Cardiac surgery patients are sicker today than in previous decades due to an aging population and a rising complexity in medical care. There is an increasing reliance on noncardiac surgeons to care for these patients. The optimal postoperative providers and structure of the ICU where patients are cared for remain unclear, but what is irrefutable is patients’ increased postoperative morbidity. Pulmonary complications are a leading cause of morbidity in these patients, occurring in up to one-fifth of cases (Szelowski LA, et al. Curr Probl Surg. 2015;52[1]:531). Common pulmonary complications of cardiac surgery are listed in Table 1. Those complications, captured by The Society of Thoracic Surgeons (STS) Cardiac Surgery Database, include receiving ventilation longer than 24 hours, pneumonia, pulmonary embolism, and pleural effusion requiring drainage (The Society of Thoracic Surgeons. STS National Database. https://www.sts.org/registries-research-center/sts-national-database. Accessed January 9, 2018).

It should come as no surprise that cardiac surgery can have pronounced effects on lung function. The anesthetic agents, chest wall alteration, and direct lung manipulation can all affect pulmonary parameters. Functional residual capacity (FRC) can decrease by up to 20% with anesthesia (Szelowski LA, et al. Curr Probl Surg. 2015;52[1]:531), and the thoracic manipulation and alteration of rib cage mechanics with a classic median sternotomy approach can lead to decreases in forced vital capacity (FVC) and expiratory volume in the first second of forced expiration (FEV₁) that can last for months after surgery. Use of the cardiopulmonary bypass circuit can also lead to bronchoconstriction. These changes in pulmonary function are less pronounced in alternative surgical approaches, such as partial sternotomies (Weissman C. Seminars in Cardiothoracic and Vascular Anesthesia: Pulmonary Complications After Cardiac Surgery. Glen Head, NY: Westminister Publications; 2004).

The most frequent pulmonary consequence of cardiac surgery is atelectasis, seen on postoperative chest radiographs in approximately 50% to 90% of patients (Szelowski LA, et al. Curr Probl Surg. 2015;52[1]:531). Induction, apnea during cardiopulmonary bypass, manual compression of the lungs for surgical exposure, internal mammary harvesting, and pleurotomy can lead to atelectasis in the intraoperative setting while weak cough, poor inspiratory efforts, interstitial edema, and immobility further contribute postoperatively (Weissman 2004). While frequently seen, clinically significant pulmonary consequences from this radiographic finding alone are rare (Weissman 2004).

Pleural effusions are seen on immediate postoperative chest radiographs in the majority of patients. Additionally, 10% to 40% of patients develop pleural effusions 2 to 3 weeks after surgery secondary to postpericardiotomy syndrome. While some effusions require drainage and further intervention (eg, hemothorax), most effusions require no specific treatment and resolve over time (Weissman 2004).

The prevalence of pneumonia following cardiac surgery varies based on differences in study populations and diagnostic criteria, but it remains an important source of morbidity and mortality. In one series, postoperative pneumonia occurred in 3.1% of patients, with higher rates observed in patients who were older, had worse left ventricular ejection fraction, had COPD, experienced longer bypass times, and received more red blood cell transfusions in the operating room (Allou N, et al. Crit Care Med. 2014;42[5]:1150). A meta-analysis found that an average of 6.37% of patients developed ventilator-associated pneumonia (VAP), and this rose to 35.2% in those receiving ventilation for greater than 48 hours. Those who developed VAP had an odds ratio of dying of 15.18 (95% CI 5.81-39.68) compared with those who did not (He S, et al. J Thorac Cardiovasc Surg. 2014;148[6]:3148).

A small proportion of patients go on to develop ARDS. While relatively uncommon, ARDS carries a high mortality rate. Many possible etiologies for ARDS in cardiac surgery patients have been proposed, including an inflammatory response related to the cardiopulmonary bypass circuit, reperfusion injury secondary to reduced pulmonary blood flow during bypass, protamine administration, transfusion, hypothermia, and lack of ventilation during bypass (Weissman 2004); (Stephens RS, et al. Ann Thorac Surg. 2013;95[3]:1122). Type of surgery may also play a role, as patients who undergo aortic surgery are at an even greater risk (Stephens 2013). As with other cases of ARDS, treatment is supportive: low tidal volume ventilation and careful management of fluid balance, as well as paralysis, prone positioning, and consideration for extracorporeal membrane oxygenation (ECMO), as appropriate (Stephens 2013).

Therapies to prevent postoperative pulmonary complications have included early extubation, aggressive pain control, deep breathing, physical therapy, early mobilization, and noninvasive ventilation in the form of CPAP and intermittent positive pressure breathing. A meta-analysis of 18 trials looking at the use of various forms of prophylactic postoperative physiotherapy did not show a difference in any measured clinical outcome (Pasquina P, Walder B. Br Med J. 2003;327[7428]:1379).

However, the heterogeneity, short follow-up, and low quality of included studies made it difficult to draw meaningful conclusions on the benefit or lack thereof for these therapies. More recent studies have shown promise for chest physiotherapy started several weeks prior to elective coronary bypass graft surgery and extended CPAP via nasal CPAP mask immediately following extubation (Hulzebos EH. JAMA. 2006;296[15]:1851), (Stephens 2013).

Ongoing areas for improvement include further clarification and standardization of best practices for postcardiac surgery patients, including blood product transfusion, optimal tidal volumes for surgical and postsurgical ventilation, timing of extubation, and the use of preventive therapies in the pre- and postsurgical periods. As providers who care for these patients, understanding how we can improve their postoperative pulmonary recovery will allow us to enhance our patient’s experience.

Dr. Noel is a Critical Care Fellow, Cooper Medical School of Rowan University, Camden, New Jersey.

Cardiac surgery patients are sicker today than in previous decades due to an aging population and a rising complexity in medical care. There is an increasing reliance on noncardiac surgeons to care for these patients. The optimal postoperative providers and structure of the ICU where patients are cared for remain unclear, but what is irrefutable is patients’ increased postoperative morbidity. Pulmonary complications are a leading cause of morbidity in these patients, occurring in up to one-fifth of cases (Szelowski LA, et al. Curr Probl Surg. 2015;52[1]:531). Common pulmonary complications of cardiac surgery are listed in Table 1. Those complications, captured by The Society of Thoracic Surgeons (STS) Cardiac Surgery Database, include receiving ventilation longer than 24 hours, pneumonia, pulmonary embolism, and pleural effusion requiring drainage (The Society of Thoracic Surgeons. STS National Database. https://www.sts.org/registries-research-center/sts-national-database. Accessed January 9, 2018).

It should come as no surprise that cardiac surgery can have pronounced effects on lung function. The anesthetic agents, chest wall alteration, and direct lung manipulation can all affect pulmonary parameters. Functional residual capacity (FRC) can decrease by up to 20% with anesthesia (Szelowski LA, et al. Curr Probl Surg. 2015;52[1]:531), and the thoracic manipulation and alteration of rib cage mechanics with a classic median sternotomy approach can lead to decreases in forced vital capacity (FVC) and expiratory volume in the first second of forced expiration (FEV₁) that can last for months after surgery. Use of the cardiopulmonary bypass circuit can also lead to bronchoconstriction. These changes in pulmonary function are less pronounced in alternative surgical approaches, such as partial sternotomies (Weissman C. Seminars in Cardiothoracic and Vascular Anesthesia: Pulmonary Complications After Cardiac Surgery. Glen Head, NY: Westminister Publications; 2004).

The most frequent pulmonary consequence of cardiac surgery is atelectasis, seen on postoperative chest radiographs in approximately 50% to 90% of patients (Szelowski LA, et al. Curr Probl Surg. 2015;52[1]:531). Induction, apnea during cardiopulmonary bypass, manual compression of the lungs for surgical exposure, internal mammary harvesting, and pleurotomy can lead to atelectasis in the intraoperative setting while weak cough, poor inspiratory efforts, interstitial edema, and immobility further contribute postoperatively (Weissman 2004). While frequently seen, clinically significant pulmonary consequences from this radiographic finding alone are rare (Weissman 2004).

Pleural effusions are seen on immediate postoperative chest radiographs in the majority of patients. Additionally, 10% to 40% of patients develop pleural effusions 2 to 3 weeks after surgery secondary to postpericardiotomy syndrome. While some effusions require drainage and further intervention (eg, hemothorax), most effusions require no specific treatment and resolve over time (Weissman 2004).

The prevalence of pneumonia following cardiac surgery varies based on differences in study populations and diagnostic criteria, but it remains an important source of morbidity and mortality. In one series, postoperative pneumonia occurred in 3.1% of patients, with higher rates observed in patients who were older, had worse left ventricular ejection fraction, had COPD, experienced longer bypass times, and received more red blood cell transfusions in the operating room (Allou N, et al. Crit Care Med. 2014;42[5]:1150). A meta-analysis found that an average of 6.37% of patients developed ventilator-associated pneumonia (VAP), and this rose to 35.2% in those receiving ventilation for greater than 48 hours. Those who developed VAP had an odds ratio of dying of 15.18 (95% CI 5.81-39.68) compared with those who did not (He S, et al. J Thorac Cardiovasc Surg. 2014;148[6]:3148).

A small proportion of patients go on to develop ARDS. While relatively uncommon, ARDS carries a high mortality rate. Many possible etiologies for ARDS in cardiac surgery patients have been proposed, including an inflammatory response related to the cardiopulmonary bypass circuit, reperfusion injury secondary to reduced pulmonary blood flow during bypass, protamine administration, transfusion, hypothermia, and lack of ventilation during bypass (Weissman 2004); (Stephens RS, et al. Ann Thorac Surg. 2013;95[3]:1122). Type of surgery may also play a role, as patients who undergo aortic surgery are at an even greater risk (Stephens 2013). As with other cases of ARDS, treatment is supportive: low tidal volume ventilation and careful management of fluid balance, as well as paralysis, prone positioning, and consideration for extracorporeal membrane oxygenation (ECMO), as appropriate (Stephens 2013).

Therapies to prevent postoperative pulmonary complications have included early extubation, aggressive pain control, deep breathing, physical therapy, early mobilization, and noninvasive ventilation in the form of CPAP and intermittent positive pressure breathing. A meta-analysis of 18 trials looking at the use of various forms of prophylactic postoperative physiotherapy did not show a difference in any measured clinical outcome (Pasquina P, Walder B. Br Med J. 2003;327[7428]:1379).

However, the heterogeneity, short follow-up, and low quality of included studies made it difficult to draw meaningful conclusions on the benefit or lack thereof for these therapies. More recent studies have shown promise for chest physiotherapy started several weeks prior to elective coronary bypass graft surgery and extended CPAP via nasal CPAP mask immediately following extubation (Hulzebos EH. JAMA. 2006;296[15]:1851), (Stephens 2013).

Ongoing areas for improvement include further clarification and standardization of best practices for postcardiac surgery patients, including blood product transfusion, optimal tidal volumes for surgical and postsurgical ventilation, timing of extubation, and the use of preventive therapies in the pre- and postsurgical periods. As providers who care for these patients, understanding how we can improve their postoperative pulmonary recovery will allow us to enhance our patient’s experience.

Dr. Noel is a Critical Care Fellow, Cooper Medical School of Rowan University, Camden, New Jersey.

Cardiac surgery patients are sicker today than in previous decades due to an aging population and a rising complexity in medical care. There is an increasing reliance on noncardiac surgeons to care for these patients. The optimal postoperative providers and structure of the ICU where patients are cared for remain unclear, but what is irrefutable is patients’ increased postoperative morbidity. Pulmonary complications are a leading cause of morbidity in these patients, occurring in up to one-fifth of cases (Szelowski LA, et al. Curr Probl Surg. 2015;52[1]:531). Common pulmonary complications of cardiac surgery are listed in Table 1. Those complications, captured by The Society of Thoracic Surgeons (STS) Cardiac Surgery Database, include receiving ventilation longer than 24 hours, pneumonia, pulmonary embolism, and pleural effusion requiring drainage (The Society of Thoracic Surgeons. STS National Database. https://www.sts.org/registries-research-center/sts-national-database. Accessed January 9, 2018).

It should come as no surprise that cardiac surgery can have pronounced effects on lung function. The anesthetic agents, chest wall alteration, and direct lung manipulation can all affect pulmonary parameters. Functional residual capacity (FRC) can decrease by up to 20% with anesthesia (Szelowski LA, et al. Curr Probl Surg. 2015;52[1]:531), and the thoracic manipulation and alteration of rib cage mechanics with a classic median sternotomy approach can lead to decreases in forced vital capacity (FVC) and expiratory volume in the first second of forced expiration (FEV₁) that can last for months after surgery. Use of the cardiopulmonary bypass circuit can also lead to bronchoconstriction. These changes in pulmonary function are less pronounced in alternative surgical approaches, such as partial sternotomies (Weissman C. Seminars in Cardiothoracic and Vascular Anesthesia: Pulmonary Complications After Cardiac Surgery. Glen Head, NY: Westminister Publications; 2004).

The most frequent pulmonary consequence of cardiac surgery is atelectasis, seen on postoperative chest radiographs in approximately 50% to 90% of patients (Szelowski LA, et al. Curr Probl Surg. 2015;52[1]:531). Induction, apnea during cardiopulmonary bypass, manual compression of the lungs for surgical exposure, internal mammary harvesting, and pleurotomy can lead to atelectasis in the intraoperative setting while weak cough, poor inspiratory efforts, interstitial edema, and immobility further contribute postoperatively (Weissman 2004). While frequently seen, clinically significant pulmonary consequences from this radiographic finding alone are rare (Weissman 2004).

Pleural effusions are seen on immediate postoperative chest radiographs in the majority of patients. Additionally, 10% to 40% of patients develop pleural effusions 2 to 3 weeks after surgery secondary to postpericardiotomy syndrome. While some effusions require drainage and further intervention (eg, hemothorax), most effusions require no specific treatment and resolve over time (Weissman 2004).

The prevalence of pneumonia following cardiac surgery varies based on differences in study populations and diagnostic criteria, but it remains an important source of morbidity and mortality. In one series, postoperative pneumonia occurred in 3.1% of patients, with higher rates observed in patients who were older, had worse left ventricular ejection fraction, had COPD, experienced longer bypass times, and received more red blood cell transfusions in the operating room (Allou N, et al. Crit Care Med. 2014;42[5]:1150). A meta-analysis found that an average of 6.37% of patients developed ventilator-associated pneumonia (VAP), and this rose to 35.2% in those receiving ventilation for greater than 48 hours. Those who developed VAP had an odds ratio of dying of 15.18 (95% CI 5.81-39.68) compared with those who did not (He S, et al. J Thorac Cardiovasc Surg. 2014;148[6]:3148).

A small proportion of patients go on to develop ARDS. While relatively uncommon, ARDS carries a high mortality rate. Many possible etiologies for ARDS in cardiac surgery patients have been proposed, including an inflammatory response related to the cardiopulmonary bypass circuit, reperfusion injury secondary to reduced pulmonary blood flow during bypass, protamine administration, transfusion, hypothermia, and lack of ventilation during bypass (Weissman 2004); (Stephens RS, et al. Ann Thorac Surg. 2013;95[3]:1122). Type of surgery may also play a role, as patients who undergo aortic surgery are at an even greater risk (Stephens 2013). As with other cases of ARDS, treatment is supportive: low tidal volume ventilation and careful management of fluid balance, as well as paralysis, prone positioning, and consideration for extracorporeal membrane oxygenation (ECMO), as appropriate (Stephens 2013).

Therapies to prevent postoperative pulmonary complications have included early extubation, aggressive pain control, deep breathing, physical therapy, early mobilization, and noninvasive ventilation in the form of CPAP and intermittent positive pressure breathing. A meta-analysis of 18 trials looking at the use of various forms of prophylactic postoperative physiotherapy did not show a difference in any measured clinical outcome (Pasquina P, Walder B. Br Med J. 2003;327[7428]:1379).

However, the heterogeneity, short follow-up, and low quality of included studies made it difficult to draw meaningful conclusions on the benefit or lack thereof for these therapies. More recent studies have shown promise for chest physiotherapy started several weeks prior to elective coronary bypass graft surgery and extended CPAP via nasal CPAP mask immediately following extubation (Hulzebos EH. JAMA. 2006;296[15]:1851), (Stephens 2013).

Ongoing areas for improvement include further clarification and standardization of best practices for postcardiac surgery patients, including blood product transfusion, optimal tidal volumes for surgical and postsurgical ventilation, timing of extubation, and the use of preventive therapies in the pre- and postsurgical periods. As providers who care for these patients, understanding how we can improve their postoperative pulmonary recovery will allow us to enhance our patient’s experience.

Dr. Noel is a Critical Care Fellow, Cooper Medical School of Rowan University, Camden, New Jersey.

Office blood pressure measurement is not sufficient monitoring for women who have experienced severe preeclampsia, as it misses forms of hypertension commonly experienced in that population, according to a study published Feb. 5 in Hypertension.

Researchers at Erasmus University, Rotterdam, the Netherlands, conducted a retrospective cohort study of 200 women who underwent 24-hour ambulatory BP monitoring and office BP measurement at a 1-year follow-up for delivery with severe preeclampsia. Measurements were taken between 9 months and 15 months after delivery.

copyright Sohel_Parvez_Haque/Thinkstock

[email protected]

SOURCE: Benschop L et al. Hypertension. 2018 Feb;71:491-8.

Office blood pressure measurement is not sufficient monitoring for women who have experienced severe preeclampsia, as it misses forms of hypertension commonly experienced in that population, according to a study published Feb. 5 in Hypertension.

Researchers at Erasmus University, Rotterdam, the Netherlands, conducted a retrospective cohort study of 200 women who underwent 24-hour ambulatory BP monitoring and office BP measurement at a 1-year follow-up for delivery with severe preeclampsia. Measurements were taken between 9 months and 15 months after delivery.

copyright Sohel_Parvez_Haque/Thinkstock

[email protected]

SOURCE: Benschop L et al. Hypertension. 2018 Feb;71:491-8.

Office blood pressure measurement is not sufficient monitoring for women who have experienced severe preeclampsia, as it misses forms of hypertension commonly experienced in that population, according to a study published Feb. 5 in Hypertension.

Researchers at Erasmus University, Rotterdam, the Netherlands, conducted a retrospective cohort study of 200 women who underwent 24-hour ambulatory BP monitoring and office BP measurement at a 1-year follow-up for delivery with severe preeclampsia. Measurements were taken between 9 months and 15 months after delivery.

copyright Sohel_Parvez_Haque/Thinkstock

[email protected]

SOURCE: Benschop L et al. Hypertension. 2018 Feb;71:491-8.

Two years ago, a panel appointed by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine, referred to as a consensus conference, proposed a new definition for sepsis and new diagnostic criteria for sepsis and septic shock, known as Sepsis-3 (Singer M, et al. JAMA. 2016;315[8]:801). The panel proposed that sepsis be defined as life-threatening organ dysfunction due to a dysregulated host response to infection. Upon reflection, one could see that what we had called definitions of sepsis, severe sepsis, and septic shock for over 2 decades actually represented diagnostic criteria more than concise definitions. In that regard, a concise definition is a useful addition in the tool kit for training all health-care professionals to recognize sepsis and to treat it early and aggressively.

However, the diagnostic criteria leave something to be desired, in terms of both practicality and sensitivity for detecting patients whose infection has made them seriously ill. Those who participate in quality improvement efforts in their own hospitals will recognize that to promote change and to achieve a goal of better, higher quality care, it is important to remove obstacles in the system and to structure it so that doing the right thing is easier than not doing it. For sepsis, the first step in the process, recognizing that sepsis is present, has always been complex enough that it has been the bane of the enterprise. As many as two-thirds of patients with sepsis presenting to the ED with severe sepsis never receive that diagnosis while in the hospital. (Deis AS, et al. Chest. 2018;153[1]:39). As any sepsis core measure coordinator can attest, diagnostic criteria that are readily visible on retrospective examination are often unnoticed or misinterpreted in real time.

The crux of this issue is that the very entity of sepsis is not a definite thing but a not-quite-focused idea. Much is known of pathophysiologic features that seem to be important, but there is no one unifying pathologic condition. Contrast that with another critical illness, myocardial infarction. The very name states the unifying pathology. Our predecessors were able to work backward from an understanding that acute blockage of a small artery led to ischemia and infarction, in order to identify methods to detect it while it is happening—measuring enzymes and evaluating an ECG. For sepsis, we don’t even understand why patients are sick or why they die. There is a complex interaction of inflammation, microcirculatory thrombosis, mitochondrial dysfunction, immune suppression, but there is no one combination of those things that is yet understood in a way that lends itself to diagnostic testing. The best we can say is that the patient reacted to their infection in a way that was detrimental to their own body’s functioning. Rather than recognizing a few symptoms and sending a confirmatory test, with sepsis, we must tote up the signs and symptoms in the domains of recognizing infection and recognizing organ dysfunction, then determine whether they are present in sufficient amounts; it is an exercise that requires mental discipline.

If the diagnostic criteria we use, whether Sepsis-1, 2, or 3, are all gross descriptions of complex internal interactions that are not specific, then the syndrome that any of these criteria identifies is also not specific for anything particular. It falls to the medical community, as a whole, to determine exactly what it is that we desire a given syndrome to be indicative of. The Sepsis-3 authors decided that the appropriate syndrome should predict death or prolonged ICU stay. They used several large data sets to develop and validate infection-associated variables that would have good predictive ability for that outcome, and they compared what they found with sepsis by the Sepsis-1 definition, infection plus SIRS (Seymour C, et al. JAMA. 2016;315[8]:762). Infection + SIRS is a strawman in this comparison, because they tested its predictive ability for the outcome against that of the Sequential Organ Failure Assessment (SOFA) and the Logistic Organ Dysfunction Score (LODS). These two scoring systems were developed as severity of injury scales and validated as mortality predictors; the higher the score, the likelier mortality, whereas SIRS clearly contains no information about organ dysfunction. The comparator of interest for this outcome is actually severe sepsis, infection plus SIRS plus organ dysfunction.

Although the criteria the Sepsis-3 investigators used for defining patients with suspected infection were novel and reasonable, we lack additional important information about the patients they studied. They did not report the spectrum of treatments for sepsis in their cohort, whether early or late, adequate or inadequate, so it is impossible to determine whether the criteria address patients who are undertreated, patients who are treated late, patients who will die regardless of adequate therapy, or some combination. In other words, there is no way to tell whether patients who were recognized early in their course via Sepsis-1 criteria and treated aggressively and effectively may have avoided shock, ICU admission, and death. It is, of course, the business of physicians and nurses to help patients avoid exactly those things. Multiple studies have now demonstrated that SIRS criteria are more sensitive than SOFA-based screens, specifically qSOFA, for identifying infection with organ dysfunction, and that qSOFA is more specific for mortality (Serafim, et al. Chest. 2017; http://dx.doi.org/10.1016/j.chest.2017.12.015).

In contrast, the Sepsis-1 authors proposed infection plus SIRS as a sensitive screening tool that could warn of the possibility of an associated organ dysfunction (Sprung, et al. Crit Care Med. 2017;45[9]:1564). Previous to the Sepsis-1 conference, Bone and colleagues had defined the sepsis syndrome, which incorporated both SIRS and organ dysfunction (Bone, et al. Crit Care Med. 1989;17[5]:389). It was the collective insight of the Sepsis-1 participants to recognize that SIRS induced by infection could be a harbinger of organ failure. The Sepsis-3 authors believe that SIRS is a “normal and adaptive” part of infection and that it is “not useful” in the diagnosis of sepsis. That analysis neglects a couple of important things about SIRS. First, numerous studies demonstrate that infection with SIRS is associated with a mortality rate of 7% to 9%, which is by no means trivial (Rangel-Frausto MS, et al. JAMA. 1995;273[2]:117). Second, the components of SIRS have been recognized as representative of serious illness for millennia; the assertion that the Sepsis-1 definitions are not evidence-based is mistaken and discounts the collective experience of the medical profession.

Finally, SIRS is criticized on the basis of being nonspecific. “If I climb a flight of stairs, I get SIRS.” This is clearly a true statement. In fact, one could propose that the name could more accurately be Systemic Stress Response Syndrome, though “scissors” is certainly less catchy than “sirs” when one says it aloud. However, the critique neglects an important concept, encapsulated in Bayes’ Theorem. The value of any positive test result is largely dependent on the prevalence of the disease being tested for in the population being tested. It is unlikely that the prevalence of sepsis is very high among patients whose SIRS is induced by climbing a flight of stairs. On the other hand, tachycardia and tachypnea in a patient who is indulging in no activity while lying on a bed feeling miserable should prompt a search for both the infection that could be causing it and the organ dysfunction that could be associated with it. The specificity of SIRS derives from the population in which it is witnessed, and its sensitivity is to be respected.

To quote a friend, the remarkable CEO of a small Kansas hospital, “If a patient with an infection feels bad enough that they climb up on that gurney and place themselves at our mercy, we owe it to them to prove why they don’t have sepsis, rather than why they do.”

Editor’s Comment

The progress made in the last several years emphasizes the importance of early identification and aggressive treatment of sepsis. The Third International Consensus Definitions (Sepsis-3) have sparked great controversy in the sepsis community, because they delay the recognition of sepsis until organ damage occurs. In this Critical Care Commentary, Dr. Steven Q. Simpson asserts with solid arguments that the use of a screening tool with higher specificity for mortality, at the expense of sensitivity, is not a step in the right direction. Moving away from criteria that have been widely adopted in clinical trials and quality improvement initiatives throughout the world can be a setback in the battle to improve sepsis outcomes. Until prospectively validated criteria that allow earlier identification of sepsis are developed, there is no compelling reason for change.

Angel Coz, MD, FCCP
Section Editor

Dr. Simpson is Professor, Interim Director; Division of Pulmonary and Critical Care Medicine, University of Kansas, Kansas City, Kansas.

Two years ago, a panel appointed by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine, referred to as a consensus conference, proposed a new definition for sepsis and new diagnostic criteria for sepsis and septic shock, known as Sepsis-3 (Singer M, et al. JAMA. 2016;315[8]:801). The panel proposed that sepsis be defined as life-threatening organ dysfunction due to a dysregulated host response to infection. Upon reflection, one could see that what we had called definitions of sepsis, severe sepsis, and septic shock for over 2 decades actually represented diagnostic criteria more than concise definitions. In that regard, a concise definition is a useful addition in the tool kit for training all health-care professionals to recognize sepsis and to treat it early and aggressively.

However, the diagnostic criteria leave something to be desired, in terms of both practicality and sensitivity for detecting patients whose infection has made them seriously ill. Those who participate in quality improvement efforts in their own hospitals will recognize that to promote change and to achieve a goal of better, higher quality care, it is important to remove obstacles in the system and to structure it so that doing the right thing is easier than not doing it. For sepsis, the first step in the process, recognizing that sepsis is present, has always been complex enough that it has been the bane of the enterprise. As many as two-thirds of patients with sepsis presenting to the ED with severe sepsis never receive that diagnosis while in the hospital. (Deis AS, et al. Chest. 2018;153[1]:39). As any sepsis core measure coordinator can attest, diagnostic criteria that are readily visible on retrospective examination are often unnoticed or misinterpreted in real time.

The crux of this issue is that the very entity of sepsis is not a definite thing but a not-quite-focused idea. Much is known of pathophysiologic features that seem to be important, but there is no one unifying pathologic condition. Contrast that with another critical illness, myocardial infarction. The very name states the unifying pathology. Our predecessors were able to work backward from an understanding that acute blockage of a small artery led to ischemia and infarction, in order to identify methods to detect it while it is happening—measuring enzymes and evaluating an ECG. For sepsis, we don’t even understand why patients are sick or why they die. There is a complex interaction of inflammation, microcirculatory thrombosis, mitochondrial dysfunction, immune suppression, but there is no one combination of those things that is yet understood in a way that lends itself to diagnostic testing. The best we can say is that the patient reacted to their infection in a way that was detrimental to their own body’s functioning. Rather than recognizing a few symptoms and sending a confirmatory test, with sepsis, we must tote up the signs and symptoms in the domains of recognizing infection and recognizing organ dysfunction, then determine whether they are present in sufficient amounts; it is an exercise that requires mental discipline.

If the diagnostic criteria we use, whether Sepsis-1, 2, or 3, are all gross descriptions of complex internal interactions that are not specific, then the syndrome that any of these criteria identifies is also not specific for anything particular. It falls to the medical community, as a whole, to determine exactly what it is that we desire a given syndrome to be indicative of. The Sepsis-3 authors decided that the appropriate syndrome should predict death or prolonged ICU stay. They used several large data sets to develop and validate infection-associated variables that would have good predictive ability for that outcome, and they compared what they found with sepsis by the Sepsis-1 definition, infection plus SIRS (Seymour C, et al. JAMA. 2016;315[8]:762). Infection + SIRS is a strawman in this comparison, because they tested its predictive ability for the outcome against that of the Sequential Organ Failure Assessment (SOFA) and the Logistic Organ Dysfunction Score (LODS). These two scoring systems were developed as severity of injury scales and validated as mortality predictors; the higher the score, the likelier mortality, whereas SIRS clearly contains no information about organ dysfunction. The comparator of interest for this outcome is actually severe sepsis, infection plus SIRS plus organ dysfunction.

Although the criteria the Sepsis-3 investigators used for defining patients with suspected infection were novel and reasonable, we lack additional important information about the patients they studied. They did not report the spectrum of treatments for sepsis in their cohort, whether early or late, adequate or inadequate, so it is impossible to determine whether the criteria address patients who are undertreated, patients who are treated late, patients who will die regardless of adequate therapy, or some combination. In other words, there is no way to tell whether patients who were recognized early in their course via Sepsis-1 criteria and treated aggressively and effectively may have avoided shock, ICU admission, and death. It is, of course, the business of physicians and nurses to help patients avoid exactly those things. Multiple studies have now demonstrated that SIRS criteria are more sensitive than SOFA-based screens, specifically qSOFA, for identifying infection with organ dysfunction, and that qSOFA is more specific for mortality (Serafim, et al. Chest. 2017; http://dx.doi.org/10.1016/j.chest.2017.12.015).

In contrast, the Sepsis-1 authors proposed infection plus SIRS as a sensitive screening tool that could warn of the possibility of an associated organ dysfunction (Sprung, et al. Crit Care Med. 2017;45[9]:1564). Previous to the Sepsis-1 conference, Bone and colleagues had defined the sepsis syndrome, which incorporated both SIRS and organ dysfunction (Bone, et al. Crit Care Med. 1989;17[5]:389). It was the collective insight of the Sepsis-1 participants to recognize that SIRS induced by infection could be a harbinger of organ failure. The Sepsis-3 authors believe that SIRS is a “normal and adaptive” part of infection and that it is “not useful” in the diagnosis of sepsis. That analysis neglects a couple of important things about SIRS. First, numerous studies demonstrate that infection with SIRS is associated with a mortality rate of 7% to 9%, which is by no means trivial (Rangel-Frausto MS, et al. JAMA. 1995;273[2]:117). Second, the components of SIRS have been recognized as representative of serious illness for millennia; the assertion that the Sepsis-1 definitions are not evidence-based is mistaken and discounts the collective experience of the medical profession.

Finally, SIRS is criticized on the basis of being nonspecific. “If I climb a flight of stairs, I get SIRS.” This is clearly a true statement. In fact, one could propose that the name could more accurately be Systemic Stress Response Syndrome, though “scissors” is certainly less catchy than “sirs” when one says it aloud. However, the critique neglects an important concept, encapsulated in Bayes’ Theorem. The value of any positive test result is largely dependent on the prevalence of the disease being tested for in the population being tested. It is unlikely that the prevalence of sepsis is very high among patients whose SIRS is induced by climbing a flight of stairs. On the other hand, tachycardia and tachypnea in a patient who is indulging in no activity while lying on a bed feeling miserable should prompt a search for both the infection that could be causing it and the organ dysfunction that could be associated with it. The specificity of SIRS derives from the population in which it is witnessed, and its sensitivity is to be respected.

To quote a friend, the remarkable CEO of a small Kansas hospital, “If a patient with an infection feels bad enough that they climb up on that gurney and place themselves at our mercy, we owe it to them to prove why they don’t have sepsis, rather than why they do.”

Editor’s Comment

The progress made in the last several years emphasizes the importance of early identification and aggressive treatment of sepsis. The Third International Consensus Definitions (Sepsis-3) have sparked great controversy in the sepsis community, because they delay the recognition of sepsis until organ damage occurs. In this Critical Care Commentary, Dr. Steven Q. Simpson asserts with solid arguments that the use of a screening tool with higher specificity for mortality, at the expense of sensitivity, is not a step in the right direction. Moving away from criteria that have been widely adopted in clinical trials and quality improvement initiatives throughout the world can be a setback in the battle to improve sepsis outcomes. Until prospectively validated criteria that allow earlier identification of sepsis are developed, there is no compelling reason for change.

Angel Coz, MD, FCCP
Section Editor

Dr. Simpson is Professor, Interim Director; Division of Pulmonary and Critical Care Medicine, University of Kansas, Kansas City, Kansas.

Two years ago, a panel appointed by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine, referred to as a consensus conference, proposed a new definition for sepsis and new diagnostic criteria for sepsis and septic shock, known as Sepsis-3 (Singer M, et al. JAMA. 2016;315[8]:801). The panel proposed that sepsis be defined as life-threatening organ dysfunction due to a dysregulated host response to infection. Upon reflection, one could see that what we had called definitions of sepsis, severe sepsis, and septic shock for over 2 decades actually represented diagnostic criteria more than concise definitions. In that regard, a concise definition is a useful addition in the tool kit for training all health-care professionals to recognize sepsis and to treat it early and aggressively.

However, the diagnostic criteria leave something to be desired, in terms of both practicality and sensitivity for detecting patients whose infection has made them seriously ill. Those who participate in quality improvement efforts in their own hospitals will recognize that to promote change and to achieve a goal of better, higher quality care, it is important to remove obstacles in the system and to structure it so that doing the right thing is easier than not doing it. For sepsis, the first step in the process, recognizing that sepsis is present, has always been complex enough that it has been the bane of the enterprise. As many as two-thirds of patients with sepsis presenting to the ED with severe sepsis never receive that diagnosis while in the hospital. (Deis AS, et al. Chest. 2018;153[1]:39). As any sepsis core measure coordinator can attest, diagnostic criteria that are readily visible on retrospective examination are often unnoticed or misinterpreted in real time.

The crux of this issue is that the very entity of sepsis is not a definite thing but a not-quite-focused idea. Much is known of pathophysiologic features that seem to be important, but there is no one unifying pathologic condition. Contrast that with another critical illness, myocardial infarction. The very name states the unifying pathology. Our predecessors were able to work backward from an understanding that acute blockage of a small artery led to ischemia and infarction, in order to identify methods to detect it while it is happening—measuring enzymes and evaluating an ECG. For sepsis, we don’t even understand why patients are sick or why they die. There is a complex interaction of inflammation, microcirculatory thrombosis, mitochondrial dysfunction, immune suppression, but there is no one combination of those things that is yet understood in a way that lends itself to diagnostic testing. The best we can say is that the patient reacted to their infection in a way that was detrimental to their own body’s functioning. Rather than recognizing a few symptoms and sending a confirmatory test, with sepsis, we must tote up the signs and symptoms in the domains of recognizing infection and recognizing organ dysfunction, then determine whether they are present in sufficient amounts; it is an exercise that requires mental discipline.

If the diagnostic criteria we use, whether Sepsis-1, 2, or 3, are all gross descriptions of complex internal interactions that are not specific, then the syndrome that any of these criteria identifies is also not specific for anything particular. It falls to the medical community, as a whole, to determine exactly what it is that we desire a given syndrome to be indicative of. The Sepsis-3 authors decided that the appropriate syndrome should predict death or prolonged ICU stay. They used several large data sets to develop and validate infection-associated variables that would have good predictive ability for that outcome, and they compared what they found with sepsis by the Sepsis-1 definition, infection plus SIRS (Seymour C, et al. JAMA. 2016;315[8]:762). Infection + SIRS is a strawman in this comparison, because they tested its predictive ability for the outcome against that of the Sequential Organ Failure Assessment (SOFA) and the Logistic Organ Dysfunction Score (LODS). These two scoring systems were developed as severity of injury scales and validated as mortality predictors; the higher the score, the likelier mortality, whereas SIRS clearly contains no information about organ dysfunction. The comparator of interest for this outcome is actually severe sepsis, infection plus SIRS plus organ dysfunction.

Although the criteria the Sepsis-3 investigators used for defining patients with suspected infection were novel and reasonable, we lack additional important information about the patients they studied. They did not report the spectrum of treatments for sepsis in their cohort, whether early or late, adequate or inadequate, so it is impossible to determine whether the criteria address patients who are undertreated, patients who are treated late, patients who will die regardless of adequate therapy, or some combination. In other words, there is no way to tell whether patients who were recognized early in their course via Sepsis-1 criteria and treated aggressively and effectively may have avoided shock, ICU admission, and death. It is, of course, the business of physicians and nurses to help patients avoid exactly those things. Multiple studies have now demonstrated that SIRS criteria are more sensitive than SOFA-based screens, specifically qSOFA, for identifying infection with organ dysfunction, and that qSOFA is more specific for mortality (Serafim, et al. Chest. 2017; http://dx.doi.org/10.1016/j.chest.2017.12.015).

In contrast, the Sepsis-1 authors proposed infection plus SIRS as a sensitive screening tool that could warn of the possibility of an associated organ dysfunction (Sprung, et al. Crit Care Med. 2017;45[9]:1564). Previous to the Sepsis-1 conference, Bone and colleagues had defined the sepsis syndrome, which incorporated both SIRS and organ dysfunction (Bone, et al. Crit Care Med. 1989;17[5]:389). It was the collective insight of the Sepsis-1 participants to recognize that SIRS induced by infection could be a harbinger of organ failure. The Sepsis-3 authors believe that SIRS is a “normal and adaptive” part of infection and that it is “not useful” in the diagnosis of sepsis. That analysis neglects a couple of important things about SIRS. First, numerous studies demonstrate that infection with SIRS is associated with a mortality rate of 7% to 9%, which is by no means trivial (Rangel-Frausto MS, et al. JAMA. 1995;273[2]:117). Second, the components of SIRS have been recognized as representative of serious illness for millennia; the assertion that the Sepsis-1 definitions are not evidence-based is mistaken and discounts the collective experience of the medical profession.

Finally, SIRS is criticized on the basis of being nonspecific. “If I climb a flight of stairs, I get SIRS.” This is clearly a true statement. In fact, one could propose that the name could more accurately be Systemic Stress Response Syndrome, though “scissors” is certainly less catchy than “sirs” when one says it aloud. However, the critique neglects an important concept, encapsulated in Bayes’ Theorem. The value of any positive test result is largely dependent on the prevalence of the disease being tested for in the population being tested. It is unlikely that the prevalence of sepsis is very high among patients whose SIRS is induced by climbing a flight of stairs. On the other hand, tachycardia and tachypnea in a patient who is indulging in no activity while lying on a bed feeling miserable should prompt a search for both the infection that could be causing it and the organ dysfunction that could be associated with it. The specificity of SIRS derives from the population in which it is witnessed, and its sensitivity is to be respected.

To quote a friend, the remarkable CEO of a small Kansas hospital, “If a patient with an infection feels bad enough that they climb up on that gurney and place themselves at our mercy, we owe it to them to prove why they don’t have sepsis, rather than why they do.”

Editor’s Comment

The progress made in the last several years emphasizes the importance of early identification and aggressive treatment of sepsis. The Third International Consensus Definitions (Sepsis-3) have sparked great controversy in the sepsis community, because they delay the recognition of sepsis until organ damage occurs. In this Critical Care Commentary, Dr. Steven Q. Simpson asserts with solid arguments that the use of a screening tool with higher specificity for mortality, at the expense of sensitivity, is not a step in the right direction. Moving away from criteria that have been widely adopted in clinical trials and quality improvement initiatives throughout the world can be a setback in the battle to improve sepsis outcomes. Until prospectively validated criteria that allow earlier identification of sepsis are developed, there is no compelling reason for change.

Angel Coz, MD, FCCP
Section Editor

Dr. Simpson is Professor, Interim Director; Division of Pulmonary and Critical Care Medicine, University of Kansas, Kansas City, Kansas.

Have you shopped at the CHEST Store lately? We’ve recently updated our merchandise to include several new items perfect for staff gifts or for yourself. Along with our old standbys, including lab coats and scrubs, we now feature CHEST-branded scarves, knit caps (perfect for winter), and insulated hot and cold drink mugs. And don’t forget, most items are customizable for a small, additional fee. For the more education-inclined, the store also features the best in CHEST print, including CHEST SEEK^TM volumes, Coding for Chest Medicine, patient education guides, and much more.

Products can be ordered online, and most items are sold on-site at our live learning and board review courses and at the CHEST Annual Meeting. If you can’t purchase in person, visit the store at chestnet.org/store to stock up.

Have you shopped at the CHEST Store lately? We’ve recently updated our merchandise to include several new items perfect for staff gifts or for yourself. Along with our old standbys, including lab coats and scrubs, we now feature CHEST-branded scarves, knit caps (perfect for winter), and insulated hot and cold drink mugs. And don’t forget, most items are customizable for a small, additional fee. For the more education-inclined, the store also features the best in CHEST print, including CHEST SEEK^TM volumes, Coding for Chest Medicine, patient education guides, and much more.

Products can be ordered online, and most items are sold on-site at our live learning and board review courses and at the CHEST Annual Meeting. If you can’t purchase in person, visit the store at chestnet.org/store to stock up.

Have you shopped at the CHEST Store lately? We’ve recently updated our merchandise to include several new items perfect for staff gifts or for yourself. Along with our old standbys, including lab coats and scrubs, we now feature CHEST-branded scarves, knit caps (perfect for winter), and insulated hot and cold drink mugs. And don’t forget, most items are customizable for a small, additional fee. For the more education-inclined, the store also features the best in CHEST print, including CHEST SEEK^TM volumes, Coding for Chest Medicine, patient education guides, and much more.

Products can be ordered online, and most items are sold on-site at our live learning and board review courses and at the CHEST Annual Meeting. If you can’t purchase in person, visit the store at chestnet.org/store to stock up.

CHEST has been informed of the following members’ deaths.

We extend our sincere condolences.

Nagesh V Salian, MD, FCCP (2016)

Ted A Calinog, MD, FCCP (2017)

Azam Ansari, MD (2017)

Arthur E. Schmidt, MD, FCCP (2017)

CHEST has been informed of the following members’ deaths.

We extend our sincere condolences.

Nagesh V Salian, MD, FCCP (2016)

Ted A Calinog, MD, FCCP (2017)

Azam Ansari, MD (2017)

Arthur E. Schmidt, MD, FCCP (2017)

CHEST has been informed of the following members’ deaths.

We extend our sincere condolences.

Nagesh V Salian, MD, FCCP (2016)

Ted A Calinog, MD, FCCP (2017)

Azam Ansari, MD (2017)

Arthur E. Schmidt, MD, FCCP (2017)

Giants In Chest Medicine Professor Nan-shan Zhong, MD.

By Wei-jie Guan.

Original Research

Long-term Use of Inhaled Corticosteroids in COPD and the Risk of Fracture. By Dr. A. V. Gonzalez, et al.

Cardiac Troponin Values in Patients With Acute Coronary Syndrome and Sleep Apnea: A Pilot Study. By Dr. A. Sánchez-de-la-Torre, et al.

CA-125 in Disease Progression and Treatment of Lymphangioleiomyomatosis. By Dr. C. G. Glasgow, et al.

Evidence-Based Medicine

Cough Due to TB and Other Chronic Infections: CHEST Guideline and Expert Panel Report. By Dr. S. K. Field, et al, on behalf of the CHEST Expert Cough Panel.

Giants In Chest Medicine Professor Nan-shan Zhong, MD.

By Wei-jie Guan.

Original Research

Long-term Use of Inhaled Corticosteroids in COPD and the Risk of Fracture. By Dr. A. V. Gonzalez, et al.

Cardiac Troponin Values in Patients With Acute Coronary Syndrome and Sleep Apnea: A Pilot Study. By Dr. A. Sánchez-de-la-Torre, et al.

CA-125 in Disease Progression and Treatment of Lymphangioleiomyomatosis. By Dr. C. G. Glasgow, et al.

Evidence-Based Medicine

Cough Due to TB and Other Chronic Infections: CHEST Guideline and Expert Panel Report. By Dr. S. K. Field, et al, on behalf of the CHEST Expert Cough Panel.

Giants In Chest Medicine Professor Nan-shan Zhong, MD.

By Wei-jie Guan.

Original Research

Long-term Use of Inhaled Corticosteroids in COPD and the Risk of Fracture. By Dr. A. V. Gonzalez, et al.

Cardiac Troponin Values in Patients With Acute Coronary Syndrome and Sleep Apnea: A Pilot Study. By Dr. A. Sánchez-de-la-Torre, et al.

CA-125 in Disease Progression and Treatment of Lymphangioleiomyomatosis. By Dr. C. G. Glasgow, et al.

Evidence-Based Medicine

Cough Due to TB and Other Chronic Infections: CHEST Guideline and Expert Panel Report. By Dr. S. K. Field, et al, on behalf of the CHEST Expert Cough Panel.

KAUAI, HAWAII – Imiquimod on the lip can be extremely painful, but it works wonders for actinic cheilitis, sometimes with only a few treatments.

Also, photodynamic therapy for actinic keratoses (AKs) doesn’t have to hurt. You just have to adjust the aminolevulinic acid incubation time and how long patients stay under the lamp, advised Theodore Rosen, MD, professor of dermatology at Baylor College of Medicine, Houston.

These are just a few of the tips Dr. Rosen shared in a presentation about AKs at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

In a video interview after his talk, he went into detail about the use of imiquimod for actinic cheilitis – AKs of the lip – and painless PDT, as well as how to discuss AKs with patients – and a quick, clever way to help distinguish AKs from squamous cell carcinoma.

Dr. Rosen is an adviser to Aclaris, Cipher, Pfizer, and Valeant.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

[email protected]

KAUAI, HAWAII – Imiquimod on the lip can be extremely painful, but it works wonders for actinic cheilitis, sometimes with only a few treatments.

Also, photodynamic therapy for actinic keratoses (AKs) doesn’t have to hurt. You just have to adjust the aminolevulinic acid incubation time and how long patients stay under the lamp, advised Theodore Rosen, MD, professor of dermatology at Baylor College of Medicine, Houston.

These are just a few of the tips Dr. Rosen shared in a presentation about AKs at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

In a video interview after his talk, he went into detail about the use of imiquimod for actinic cheilitis – AKs of the lip – and painless PDT, as well as how to discuss AKs with patients – and a quick, clever way to help distinguish AKs from squamous cell carcinoma.

Dr. Rosen is an adviser to Aclaris, Cipher, Pfizer, and Valeant.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

[email protected]

KAUAI, HAWAII – Imiquimod on the lip can be extremely painful, but it works wonders for actinic cheilitis, sometimes with only a few treatments.

Also, photodynamic therapy for actinic keratoses (AKs) doesn’t have to hurt. You just have to adjust the aminolevulinic acid incubation time and how long patients stay under the lamp, advised Theodore Rosen, MD, professor of dermatology at Baylor College of Medicine, Houston.

These are just a few of the tips Dr. Rosen shared in a presentation about AKs at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

In a video interview after his talk, he went into detail about the use of imiquimod for actinic cheilitis – AKs of the lip – and painless PDT, as well as how to discuss AKs with patients – and a quick, clever way to help distinguish AKs from squamous cell carcinoma.

Dr. Rosen is an adviser to Aclaris, Cipher, Pfizer, and Valeant.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

[email protected]

SAN FRANCISCO – The order in which targeted therapies are given to patients with previously treated metastatic colorectal cancer can have a marked impact on overall survival, according to results of the REVERCE trial reported at the 2018 GI Cancers Symposium.

Investigators led by Kohei Shitara, MD, National Cancer Center Hospital East, Kashiwa, Japan, enrolled in the multicenter, phase 2, randomized trial 101 patients with mainly KRAS wild-type metastatic colorectal cancer who had previously received fluoropyrimidine, oxaliplatin, and irinotecan, but not any therapy targeting epidermal growth factor receptor (EGFR).

Clinical implications

“The amount of difference in overall survival [between sequences] was pretty striking. These were patients in second line and third line,” commented session chair Michael J. Hall, MD, of Fox Chase Cancer Center, Philadelphia.

Study details

The REVERCE investigators planned to enroll 180 patients in the trial but stopped after 101 patients because of slow accrual. Most of those studied had previously received bevacizumab.

About 70% of patients in the regorafenib-first group needed a dose reduction at some point, compared with about 30% in the cetuximab-first group, a difference likely related to the longer duration of treatment for the former, Dr. Shitara speculated.

Median overall survival was 17.4 months when regorafenib was given first and 11.6 months when cetuximab was give first (hazard ratio, 0.61; P = .029), according to data reported at the symposium, which was sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

In subgroup analyses, the regorafenib-first strategy yielded significantly better overall survival among patients with left-sided tumors (HR, 0.51; P = .011), but not among those with right-sided tumors (HR, 0.88).

The regorafenib-first strategy had similar benefit when restricted to patients with RAS/RAF wild-type tumors (18.2 vs. 12.7 months; HR, 0.60; P = .036).

Analysis of blood samples collected after the first agent indicated that 26% of patients had emergence of a RAS mutation after receiving cetuximab. However, these patients did not appear to have worse overall survival, according to Dr. Shitara.

Progression-free survival on the first agent was 2.4 months in the regorafenib-first group and 4.2 months in the cetuximab-first group, a nonsignificant difference. In contrast, for the second treatment, it was 5.2 months in the regorafenib-first group and just 1.8 months in the cetuximab-first group (HR, 0.29; P less than .0001).

Dr. Shitara disclosed that he receives honoraria from Abbvie, Novartis, Ono Pharmaceutical, and Yakult; has a consulting or advisory role with Astellas Pharma, Bristol-Myers Squibb, Lilly, Pfizer, and Takeda; and that his institution receives research funding from Chugai Pharma, Daiichi Sankyo, Dainippon Sumitomo Pharma, Lilly, MSD, Taiho Pharmaceutical, and Yakult. The trial was funded by Bayer Yahin.

SOURCE: Shitara et al. GI Cancers Symposium Abstract 557

SAN FRANCISCO – The order in which targeted therapies are given to patients with previously treated metastatic colorectal cancer can have a marked impact on overall survival, according to results of the REVERCE trial reported at the 2018 GI Cancers Symposium.

Investigators led by Kohei Shitara, MD, National Cancer Center Hospital East, Kashiwa, Japan, enrolled in the multicenter, phase 2, randomized trial 101 patients with mainly KRAS wild-type metastatic colorectal cancer who had previously received fluoropyrimidine, oxaliplatin, and irinotecan, but not any therapy targeting epidermal growth factor receptor (EGFR).

Clinical implications

“The amount of difference in overall survival [between sequences] was pretty striking. These were patients in second line and third line,” commented session chair Michael J. Hall, MD, of Fox Chase Cancer Center, Philadelphia.

Study details

The REVERCE investigators planned to enroll 180 patients in the trial but stopped after 101 patients because of slow accrual. Most of those studied had previously received bevacizumab.

About 70% of patients in the regorafenib-first group needed a dose reduction at some point, compared with about 30% in the cetuximab-first group, a difference likely related to the longer duration of treatment for the former, Dr. Shitara speculated.

Median overall survival was 17.4 months when regorafenib was given first and 11.6 months when cetuximab was give first (hazard ratio, 0.61; P = .029), according to data reported at the symposium, which was sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

In subgroup analyses, the regorafenib-first strategy yielded significantly better overall survival among patients with left-sided tumors (HR, 0.51; P = .011), but not among those with right-sided tumors (HR, 0.88).

The regorafenib-first strategy had similar benefit when restricted to patients with RAS/RAF wild-type tumors (18.2 vs. 12.7 months; HR, 0.60; P = .036).

Analysis of blood samples collected after the first agent indicated that 26% of patients had emergence of a RAS mutation after receiving cetuximab. However, these patients did not appear to have worse overall survival, according to Dr. Shitara.

Progression-free survival on the first agent was 2.4 months in the regorafenib-first group and 4.2 months in the cetuximab-first group, a nonsignificant difference. In contrast, for the second treatment, it was 5.2 months in the regorafenib-first group and just 1.8 months in the cetuximab-first group (HR, 0.29; P less than .0001).

Dr. Shitara disclosed that he receives honoraria from Abbvie, Novartis, Ono Pharmaceutical, and Yakult; has a consulting or advisory role with Astellas Pharma, Bristol-Myers Squibb, Lilly, Pfizer, and Takeda; and that his institution receives research funding from Chugai Pharma, Daiichi Sankyo, Dainippon Sumitomo Pharma, Lilly, MSD, Taiho Pharmaceutical, and Yakult. The trial was funded by Bayer Yahin.

SOURCE: Shitara et al. GI Cancers Symposium Abstract 557

SAN FRANCISCO – The order in which targeted therapies are given to patients with previously treated metastatic colorectal cancer can have a marked impact on overall survival, according to results of the REVERCE trial reported at the 2018 GI Cancers Symposium.

Investigators led by Kohei Shitara, MD, National Cancer Center Hospital East, Kashiwa, Japan, enrolled in the multicenter, phase 2, randomized trial 101 patients with mainly KRAS wild-type metastatic colorectal cancer who had previously received fluoropyrimidine, oxaliplatin, and irinotecan, but not any therapy targeting epidermal growth factor receptor (EGFR).

Clinical implications

“The amount of difference in overall survival [between sequences] was pretty striking. These were patients in second line and third line,” commented session chair Michael J. Hall, MD, of Fox Chase Cancer Center, Philadelphia.

Study details

The REVERCE investigators planned to enroll 180 patients in the trial but stopped after 101 patients because of slow accrual. Most of those studied had previously received bevacizumab.

About 70% of patients in the regorafenib-first group needed a dose reduction at some point, compared with about 30% in the cetuximab-first group, a difference likely related to the longer duration of treatment for the former, Dr. Shitara speculated.

Median overall survival was 17.4 months when regorafenib was given first and 11.6 months when cetuximab was give first (hazard ratio, 0.61; P = .029), according to data reported at the symposium, which was sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

In subgroup analyses, the regorafenib-first strategy yielded significantly better overall survival among patients with left-sided tumors (HR, 0.51; P = .011), but not among those with right-sided tumors (HR, 0.88).

The regorafenib-first strategy had similar benefit when restricted to patients with RAS/RAF wild-type tumors (18.2 vs. 12.7 months; HR, 0.60; P = .036).

Analysis of blood samples collected after the first agent indicated that 26% of patients had emergence of a RAS mutation after receiving cetuximab. However, these patients did not appear to have worse overall survival, according to Dr. Shitara.

Progression-free survival on the first agent was 2.4 months in the regorafenib-first group and 4.2 months in the cetuximab-first group, a nonsignificant difference. In contrast, for the second treatment, it was 5.2 months in the regorafenib-first group and just 1.8 months in the cetuximab-first group (HR, 0.29; P less than .0001).

Dr. Shitara disclosed that he receives honoraria from Abbvie, Novartis, Ono Pharmaceutical, and Yakult; has a consulting or advisory role with Astellas Pharma, Bristol-Myers Squibb, Lilly, Pfizer, and Takeda; and that his institution receives research funding from Chugai Pharma, Daiichi Sankyo, Dainippon Sumitomo Pharma, Lilly, MSD, Taiho Pharmaceutical, and Yakult. The trial was funded by Bayer Yahin.

SOURCE: Shitara et al. GI Cancers Symposium Abstract 557

Our first daughter was born during my last year in medical school, and our second was born as I was finishing my second year in residency. Seeing those two little darlings grow and develop was a critical supplement to my pediatric training. And, watching my wife initially struggle and then succeed with breastfeeding provided a very personal experience and education about lactation that my interactions in the hospital and outpatient clinics didn’t offer.

We considered ourselves lucky because my wife wasn’t facing the additional challenge of returning to an out-of-the-home job. However, our good fortune did not confer immunity against the anxiety, insecurity, discomfort, and sleep deprivation–induced frustrations of breastfeeding. Watching my wife navigate the choppy waters of lactation certainly influenced my approach to counseling new mothers over my subsequent 4 decades of practice. I think I was a more sympathetic and realistic adviser based on my first-hand observations.

©Lev Olkha/iStockphoto.com

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.”

Our first daughter was born during my last year in medical school, and our second was born as I was finishing my second year in residency. Seeing those two little darlings grow and develop was a critical supplement to my pediatric training. And, watching my wife initially struggle and then succeed with breastfeeding provided a very personal experience and education about lactation that my interactions in the hospital and outpatient clinics didn’t offer.

We considered ourselves lucky because my wife wasn’t facing the additional challenge of returning to an out-of-the-home job. However, our good fortune did not confer immunity against the anxiety, insecurity, discomfort, and sleep deprivation–induced frustrations of breastfeeding. Watching my wife navigate the choppy waters of lactation certainly influenced my approach to counseling new mothers over my subsequent 4 decades of practice. I think I was a more sympathetic and realistic adviser based on my first-hand observations.

©Lev Olkha/iStockphoto.com

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.”

Our first daughter was born during my last year in medical school, and our second was born as I was finishing my second year in residency. Seeing those two little darlings grow and develop was a critical supplement to my pediatric training. And, watching my wife initially struggle and then succeed with breastfeeding provided a very personal experience and education about lactation that my interactions in the hospital and outpatient clinics didn’t offer.

We considered ourselves lucky because my wife wasn’t facing the additional challenge of returning to an out-of-the-home job. However, our good fortune did not confer immunity against the anxiety, insecurity, discomfort, and sleep deprivation–induced frustrations of breastfeeding. Watching my wife navigate the choppy waters of lactation certainly influenced my approach to counseling new mothers over my subsequent 4 decades of practice. I think I was a more sympathetic and realistic adviser based on my first-hand observations.

©Lev Olkha/iStockphoto.com

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.”

SNOWMASS, COLO. – After years of dazzlingly declining mortality due to ST-elevation MI, progress has stalled, Ajay J. Kirtane, MD, declared at the Annual Cardiovascular Conference at Snowmass.

“We have to recognize the fact that our success has somewhat plateaued. We’ve made great strides in shortening door-to-balloon times, but further reductions in [that measure] are not translating into further reductions in adverse outcomes,” observed Dr. Kirtane of Columbia University, New York.

Bruce Jancin/Frontline Medical News

What about nonculprit lesions?

A hot topic in STEMI management is what to do about residual disease in nonculprit vessels after primary PCI.

“Some people have drawn upon trials like COURAGE to inform their decision making, saying ‘Now the patient is stabilized, we’ve treated the STEMI, so we could now treat the patient like a COURAGE patient [with optimal medical therapy alone].’ I would caution against extrapolating the results of COURAGE and other stable ischemic heart disease paradigms to these types of patients. They’ve already presented with a very high risk feature – STEMI – and in addition, in the COURAGE trial there were only 118 patients that had acute coronary syndrome of less than 2 weeks’ duration out of more than 2,000 subjects,” Dr. Kirtane said.

“Intravascular ultrasound studies show that nonculprit plaques in stable angina are very different from those in STEMI: They’re typically fibrotic and stable, while even the nonculprit plaques in STEMI or non-STEMI ACS are much more inflamed and vulnerable,” he added.

He predicted clarity regarding best management in this area will come from the ongoing COMPLETE trial, a multinational study of nearly 4,000 patients randomized to staged nonculprit lesion PCI versus medical therapy plus culprit lesion-only revascularization. The study is due to be completed late in 2018.

Improving pharmacotherapy

Rates of hospital discharge on guideline-directed optimal medical therapy after primary PCI have risen steadily in recent years. However, studies indicate a significant minority of patients drop from dual-antiplatelet therapy to aspirin alone within a month after leaving the hospital.

Also, it’s essential to effectively inhibit both platelets and thrombus in the catheterization lab. But is that happening consistently? There is now evidence of delayed absorption of the potent oral antiplatelet agents in STEMI patients. Moreover, that delay is exacerbated by having morphine or fentanyl on board.

“It’s been shown that even with ticagrelor and prasugrel, in STEMI patients at 2 hours, you still don’t have sufficient inhibition of platelet aggregation, whereas if I gave one of those drugs to any of us here in the audience now we’d have full effect within an hour or 2 max. That’s one of the reasons why there’s a rationale for using an intravenous agent such as cangrelor [Kengreal], a nonthienopyridine direct P2Y12 inhibitor,” Dr. Kirtane said.
 

Transradial access for primary PCI

Dr. Kirtane argued in a recent editorial that widespread adoption of transradial PCI for STEMI will provide the next major advance in STEMI systems of care resulting in improved clinical outcomes (JAMA Cardiol. 2017 Oct 1;2[10]:1057-8).

This is a controversial issue, he acknowledged. “There are interventional cardiologists who say, ‘No way.’ ” But studies indicate that transradial PCI for STEMI reduces mortality by 16%-48% compared with transfemoral access, without a significant cost in terms of door-to-balloon time. For now, transfemoral access PCI remains the most common strategy for STEMI patients in the United States, although the use of transradial primary PCI is growing.

Dr. Kirtane reported receiving research grants from more than half a dozen medical device companies.

[email protected]

SNOWMASS, COLO. – After years of dazzlingly declining mortality due to ST-elevation MI, progress has stalled, Ajay J. Kirtane, MD, declared at the Annual Cardiovascular Conference at Snowmass.

“We have to recognize the fact that our success has somewhat plateaued. We’ve made great strides in shortening door-to-balloon times, but further reductions in [that measure] are not translating into further reductions in adverse outcomes,” observed Dr. Kirtane of Columbia University, New York.

Bruce Jancin/Frontline Medical News

What about nonculprit lesions?

A hot topic in STEMI management is what to do about residual disease in nonculprit vessels after primary PCI.

“Some people have drawn upon trials like COURAGE to inform their decision making, saying ‘Now the patient is stabilized, we’ve treated the STEMI, so we could now treat the patient like a COURAGE patient [with optimal medical therapy alone].’ I would caution against extrapolating the results of COURAGE and other stable ischemic heart disease paradigms to these types of patients. They’ve already presented with a very high risk feature – STEMI – and in addition, in the COURAGE trial there were only 118 patients that had acute coronary syndrome of less than 2 weeks’ duration out of more than 2,000 subjects,” Dr. Kirtane said.

“Intravascular ultrasound studies show that nonculprit plaques in stable angina are very different from those in STEMI: They’re typically fibrotic and stable, while even the nonculprit plaques in STEMI or non-STEMI ACS are much more inflamed and vulnerable,” he added.

He predicted clarity regarding best management in this area will come from the ongoing COMPLETE trial, a multinational study of nearly 4,000 patients randomized to staged nonculprit lesion PCI versus medical therapy plus culprit lesion-only revascularization. The study is due to be completed late in 2018.

Improving pharmacotherapy

Rates of hospital discharge on guideline-directed optimal medical therapy after primary PCI have risen steadily in recent years. However, studies indicate a significant minority of patients drop from dual-antiplatelet therapy to aspirin alone within a month after leaving the hospital.

Also, it’s essential to effectively inhibit both platelets and thrombus in the catheterization lab. But is that happening consistently? There is now evidence of delayed absorption of the potent oral antiplatelet agents in STEMI patients. Moreover, that delay is exacerbated by having morphine or fentanyl on board.

“It’s been shown that even with ticagrelor and prasugrel, in STEMI patients at 2 hours, you still don’t have sufficient inhibition of platelet aggregation, whereas if I gave one of those drugs to any of us here in the audience now we’d have full effect within an hour or 2 max. That’s one of the reasons why there’s a rationale for using an intravenous agent such as cangrelor [Kengreal], a nonthienopyridine direct P2Y12 inhibitor,” Dr. Kirtane said.
 

Transradial access for primary PCI

Dr. Kirtane argued in a recent editorial that widespread adoption of transradial PCI for STEMI will provide the next major advance in STEMI systems of care resulting in improved clinical outcomes (JAMA Cardiol. 2017 Oct 1;2[10]:1057-8).

This is a controversial issue, he acknowledged. “There are interventional cardiologists who say, ‘No way.’ ” But studies indicate that transradial PCI for STEMI reduces mortality by 16%-48% compared with transfemoral access, without a significant cost in terms of door-to-balloon time. For now, transfemoral access PCI remains the most common strategy for STEMI patients in the United States, although the use of transradial primary PCI is growing.

Dr. Kirtane reported receiving research grants from more than half a dozen medical device companies.

[email protected]

SNOWMASS, COLO. – After years of dazzlingly declining mortality due to ST-elevation MI, progress has stalled, Ajay J. Kirtane, MD, declared at the Annual Cardiovascular Conference at Snowmass.

“We have to recognize the fact that our success has somewhat plateaued. We’ve made great strides in shortening door-to-balloon times, but further reductions in [that measure] are not translating into further reductions in adverse outcomes,” observed Dr. Kirtane of Columbia University, New York.

Bruce Jancin/Frontline Medical News

What about nonculprit lesions?

A hot topic in STEMI management is what to do about residual disease in nonculprit vessels after primary PCI.

“Some people have drawn upon trials like COURAGE to inform their decision making, saying ‘Now the patient is stabilized, we’ve treated the STEMI, so we could now treat the patient like a COURAGE patient [with optimal medical therapy alone].’ I would caution against extrapolating the results of COURAGE and other stable ischemic heart disease paradigms to these types of patients. They’ve already presented with a very high risk feature – STEMI – and in addition, in the COURAGE trial there were only 118 patients that had acute coronary syndrome of less than 2 weeks’ duration out of more than 2,000 subjects,” Dr. Kirtane said.

“Intravascular ultrasound studies show that nonculprit plaques in stable angina are very different from those in STEMI: They’re typically fibrotic and stable, while even the nonculprit plaques in STEMI or non-STEMI ACS are much more inflamed and vulnerable,” he added.

He predicted clarity regarding best management in this area will come from the ongoing COMPLETE trial, a multinational study of nearly 4,000 patients randomized to staged nonculprit lesion PCI versus medical therapy plus culprit lesion-only revascularization. The study is due to be completed late in 2018.

Improving pharmacotherapy

Rates of hospital discharge on guideline-directed optimal medical therapy after primary PCI have risen steadily in recent years. However, studies indicate a significant minority of patients drop from dual-antiplatelet therapy to aspirin alone within a month after leaving the hospital.

Also, it’s essential to effectively inhibit both platelets and thrombus in the catheterization lab. But is that happening consistently? There is now evidence of delayed absorption of the potent oral antiplatelet agents in STEMI patients. Moreover, that delay is exacerbated by having morphine or fentanyl on board.

“It’s been shown that even with ticagrelor and prasugrel, in STEMI patients at 2 hours, you still don’t have sufficient inhibition of platelet aggregation, whereas if I gave one of those drugs to any of us here in the audience now we’d have full effect within an hour or 2 max. That’s one of the reasons why there’s a rationale for using an intravenous agent such as cangrelor [Kengreal], a nonthienopyridine direct P2Y12 inhibitor,” Dr. Kirtane said.
 

Transradial access for primary PCI

Dr. Kirtane argued in a recent editorial that widespread adoption of transradial PCI for STEMI will provide the next major advance in STEMI systems of care resulting in improved clinical outcomes (JAMA Cardiol. 2017 Oct 1;2[10]:1057-8).

This is a controversial issue, he acknowledged. “There are interventional cardiologists who say, ‘No way.’ ” But studies indicate that transradial PCI for STEMI reduces mortality by 16%-48% compared with transfemoral access, without a significant cost in terms of door-to-balloon time. For now, transfemoral access PCI remains the most common strategy for STEMI patients in the United States, although the use of transradial primary PCI is growing.

Dr. Kirtane reported receiving research grants from more than half a dozen medical device companies.

[email protected]