Crit Care Med. 2014;190[1]:70). It remains unknown whether prone ventilation would remain of significant benefit should a high PEEP approach be employed.
Prone ventilation clearly has its adherents (Albert, RK, Ann Am Thorac Soc. 2020;17[1]:24), although underutilization remains prevalent perhaps due to its somewhat cumbersome nature. While it might have been interesting had ROSE performed a simultaneous assessment of prone ventilation along with NMB via a factorial trial design, clinicians remain at the crossroads of how to escalate ventilator support in the ARDS patient with worsening, if not refractory hypoxemia. The use of NMB with a high PEEP approach often allows for recruitment and a concomitant lowering of FiO2 to acceptable levels in advance of the utilization of prone ventilation. Although some clinicians are able to successfully utilize prone ventilation without NMB, many are not, and NMB use was widespread in PROSEVA.
With no evidence of harm, the employment of NMB in the setting of Berlin severe ARDS is entirely justifiable, whether occurring early or late in the clinical course, regardless of, or potentially with the concomitant employment of prone ventilation. These two rescue modalities remain first line and, despite evidence to the contrary (Li, et al. Am J Respir Crit Care Med. 2018;197[8]:991) should be employed in advance of others, most notably extracorporeal support.
Dr. Hyzy is with the Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor.
Nutrition support during adult critical illness
Many critically ill patients you care for cannot maintain volitional oral intake. Therefore, nutrition support, through enteral or parenteral routes, remains a cornerstone in ensuring our critically ill patients receive substrates like glucose and protein. To understand the supportive role of nutrition during critical illness, let’s identify and contextualize the different phases of critical illness.
Phases of critical illness
The European Society of Parenteral and Enteral Nutrition’s (ESPEN) 2018 critical care nutrition guideline incorporates stages of critical illness in making nutrition recommendations (Singer P et al. Clin Nutr. 2019;38:48-79). The first week of critical illness is the acute phase and hallmarked by catabolism and metabolic and hemodynamic instability. The late phase is thereafter and hallmarked by rehabilitation and anabolism or chronic critical illness. The acute phase is further divided into early (days 1-2) and late acute phase (days 3-7). The time-points are arbitrary and merely serve as placeholders. An objective marker to distinguish phases does not exist and transition periods will be different for each patient.
Acute phase
Critical illness defining conditions like circulatory shock, respiratory failure, and trauma are stressors and lead to two key acute phase perturbations that nutrition may have a role in altering:
The first is hypercatabolism. Critical illness defining conditions activate neuroendocrine, inflammatory/immune, adipokine, and GI tract hormone pathways that increase serum glucagon, cortisol, and catecholamines to promote glycogenolysis, gluconeogenesis, insulin resistance, protein catabolism, and restricted/impaired anabolism.
The second is gut dysfunction. During health, there is cross-talk signaling that occurs between commensal bacteria, epithelium, and the immune system, which maintains gut barrier functions, achieved, for example, by promoting tight junction protein production. Acute critical illness pathophysiology loosens epithelial tight junctions, and the gut barrier is breached, creating an opportunity for downstream migration of pancreatic enzymes and cytokines. Furthermore, the microbiome morphs into a virulent pathobiome, which induces gut-derived inflammation.
When, where, and how much should we feed critically ill patients?
Since the acute phase of critical illness begins a series of events leading to negative energy balance and gut dysfunction, you might find early nutrition provision intuitive. Indeed, the 2016 ASPEN/SCCM and 2018 ESPEN critical care nutrition guidelines recommend early (within 24-48 hours of ICU admission) enteral nutrition (EN), delivered into the stomach, for all critically ill patients unable to maintain volitional intake. Meta-analyses of randomized controlled trials (RCT) conducted between1979 and 2013 show early EN reduces both mortality and infectious complications, compared with no early nutrition (McClave SA et al. JPEN. 2016;40:159-211).
RCT level data do not show superiority of EN over parenteral nutrition (PN). Nonetheless, early EN is recommended over PN because it maintains epithelial barrier function and supports immunity.
What is the optimal nutrition dose? The 2016 ASPEN/SCCM guideline recommends getting to >80% estimated energy goal within 48-72 hours in patients with high nutrition risk while the 2018 ESPEN guideline suggests maintaining a hypocaloric, or not exceeding 70% of prescribed energy goal, during the early acute phase. The recommendation is based on meta-analyses of RCTs conducted between 2011 and 2017, which shows no mortality difference between hypocaloric and isocaloric nutrition.
Biologically plausible rationale for starting hypocaloric, as opposed to full dose nutrition, during the acute phase of critical illness includes: (a) the acute phase represents a period of hemodynamic instability and mitochondrial dysfunction, and full-dose EN may lead to feeding intolerance and lack of substrate utilization, respectively; (b) in those with risk factors (like pre-existing malnutrition), starting full dose nutrition may lead to refeeding syndrome; and (c) endogenous glucose production occurs during the acute phase, and full dose nutrition may worsen hyperglycemia.
Therefore, during the early acute phase of critical illness, hypocaloric feeding using an isosmotic formula, with a slow up-titration to goal rate thereafter, while monitoring for feeding intolerance and refeeding syndrome is a reasonable starting point.
What is the role of parenteral nutrition in critical illness?
PN can be exclusive or supplemental (in a patient receiving EN). Historically, providers may have been reluctant to utilize PN for fear of infectious morbidity; however, contemporary pragmatic-design RCTs demonstrate safety with exclusive PN (Harvey SE et al. N Engl J Med. 2014;371:1673-84). When your patient has a contraindication for EN or does not tolerate it despite a trial of small bowel feeding, meta-analyses have shown a mortality benefit of early exclusive PN in malnourished patients, as compared with no nutrition (Braunschweig C et al. Am J Clin Nutr.2001;74:534-42).
As for supplemental PN (SPN), the 2016 ASPEN/SCCM guideline does not recommend it until day 7 in all critically ill patients, while the 2018 ESPEN guideline recommends its use on a case-by-case basis. Since, two trials inform SPN use. The EAT-ICU trial showed no difference in 6-month physical function between EN group and early-goal-directed nutritiongroup, which included SPN to achieve estimated energy requirement during the first week of critical illness (Allingstrup MJ et al. Intensive Care Med. 2017;43:1637-47). The TOP-UP trial compared EN alone with EN plus SPN in nutritionally high risk patients (ie, those who stand to have more complications as a result of undernutrition) and found those with a BMI < 25 kg/m2 and those with a NUTRIC score >5 who received supplemental PN atop EN had improved 30-day mortality, as compared with EN alone (Wischmeyer P et al. Crit Care. 2017;21:142). Mortality was a secondary outcome, and further study of supplemental PN in nutritionally high-risk patients is warranted. Until further data are available, supplemental PN should probably be restricted during the acute phase of critical illness.
Protein may be the important substrate
Proteolysis is the rule during critical illness, and amino acids are liberated from skeletal muscle breakdown. Using ultrasound, Puthucheary et al found a 17.7% reduction in rectus femoris cross-sectional area in 63 critically ill adults and identified muscle cellular infiltration at ICU day 10, suggesting critical illness leads to quantitative and qualitative muscle defects (Puthucheary Z et al. JAMA. 2013;15:1591-1600).
Since survivorship from critical illness is increasing, acquired loss of muscle mass may contribute to post-ICU physical functioning impairments. Thus, protein may be the most important substrate to deliver during critical illness. The 2016 ASPEN/SCCM guideline recommends 1.2 – 2.0 g/kg actual body weight (ABW)/day in nonobese critically ill patients.
Unfortunately, the optimal protein dose and the timing of intake are unknown. Observational studies suggest benefit with lower and higher doses, which creates equipoise for protein dose. The signal may be lost in heterogeneity, and observational data suggest higher protein dose may benefit patients with high nutritional risk. In terms of timing, one observational study found lower (<0.8 g/kg/d) protein dose before day 3 followed by higher (>0.8 g/kg/d) dose thereafter was associated with mortality benefit (Koekkoek WAC et al. Clin Nutr.2019;38:883-890).
Until stronger data are available to guide optimal protein dose and timing, it is reasonable to observe the 2016 ASPEN/SCCM guideline protein recommendation of at least 1.2 g/kg/day. The 2018 ESPEN guideline recommends a similar dose of 1.3 g/kg/day.
Future research and summary
Many questions remain unanswered and present opportunities for future research. Priorities for critical care nutrition research include studying the impact of combined nutrition and exercise in the acute and late phases of critical illness and identifying best tools to differentiate responses to caloric and protein intake.
In summary, critical illness has acute and late phases. The acute phase is a hypercatabolic state leading to negative energy and nitrogen balance and gut dysfunction. Take-home points for nutrition support in the acute phase of critical illness are:
1. It is reasonable to start early hypocaloric EN with an isosmotic formula with slow up-titration over the first week of critical illness while monitoring for refeeding syndrome and feeding intolerance.
2. Use exclusive PN in ICU patients with pre-existing malnutrition when EN is contraindicated or not tolerated.
3. Supplemental PN should probably be restricted during the acute phase of critical illness.
4. Optimal protein dose and timing are unknown. It is reasonable to start with at least 1.2 g/kg ABW/day in non-obese patients.
Dr. Patel is with the Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.
Dr. Rice is with the Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Vanderbilt University, Nashville, Tennessee.
Many critically ill patients you care for cannot maintain volitional oral intake. Therefore, nutrition support, through enteral or parenteral routes, remains a cornerstone in ensuring our critically ill patients receive substrates like glucose and protein. To understand the supportive role of nutrition during critical illness, let’s identify and contextualize the different phases of critical illness.
Phases of critical illness
The European Society of Parenteral and Enteral Nutrition’s (ESPEN) 2018 critical care nutrition guideline incorporates stages of critical illness in making nutrition recommendations (Singer P et al. Clin Nutr. 2019;38:48-79). The first week of critical illness is the acute phase and hallmarked by catabolism and metabolic and hemodynamic instability. The late phase is thereafter and hallmarked by rehabilitation and anabolism or chronic critical illness. The acute phase is further divided into early (days 1-2) and late acute phase (days 3-7). The time-points are arbitrary and merely serve as placeholders. An objective marker to distinguish phases does not exist and transition periods will be different for each patient.
Acute phase
Critical illness defining conditions like circulatory shock, respiratory failure, and trauma are stressors and lead to two key acute phase perturbations that nutrition may have a role in altering:
The first is hypercatabolism. Critical illness defining conditions activate neuroendocrine, inflammatory/immune, adipokine, and GI tract hormone pathways that increase serum glucagon, cortisol, and catecholamines to promote glycogenolysis, gluconeogenesis, insulin resistance, protein catabolism, and restricted/impaired anabolism.
The second is gut dysfunction. During health, there is cross-talk signaling that occurs between commensal bacteria, epithelium, and the immune system, which maintains gut barrier functions, achieved, for example, by promoting tight junction protein production. Acute critical illness pathophysiology loosens epithelial tight junctions, and the gut barrier is breached, creating an opportunity for downstream migration of pancreatic enzymes and cytokines. Furthermore, the microbiome morphs into a virulent pathobiome, which induces gut-derived inflammation.
When, where, and how much should we feed critically ill patients?
Since the acute phase of critical illness begins a series of events leading to negative energy balance and gut dysfunction, you might find early nutrition provision intuitive. Indeed, the 2016 ASPEN/SCCM and 2018 ESPEN critical care nutrition guidelines recommend early (within 24-48 hours of ICU admission) enteral nutrition (EN), delivered into the stomach, for all critically ill patients unable to maintain volitional intake. Meta-analyses of randomized controlled trials (RCT) conducted between1979 and 2013 show early EN reduces both mortality and infectious complications, compared with no early nutrition (McClave SA et al. JPEN. 2016;40:159-211).
RCT level data do not show superiority of EN over parenteral nutrition (PN). Nonetheless, early EN is recommended over PN because it maintains epithelial barrier function and supports immunity.
What is the optimal nutrition dose? The 2016 ASPEN/SCCM guideline recommends getting to >80% estimated energy goal within 48-72 hours in patients with high nutrition risk while the 2018 ESPEN guideline suggests maintaining a hypocaloric, or not exceeding 70% of prescribed energy goal, during the early acute phase. The recommendation is based on meta-analyses of RCTs conducted between 2011 and 2017, which shows no mortality difference between hypocaloric and isocaloric nutrition.
Biologically plausible rationale for starting hypocaloric, as opposed to full dose nutrition, during the acute phase of critical illness includes: (a) the acute phase represents a period of hemodynamic instability and mitochondrial dysfunction, and full-dose EN may lead to feeding intolerance and lack of substrate utilization, respectively; (b) in those with risk factors (like pre-existing malnutrition), starting full dose nutrition may lead to refeeding syndrome; and (c) endogenous glucose production occurs during the acute phase, and full dose nutrition may worsen hyperglycemia.
Therefore, during the early acute phase of critical illness, hypocaloric feeding using an isosmotic formula, with a slow up-titration to goal rate thereafter, while monitoring for feeding intolerance and refeeding syndrome is a reasonable starting point.
What is the role of parenteral nutrition in critical illness?
PN can be exclusive or supplemental (in a patient receiving EN). Historically, providers may have been reluctant to utilize PN for fear of infectious morbidity; however, contemporary pragmatic-design RCTs demonstrate safety with exclusive PN (Harvey SE et al. N Engl J Med. 2014;371:1673-84). When your patient has a contraindication for EN or does not tolerate it despite a trial of small bowel feeding, meta-analyses have shown a mortality benefit of early exclusive PN in malnourished patients, as compared with no nutrition (Braunschweig C et al. Am J Clin Nutr.2001;74:534-42).
As for supplemental PN (SPN), the 2016 ASPEN/SCCM guideline does not recommend it until day 7 in all critically ill patients, while the 2018 ESPEN guideline recommends its use on a case-by-case basis. Since, two trials inform SPN use. The EAT-ICU trial showed no difference in 6-month physical function between EN group and early-goal-directed nutritiongroup, which included SPN to achieve estimated energy requirement during the first week of critical illness (Allingstrup MJ et al. Intensive Care Med. 2017;43:1637-47). The TOP-UP trial compared EN alone with EN plus SPN in nutritionally high risk patients (ie, those who stand to have more complications as a result of undernutrition) and found those with a BMI < 25 kg/m2 and those with a NUTRIC score >5 who received supplemental PN atop EN had improved 30-day mortality, as compared with EN alone (Wischmeyer P et al. Crit Care. 2017;21:142). Mortality was a secondary outcome, and further study of supplemental PN in nutritionally high-risk patients is warranted. Until further data are available, supplemental PN should probably be restricted during the acute phase of critical illness.
Protein may be the important substrate
Proteolysis is the rule during critical illness, and amino acids are liberated from skeletal muscle breakdown. Using ultrasound, Puthucheary et al found a 17.7% reduction in rectus femoris cross-sectional area in 63 critically ill adults and identified muscle cellular infiltration at ICU day 10, suggesting critical illness leads to quantitative and qualitative muscle defects (Puthucheary Z et al. JAMA. 2013;15:1591-1600).
Since survivorship from critical illness is increasing, acquired loss of muscle mass may contribute to post-ICU physical functioning impairments. Thus, protein may be the most important substrate to deliver during critical illness. The 2016 ASPEN/SCCM guideline recommends 1.2 – 2.0 g/kg actual body weight (ABW)/day in nonobese critically ill patients.
Unfortunately, the optimal protein dose and the timing of intake are unknown. Observational studies suggest benefit with lower and higher doses, which creates equipoise for protein dose. The signal may be lost in heterogeneity, and observational data suggest higher protein dose may benefit patients with high nutritional risk. In terms of timing, one observational study found lower (<0.8 g/kg/d) protein dose before day 3 followed by higher (>0.8 g/kg/d) dose thereafter was associated with mortality benefit (Koekkoek WAC et al. Clin Nutr.2019;38:883-890).
Until stronger data are available to guide optimal protein dose and timing, it is reasonable to observe the 2016 ASPEN/SCCM guideline protein recommendation of at least 1.2 g/kg/day. The 2018 ESPEN guideline recommends a similar dose of 1.3 g/kg/day.
Future research and summary
Many questions remain unanswered and present opportunities for future research. Priorities for critical care nutrition research include studying the impact of combined nutrition and exercise in the acute and late phases of critical illness and identifying best tools to differentiate responses to caloric and protein intake.
In summary, critical illness has acute and late phases. The acute phase is a hypercatabolic state leading to negative energy and nitrogen balance and gut dysfunction. Take-home points for nutrition support in the acute phase of critical illness are:
1. It is reasonable to start early hypocaloric EN with an isosmotic formula with slow up-titration over the first week of critical illness while monitoring for refeeding syndrome and feeding intolerance.
2. Use exclusive PN in ICU patients with pre-existing malnutrition when EN is contraindicated or not tolerated.
3. Supplemental PN should probably be restricted during the acute phase of critical illness.
4. Optimal protein dose and timing are unknown. It is reasonable to start with at least 1.2 g/kg ABW/day in non-obese patients.
Dr. Patel is with the Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.
Dr. Rice is with the Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Vanderbilt University, Nashville, Tennessee.
Many critically ill patients you care for cannot maintain volitional oral intake. Therefore, nutrition support, through enteral or parenteral routes, remains a cornerstone in ensuring our critically ill patients receive substrates like glucose and protein. To understand the supportive role of nutrition during critical illness, let’s identify and contextualize the different phases of critical illness.
Phases of critical illness
The European Society of Parenteral and Enteral Nutrition’s (ESPEN) 2018 critical care nutrition guideline incorporates stages of critical illness in making nutrition recommendations (Singer P et al. Clin Nutr. 2019;38:48-79). The first week of critical illness is the acute phase and hallmarked by catabolism and metabolic and hemodynamic instability. The late phase is thereafter and hallmarked by rehabilitation and anabolism or chronic critical illness. The acute phase is further divided into early (days 1-2) and late acute phase (days 3-7). The time-points are arbitrary and merely serve as placeholders. An objective marker to distinguish phases does not exist and transition periods will be different for each patient.
Acute phase
Critical illness defining conditions like circulatory shock, respiratory failure, and trauma are stressors and lead to two key acute phase perturbations that nutrition may have a role in altering:
The first is hypercatabolism. Critical illness defining conditions activate neuroendocrine, inflammatory/immune, adipokine, and GI tract hormone pathways that increase serum glucagon, cortisol, and catecholamines to promote glycogenolysis, gluconeogenesis, insulin resistance, protein catabolism, and restricted/impaired anabolism.
The second is gut dysfunction. During health, there is cross-talk signaling that occurs between commensal bacteria, epithelium, and the immune system, which maintains gut barrier functions, achieved, for example, by promoting tight junction protein production. Acute critical illness pathophysiology loosens epithelial tight junctions, and the gut barrier is breached, creating an opportunity for downstream migration of pancreatic enzymes and cytokines. Furthermore, the microbiome morphs into a virulent pathobiome, which induces gut-derived inflammation.
When, where, and how much should we feed critically ill patients?
Since the acute phase of critical illness begins a series of events leading to negative energy balance and gut dysfunction, you might find early nutrition provision intuitive. Indeed, the 2016 ASPEN/SCCM and 2018 ESPEN critical care nutrition guidelines recommend early (within 24-48 hours of ICU admission) enteral nutrition (EN), delivered into the stomach, for all critically ill patients unable to maintain volitional intake. Meta-analyses of randomized controlled trials (RCT) conducted between1979 and 2013 show early EN reduces both mortality and infectious complications, compared with no early nutrition (McClave SA et al. JPEN. 2016;40:159-211).
RCT level data do not show superiority of EN over parenteral nutrition (PN). Nonetheless, early EN is recommended over PN because it maintains epithelial barrier function and supports immunity.
What is the optimal nutrition dose? The 2016 ASPEN/SCCM guideline recommends getting to >80% estimated energy goal within 48-72 hours in patients with high nutrition risk while the 2018 ESPEN guideline suggests maintaining a hypocaloric, or not exceeding 70% of prescribed energy goal, during the early acute phase. The recommendation is based on meta-analyses of RCTs conducted between 2011 and 2017, which shows no mortality difference between hypocaloric and isocaloric nutrition.
Biologically plausible rationale for starting hypocaloric, as opposed to full dose nutrition, during the acute phase of critical illness includes: (a) the acute phase represents a period of hemodynamic instability and mitochondrial dysfunction, and full-dose EN may lead to feeding intolerance and lack of substrate utilization, respectively; (b) in those with risk factors (like pre-existing malnutrition), starting full dose nutrition may lead to refeeding syndrome; and (c) endogenous glucose production occurs during the acute phase, and full dose nutrition may worsen hyperglycemia.
Therefore, during the early acute phase of critical illness, hypocaloric feeding using an isosmotic formula, with a slow up-titration to goal rate thereafter, while monitoring for feeding intolerance and refeeding syndrome is a reasonable starting point.
What is the role of parenteral nutrition in critical illness?
PN can be exclusive or supplemental (in a patient receiving EN). Historically, providers may have been reluctant to utilize PN for fear of infectious morbidity; however, contemporary pragmatic-design RCTs demonstrate safety with exclusive PN (Harvey SE et al. N Engl J Med. 2014;371:1673-84). When your patient has a contraindication for EN or does not tolerate it despite a trial of small bowel feeding, meta-analyses have shown a mortality benefit of early exclusive PN in malnourished patients, as compared with no nutrition (Braunschweig C et al. Am J Clin Nutr.2001;74:534-42).
As for supplemental PN (SPN), the 2016 ASPEN/SCCM guideline does not recommend it until day 7 in all critically ill patients, while the 2018 ESPEN guideline recommends its use on a case-by-case basis. Since, two trials inform SPN use. The EAT-ICU trial showed no difference in 6-month physical function between EN group and early-goal-directed nutritiongroup, which included SPN to achieve estimated energy requirement during the first week of critical illness (Allingstrup MJ et al. Intensive Care Med. 2017;43:1637-47). The TOP-UP trial compared EN alone with EN plus SPN in nutritionally high risk patients (ie, those who stand to have more complications as a result of undernutrition) and found those with a BMI < 25 kg/m2 and those with a NUTRIC score >5 who received supplemental PN atop EN had improved 30-day mortality, as compared with EN alone (Wischmeyer P et al. Crit Care. 2017;21:142). Mortality was a secondary outcome, and further study of supplemental PN in nutritionally high-risk patients is warranted. Until further data are available, supplemental PN should probably be restricted during the acute phase of critical illness.
Protein may be the important substrate
Proteolysis is the rule during critical illness, and amino acids are liberated from skeletal muscle breakdown. Using ultrasound, Puthucheary et al found a 17.7% reduction in rectus femoris cross-sectional area in 63 critically ill adults and identified muscle cellular infiltration at ICU day 10, suggesting critical illness leads to quantitative and qualitative muscle defects (Puthucheary Z et al. JAMA. 2013;15:1591-1600).
Since survivorship from critical illness is increasing, acquired loss of muscle mass may contribute to post-ICU physical functioning impairments. Thus, protein may be the most important substrate to deliver during critical illness. The 2016 ASPEN/SCCM guideline recommends 1.2 – 2.0 g/kg actual body weight (ABW)/day in nonobese critically ill patients.
Unfortunately, the optimal protein dose and the timing of intake are unknown. Observational studies suggest benefit with lower and higher doses, which creates equipoise for protein dose. The signal may be lost in heterogeneity, and observational data suggest higher protein dose may benefit patients with high nutritional risk. In terms of timing, one observational study found lower (<0.8 g/kg/d) protein dose before day 3 followed by higher (>0.8 g/kg/d) dose thereafter was associated with mortality benefit (Koekkoek WAC et al. Clin Nutr.2019;38:883-890).
Until stronger data are available to guide optimal protein dose and timing, it is reasonable to observe the 2016 ASPEN/SCCM guideline protein recommendation of at least 1.2 g/kg/day. The 2018 ESPEN guideline recommends a similar dose of 1.3 g/kg/day.
Future research and summary
Many questions remain unanswered and present opportunities for future research. Priorities for critical care nutrition research include studying the impact of combined nutrition and exercise in the acute and late phases of critical illness and identifying best tools to differentiate responses to caloric and protein intake.
In summary, critical illness has acute and late phases. The acute phase is a hypercatabolic state leading to negative energy and nitrogen balance and gut dysfunction. Take-home points for nutrition support in the acute phase of critical illness are:
1. It is reasonable to start early hypocaloric EN with an isosmotic formula with slow up-titration over the first week of critical illness while monitoring for refeeding syndrome and feeding intolerance.
2. Use exclusive PN in ICU patients with pre-existing malnutrition when EN is contraindicated or not tolerated.
3. Supplemental PN should probably be restricted during the acute phase of critical illness.
4. Optimal protein dose and timing are unknown. It is reasonable to start with at least 1.2 g/kg ABW/day in non-obese patients.
Dr. Patel is with the Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.
Dr. Rice is with the Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Vanderbilt University, Nashville, Tennessee.
Should PEEP be titrated based on esophageal pressures?
Application of basic physiology principles at bedside has changed the approach to the treatment of patients with acute respiratory distress syndrome (ARDS) and refractory hypoxemia. Current standard of care for patients with ARDS includes a low tidal volume ventilation strategy (6 mL/kg of ideal body weight), keeping plateau pressures below 30 cm H2O (Brower RG, et al. N Engl J Med. 2000;342[18]:1301), driving pressures below 15 cm H2O and adequate positive end-expiratory pressures (PEEP) to keep the alveoli open without overdistension (Villar J, et al. Crit Care Med. 2006;34[5]:1311). However, at this time, despite the awareness of the importance of this intervention, there is no consensus regarding the best method to determine ideal PEEP at the individual patient level.
A thorough understanding of the basic physiologic concepts regarding respiratory pressures is of paramount importance to be able to formulate an opinion. The transpulmonary pressure (or lung distending pressure) is the gradient caused by the difference between alveolar (PA) and pleural pressure (PPL). In order to prevent lung collapse at end-expiration, PA must remain higher than PPL such that the gradient remains outward, preventing end-expiratory collapse and atelectotrauma. To accomplish that, it is necessary to know the end-expiratory PA and PPL. Esophageal balloon pressures (PES) represent central thoracic pressures, but, despite positional and regional variations, they are a good surrogate for average “effective” PPL (Baedorf KE, et al. Med Klin Intensivmed Notfmed. 2018;113[Suppl 1]:13).
Understanding that the value of the PES represents a practical PPL makes it easier to appreciate the potential usefulness of an esophageal balloon to titrate PEEP. The objective of PEEP titration is to prevent de-recruitment, maintain alveolar aeration, and improve the functional size of aerated alveoli. If the applied PEEP is lower than the PPL, the dependent lung regions will collapse. On the other hand, if PEEP is higher than the PPL, the lung would be overdistended, causing barotrauma and hemodynamic compromise.
The question is: Should we use esophageal balloons?Yes, we should.
A single center randomized control trial (EPVent) compared PEEP titration to achieve a positive PL vs standard of care lung protective ventilation (Talmor D, et al. N Engl J Med. 2008;359:2095). The PEEP titration group used significantly higher levels of PEEP, with improved oxygenation and lung compliance. However, there was no significant difference in ventilator-free days or mortality between the groups.
Obese patients are also likely to benefit from PEEP titration guided by an esophageal balloon, as they often have higher levels of intrinsic PEEP. Therefore, the application of higher levels of PEEP to compensate for the higher levels of intrinsic PEEP may help reduce work of breathing and prevent tidal recruitment-de-recruitment and atelectasis. Additionally, low to negative transpulmonary pressures measured using the actual values of PES in obese patients and obese animal models predicted lung collapse and tidal opening and closing (Fumagalli J, et al. Crit Care Med. 2017;45[8]:1374). It is useful to remember that the compliance of the respiratory system (Crs) is the total of the sum of the compliance of the chest wall (Ccw) and the lung compliance (CL). In obese patients, Ccw has a much more significant contribution to the total Crs, and the clinician should be really interested in the CL. At the bedside, esophageal manometry can be very useful to distinguish the contribution of CL and Ccw to the total Crs.
No, we shouldn’t.
Another randomized controlled trial (EPVent-2), by the same group, compared PEEP titration guided by esophageal pressure with empirical PEEP titration, in patients with moderate to severe ARDS (Beitler JR, et al. JAMA. 2019;321[9]:846). The primary outcomes of interest, death, and mechanical ventilator-free days through day 28 were not different between the groups.
Additionally, placement of an esophageal balloon is challenging and operator-dependent. The balloon portion of the esophageal catheter should be positioned in the lower third of the esophagus, behind the heart. Catheter placement is typically performed by inserting it into the stomach to a depth of about 60 cm, and gently pressing on the abdomen and observing a sudden increase in pressure on the ventilator screen. It is then withdrawn to about 40 cm, while looking for cardiac oscillations and pressure change (Talmor D, et al. N Engl J Med. 2008;359:2095). One can see how easily it would be to insert the esophageal balloon incorrectly. A misplaced balloon won’t provide accurate PES and can potentially cause harm.
Final answer: It depends on each individual patient.
Arguments for and against using an esophageal balloon to titrate PEEP in patients with ARDS and refractory hypoxemia are ongoing. Even the two most cited and applied trials on the matter (EPVent and EPVent-2) reported contradictory results. However, when analyzed in depth, both showed better oxygenation with the use of esophageal balloon. EPVent had improvement in oxygenation as its primary endpoint, and it was significant in the esophageal balloon group. EPVent-2 had oxygenation goals, in the form of need for rescue therapies for refractory hypoxemia, as secondary endpoints. Nonetheless, the patients in the esophageal balloon group in EPVent-2 required prone positioning less frequently, had lower use of pulmonary vasodilators, and a lower rate of ECMO consultations. Even though those trials did not show a mortality benefit, both showed an oxygenation benefit.
The ideal single tool that would indicate the “perfect “PEEP for each patient remains to be described. Until then, PEEP titration guided by a combination of ARDSnet PEEP tables, while maintaining a plateau pressure below 30 cm H2O and considering a driving pressure below 15 cm H2O should be a clinician’s goal. In patients in the extremes of height and body weight, and/or with conditions that would increase intra-abdominal pressure, such as ascites, a well-placed esophageal balloon while patient is supine might be beneficial.
The truth of the matter is, PEEP should be titrated by a trained intensivist in conjunction with the multidisciplinary ICU team, at patients’ bedside taking into consideration each individual’s unique physiologic and pathophysiologic characteristics at that moment.
Dr. Gallo de Moraes is Assistant Professor of Medicine, and Dr Oeckler is Assistant Professor of Medicine, Division of Pulmonary and Critical Care, Mayo Clinic, Rochester, Minnesota.
Application of basic physiology principles at bedside has changed the approach to the treatment of patients with acute respiratory distress syndrome (ARDS) and refractory hypoxemia. Current standard of care for patients with ARDS includes a low tidal volume ventilation strategy (6 mL/kg of ideal body weight), keeping plateau pressures below 30 cm H2O (Brower RG, et al. N Engl J Med. 2000;342[18]:1301), driving pressures below 15 cm H2O and adequate positive end-expiratory pressures (PEEP) to keep the alveoli open without overdistension (Villar J, et al. Crit Care Med. 2006;34[5]:1311). However, at this time, despite the awareness of the importance of this intervention, there is no consensus regarding the best method to determine ideal PEEP at the individual patient level.
A thorough understanding of the basic physiologic concepts regarding respiratory pressures is of paramount importance to be able to formulate an opinion. The transpulmonary pressure (or lung distending pressure) is the gradient caused by the difference between alveolar (PA) and pleural pressure (PPL). In order to prevent lung collapse at end-expiration, PA must remain higher than PPL such that the gradient remains outward, preventing end-expiratory collapse and atelectotrauma. To accomplish that, it is necessary to know the end-expiratory PA and PPL. Esophageal balloon pressures (PES) represent central thoracic pressures, but, despite positional and regional variations, they are a good surrogate for average “effective” PPL (Baedorf KE, et al. Med Klin Intensivmed Notfmed. 2018;113[Suppl 1]:13).
Understanding that the value of the PES represents a practical PPL makes it easier to appreciate the potential usefulness of an esophageal balloon to titrate PEEP. The objective of PEEP titration is to prevent de-recruitment, maintain alveolar aeration, and improve the functional size of aerated alveoli. If the applied PEEP is lower than the PPL, the dependent lung regions will collapse. On the other hand, if PEEP is higher than the PPL, the lung would be overdistended, causing barotrauma and hemodynamic compromise.
The question is: Should we use esophageal balloons?Yes, we should.
A single center randomized control trial (EPVent) compared PEEP titration to achieve a positive PL vs standard of care lung protective ventilation (Talmor D, et al. N Engl J Med. 2008;359:2095). The PEEP titration group used significantly higher levels of PEEP, with improved oxygenation and lung compliance. However, there was no significant difference in ventilator-free days or mortality between the groups.
Obese patients are also likely to benefit from PEEP titration guided by an esophageal balloon, as they often have higher levels of intrinsic PEEP. Therefore, the application of higher levels of PEEP to compensate for the higher levels of intrinsic PEEP may help reduce work of breathing and prevent tidal recruitment-de-recruitment and atelectasis. Additionally, low to negative transpulmonary pressures measured using the actual values of PES in obese patients and obese animal models predicted lung collapse and tidal opening and closing (Fumagalli J, et al. Crit Care Med. 2017;45[8]:1374). It is useful to remember that the compliance of the respiratory system (Crs) is the total of the sum of the compliance of the chest wall (Ccw) and the lung compliance (CL). In obese patients, Ccw has a much more significant contribution to the total Crs, and the clinician should be really interested in the CL. At the bedside, esophageal manometry can be very useful to distinguish the contribution of CL and Ccw to the total Crs.
No, we shouldn’t.
Another randomized controlled trial (EPVent-2), by the same group, compared PEEP titration guided by esophageal pressure with empirical PEEP titration, in patients with moderate to severe ARDS (Beitler JR, et al. JAMA. 2019;321[9]:846). The primary outcomes of interest, death, and mechanical ventilator-free days through day 28 were not different between the groups.
Additionally, placement of an esophageal balloon is challenging and operator-dependent. The balloon portion of the esophageal catheter should be positioned in the lower third of the esophagus, behind the heart. Catheter placement is typically performed by inserting it into the stomach to a depth of about 60 cm, and gently pressing on the abdomen and observing a sudden increase in pressure on the ventilator screen. It is then withdrawn to about 40 cm, while looking for cardiac oscillations and pressure change (Talmor D, et al. N Engl J Med. 2008;359:2095). One can see how easily it would be to insert the esophageal balloon incorrectly. A misplaced balloon won’t provide accurate PES and can potentially cause harm.
Final answer: It depends on each individual patient.
Arguments for and against using an esophageal balloon to titrate PEEP in patients with ARDS and refractory hypoxemia are ongoing. Even the two most cited and applied trials on the matter (EPVent and EPVent-2) reported contradictory results. However, when analyzed in depth, both showed better oxygenation with the use of esophageal balloon. EPVent had improvement in oxygenation as its primary endpoint, and it was significant in the esophageal balloon group. EPVent-2 had oxygenation goals, in the form of need for rescue therapies for refractory hypoxemia, as secondary endpoints. Nonetheless, the patients in the esophageal balloon group in EPVent-2 required prone positioning less frequently, had lower use of pulmonary vasodilators, and a lower rate of ECMO consultations. Even though those trials did not show a mortality benefit, both showed an oxygenation benefit.
The ideal single tool that would indicate the “perfect “PEEP for each patient remains to be described. Until then, PEEP titration guided by a combination of ARDSnet PEEP tables, while maintaining a plateau pressure below 30 cm H2O and considering a driving pressure below 15 cm H2O should be a clinician’s goal. In patients in the extremes of height and body weight, and/or with conditions that would increase intra-abdominal pressure, such as ascites, a well-placed esophageal balloon while patient is supine might be beneficial.
The truth of the matter is, PEEP should be titrated by a trained intensivist in conjunction with the multidisciplinary ICU team, at patients’ bedside taking into consideration each individual’s unique physiologic and pathophysiologic characteristics at that moment.
Dr. Gallo de Moraes is Assistant Professor of Medicine, and Dr Oeckler is Assistant Professor of Medicine, Division of Pulmonary and Critical Care, Mayo Clinic, Rochester, Minnesota.
Application of basic physiology principles at bedside has changed the approach to the treatment of patients with acute respiratory distress syndrome (ARDS) and refractory hypoxemia. Current standard of care for patients with ARDS includes a low tidal volume ventilation strategy (6 mL/kg of ideal body weight), keeping plateau pressures below 30 cm H2O (Brower RG, et al. N Engl J Med. 2000;342[18]:1301), driving pressures below 15 cm H2O and adequate positive end-expiratory pressures (PEEP) to keep the alveoli open without overdistension (Villar J, et al. Crit Care Med. 2006;34[5]:1311). However, at this time, despite the awareness of the importance of this intervention, there is no consensus regarding the best method to determine ideal PEEP at the individual patient level.
A thorough understanding of the basic physiologic concepts regarding respiratory pressures is of paramount importance to be able to formulate an opinion. The transpulmonary pressure (or lung distending pressure) is the gradient caused by the difference between alveolar (PA) and pleural pressure (PPL). In order to prevent lung collapse at end-expiration, PA must remain higher than PPL such that the gradient remains outward, preventing end-expiratory collapse and atelectotrauma. To accomplish that, it is necessary to know the end-expiratory PA and PPL. Esophageal balloon pressures (PES) represent central thoracic pressures, but, despite positional and regional variations, they are a good surrogate for average “effective” PPL (Baedorf KE, et al. Med Klin Intensivmed Notfmed. 2018;113[Suppl 1]:13).
Understanding that the value of the PES represents a practical PPL makes it easier to appreciate the potential usefulness of an esophageal balloon to titrate PEEP. The objective of PEEP titration is to prevent de-recruitment, maintain alveolar aeration, and improve the functional size of aerated alveoli. If the applied PEEP is lower than the PPL, the dependent lung regions will collapse. On the other hand, if PEEP is higher than the PPL, the lung would be overdistended, causing barotrauma and hemodynamic compromise.
The question is: Should we use esophageal balloons?Yes, we should.
A single center randomized control trial (EPVent) compared PEEP titration to achieve a positive PL vs standard of care lung protective ventilation (Talmor D, et al. N Engl J Med. 2008;359:2095). The PEEP titration group used significantly higher levels of PEEP, with improved oxygenation and lung compliance. However, there was no significant difference in ventilator-free days or mortality between the groups.
Obese patients are also likely to benefit from PEEP titration guided by an esophageal balloon, as they often have higher levels of intrinsic PEEP. Therefore, the application of higher levels of PEEP to compensate for the higher levels of intrinsic PEEP may help reduce work of breathing and prevent tidal recruitment-de-recruitment and atelectasis. Additionally, low to negative transpulmonary pressures measured using the actual values of PES in obese patients and obese animal models predicted lung collapse and tidal opening and closing (Fumagalli J, et al. Crit Care Med. 2017;45[8]:1374). It is useful to remember that the compliance of the respiratory system (Crs) is the total of the sum of the compliance of the chest wall (Ccw) and the lung compliance (CL). In obese patients, Ccw has a much more significant contribution to the total Crs, and the clinician should be really interested in the CL. At the bedside, esophageal manometry can be very useful to distinguish the contribution of CL and Ccw to the total Crs.
No, we shouldn’t.
Another randomized controlled trial (EPVent-2), by the same group, compared PEEP titration guided by esophageal pressure with empirical PEEP titration, in patients with moderate to severe ARDS (Beitler JR, et al. JAMA. 2019;321[9]:846). The primary outcomes of interest, death, and mechanical ventilator-free days through day 28 were not different between the groups.
Additionally, placement of an esophageal balloon is challenging and operator-dependent. The balloon portion of the esophageal catheter should be positioned in the lower third of the esophagus, behind the heart. Catheter placement is typically performed by inserting it into the stomach to a depth of about 60 cm, and gently pressing on the abdomen and observing a sudden increase in pressure on the ventilator screen. It is then withdrawn to about 40 cm, while looking for cardiac oscillations and pressure change (Talmor D, et al. N Engl J Med. 2008;359:2095). One can see how easily it would be to insert the esophageal balloon incorrectly. A misplaced balloon won’t provide accurate PES and can potentially cause harm.
Final answer: It depends on each individual patient.
Arguments for and against using an esophageal balloon to titrate PEEP in patients with ARDS and refractory hypoxemia are ongoing. Even the two most cited and applied trials on the matter (EPVent and EPVent-2) reported contradictory results. However, when analyzed in depth, both showed better oxygenation with the use of esophageal balloon. EPVent had improvement in oxygenation as its primary endpoint, and it was significant in the esophageal balloon group. EPVent-2 had oxygenation goals, in the form of need for rescue therapies for refractory hypoxemia, as secondary endpoints. Nonetheless, the patients in the esophageal balloon group in EPVent-2 required prone positioning less frequently, had lower use of pulmonary vasodilators, and a lower rate of ECMO consultations. Even though those trials did not show a mortality benefit, both showed an oxygenation benefit.
The ideal single tool that would indicate the “perfect “PEEP for each patient remains to be described. Until then, PEEP titration guided by a combination of ARDSnet PEEP tables, while maintaining a plateau pressure below 30 cm H2O and considering a driving pressure below 15 cm H2O should be a clinician’s goal. In patients in the extremes of height and body weight, and/or with conditions that would increase intra-abdominal pressure, such as ascites, a well-placed esophageal balloon while patient is supine might be beneficial.
The truth of the matter is, PEEP should be titrated by a trained intensivist in conjunction with the multidisciplinary ICU team, at patients’ bedside taking into consideration each individual’s unique physiologic and pathophysiologic characteristics at that moment.
Dr. Gallo de Moraes is Assistant Professor of Medicine, and Dr Oeckler is Assistant Professor of Medicine, Division of Pulmonary and Critical Care, Mayo Clinic, Rochester, Minnesota.