EDITORIALS
Goal-directed Cardiopulmonary Resuscitation for Patients in Intensive Care Units The fundamental elements of cardiopulmonary resuscitation (CPR)— combining closed-chest cardiac massage and defibrillation—were first described and then promoted in guidelines during the 1950s and 1960s (1–3). Subsequent recommendations have focused on improving the delivery of effective CPR, for example optimizing the depth and rate of compressions, minimizing interruptions of chest compressions, and avoiding hyperventilation (4, 5). The impact has been transformative: modern CPR has improved survival rates after cardiac arrest, has become a mandatory element of clinical training, and is now provided by default to all in-hospital cardiac arrest cases unless there exist explicit directives to withhold it. However, CPR as recommended by current guidelines is largely a “one-size-fits-all” approach. All patients—regardless of size, precipitating rhythm, or underlying acute physiology—receive a standard algorithm for CPR including compression depth and rate. Improved adherence to these guidelines has been associated with better outcomes (6), but many clinicians may prefer a more nuanced approach for their individual patients. After all, we dose drugs according to renal function, adjust tidal volume to predicted body weight in patients with acute respiratory distress syndrome, and titrate vasopressors to desired blood pressure targets. Why wouldn’t we also provide CPR targeting specific physiological goals, rather than delivering the same resuscitation approach to all patients? In this issue of the Journal, Sutton and colleagues (pp. 1255– 1262) address this question directly by testing an approach that seeks to tailor CPR to an individual’s hemodynamic parameters (7). Using a swine model of cardiac arrest, they evaluated a more “patientcentric” resuscitation, in which CPR compression depth was titrated to achieve a systolic blood pressure of at least 100 mm Hg and vasopressors were adjusted to maintain coronary perfusion pressures greater than 20 mm Hg. They randomly assigned 20 pigs to receive blood pressure–targeted CPR versus resuscitation using standard CPR compression depth and repeated epinephrine dosing as recommended by American Heart Association guidelines. The differences in outcomes between the groups were dramatic: 80% of the pigs in the blood pressure–targeted CPR group survived to 24 hours, whereas no pigs survived in the standard CPR group. Most of this survival benefit was already apparent when they compared rates of successful return of spontaneous circulation after the arrest. Surprisingly, the mean compression depth and total number of vasopressor doses were actually lower among pigs in the blood pressure–targeted CPR group. The importance of the Sutton trial is that it represents a carefully controlled animal experiment that may lead to important changes in the current approach to providing CPR to some patients. Their results have biological plausibility and face validity: it makes sense that targeting CPR to deliver adequate coronary and systemic arterial pressures should work better than a more generic approach. Their findings are also concordant with those from earlier observational data in humans showing that successful return of spontaneous circulation is more likely in the setting of higher coronary perfusion pressures during CPR (8). In particular, providing blood pressure–targeted CPR may have clinical relevance to patients in intensive care units (ICUs) or Editorials
coronary care units. These patients frequently already have arterial and central venous catheters in situ during CPR, allowing for direct and immediate measurement of systemic arterial pressures and estimation of coronary perfusion pressures (calculated as the mathematical difference between arterial and right atrial diastolic pressures). The findings of this study are less likely to lead to changes in the approach to CPR in patients suffering out-of-hospital cardiac arrests, since the required hemodynamic measurements are seldom feasible. Clinicians should of course be wary of translating findings from animal research directly to the bedside. The swine cardiac arrest model that was used in this experiment has anatomical similarities to humans, including anterior–posterior chest depth and compression characteristics, but confirmatory human clinical research is required. Nevertheless, the potential benefits of CPR were first elucidated in animal experiments, and the treatment was quickly adopted into clinical practice because of a lack of alternative therapies for otherwise dire situations. In the same tradition, delivering CPR that targets a patient’s hemodynamics is an appealing approach for ICU patients who already have arterial and central venous catheters inserted—and for whom outcomes with conventional CPR remain very poor (9). Conducting randomized controlled trials to evaluate such an approach is not impossible but does present a daunting task: the incidence of cardiac arrest in ICU patients is less than 2% (10). Until such higher-level evidence becomes available, intensivists may choose to monitor—and titrate— systolic blood pressure and coronary perfusion pressure to ensure that goal-directed CPR is delivered when ICU patients develop cardiac arrest. n Author disclosures are available with the text of this article at www.atsjournals.org. Damon C. Scales, M.D., Ph.D. Department of Critical Care Medicine Sunnybrook Health Sciences Centre Toronto, Ontario, Canada and Interdepartmental Division of Critical Care Department of Medicine and Institute of Health Policy, Management and Evaluation University of Toronto Toronto, Ontario, Canada
References 1. Kouwenhoven WB, Jude JR, Knickerbocker GG. Closed-chest cardiac massage. JAMA 1960;173:1064–1067. 2. Ad Hoc Committee on Cardiopulmonary Resuscitation of the Division of Medical Sciences, National Academy of Sciences—National Research Council. Cardiopulmonary resuscitation. JAMA 1966;198: 372–379. 3. Cooper JA, Cooper JD, Cooper JM. Cardiopulmonary resuscitation: history, current practice, and future direction. Circulation 2006;114: 2839–2849. 4. Sayre MR, Koster RW, Botha M, Cave DM, Cudnik MT, Handley AJ, Hatanaka T, Hazinski MF, Jacobs I, Monsieurs K, et al.; Adult Basic
1205
EDITORIALS Life Support Chapter Collaborators. Part 5: Adult basic life support: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Circulation 2010;122:S298–S324. 5. Meaney PA, Bobrow BJ, Mancini ME, Christenson J, de Caen AR, Bhanji F, Abella BS, Kleinman ME, Edelson DP, Berg RA, et al.; CPR Quality Summit Investigators, the American Heart Association Emergency Cardiovascular Care Committee, and the Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation. Cardiopulmonary resuscitation quality: [corrected] improving cardiac resuscitation outcomes both inside and outside the hospital: a consensus statement from the American Heart Association. Circulation 2013; 128:417–435. 6. Wissenberg M, Lippert FK, Folke F, Weeke P, Hansen CM, Christensen EF, Jans H, Hansen PA, Lang-Jensen T, Olesen JB, et al. Association of national initiatives to improve cardiac arrest management with rates of bystander intervention and patient survival after out-ofhospital cardiac arrest. JAMA 2013;310:1377–1384.
7. Sutton RM, Friess SH, Naim MY, Lampe JW, Bratinov G, Weiland TR III, Garuccio M, Nadkarni VM, Becker LB, Berg RA. Patient-centric blood pressure–targeted cardiopulmonary resuscitation improves survival from cardiac arrest. Am J Respir Crit Care Med 2014;190:1255–1262. 8. Paradis NA, Martin GB, Rivers EP, Goetting MG, Appleton TJ, Feingold M, Nowak RM. Coronary perfusion pressure and the return of spontaneous circulation in human cardiopulmonary resuscitation. JAMA 1990;263: 1106–1113. 9. Tian J, Kaufman DA, Zarich S, Chan PS, Ong P, Amoateng-Adjepong Y, Manthous CA; American Heart Association National Registry for Cardiopulmonary Resuscitation Investigators. Outcomes of critically ill patients who received cardiopulmonary resuscitation. Am J Respir Crit Care Med 2010;182:501–506. 10. Gershengorn HB, Li G, Kramer A, Wunsch H. Survival and functional outcomes after cardiopulmonary resuscitation in the intensive care unit. J Crit Care 2012;27:421.e9–17.
Copyright © 2014 by the American Thoracic Society
The Infant Nose Introducing the Respiratory Tract to the World The nasopharynx is extraordinarily hospitable to bacteria. These upper airway microbes form an interface between the outside world and our lower respiratory tract, and as such, they have many implications for pulmonary biology and respiratory disease. Thanks to recent improvements in sequencing technologies, our appreciation of the upper airway bacteria is progressing rapidly. While in the womb, the airways are sterile and free of microbial exposures. With birth, however, these tissues are abruptly and ever-after exposed to a vast panoply of microbes, many of which thrive in the nasopharyngeal niche. The dynamics of nasopharyngeal colonization during these young ages was almost completely mysterious before a contribution in this issue of the Journal by Biesbroek and colleagues (pp. 1283–1292) (1). These investigators profiled nasopharyngeal samples serially collected from healthy children beginning at 1.5 months of age and continuing until 2 years of age. They used deep sequencing of 16S rRNA genes to characterize the microbial communities in these samples and machine learning algorithms to search for patterns within these communities and their changes over time. In some children, the microbiome observed at 1.5 months of age remained largely consistent throughout the examination period, suggesting early establishment of a stable microbiome structure that persisted during infancy and the toddler years. In contrast, other children had upper airway microbiomes that were less stable, changing markedly over time. Several factors were associated with the greater stability of the infant upper airway microbiome, including the types of bacteria predominating (in particular, an early colonization with Moraxella), breastfeeding, and fewer upper respiratory tract infections (URTIs). A major strength of these studies is the serial sampling of a cohort during this pivotal and interesting age range. These are first insights into the dynamics of nasopharyngeal microbiomes during infancy. Another strength of this work is the sophisticated approaches to resolving patterns among these large and complex data sets involving time series. Important limitations include the rather small size and narrow composition of the 1206
population studied and the reliance on parental reporting for outcomes of interest beyond microbiome data (e.g., URTIs were based on parental reports). Associations based on small numbers of participants with crude clinical information deserve caution. Another limitation is that the microbiome characterization was restricted entirely to bacterial inferences from 16S rRNA sequencing, so components of these microbial communities other than the relative composition of bacterial members were unexamined. This combination of strengths and limitations in the study design enabled the investigators to conclude that stable bacterial microbiomes are established quite early in the nasopharynges of some, but not all, infants and suggest that unstable nasopharyngeal microbiomes may associate positively with URTIs and negatively with Moraxella and breastfeeding. The association of nasopharyngeal microbiome instability with increased URTIs is intriguing. Does a stable microbiome help prevent infection? Do underlying host factors such as immunity parameters independently drive both outcomes, making microbiomes less stable and infections more likely? Do infections (e.g., by respiratory viruses) disrupt the nasopharyngeal microbiome and make it less stable? All seem reasonable possibilities, and they may be interacting (2). An experimental rhinovirus infection in adults is sufficient to alter the lower airway microbiome in patients with chronic obstructive pulmonary disease, but not healthy participants (3), suggesting that the relationships among URTIs, host factors, and airway microbiota are not linear, one-way relationships. The present publication does not shed light on mechanistic or causal relationships between microbiome stability and URTIs in young children, but by forwarding these relationships, it inspires future lines of investigation. In addition to the URTIs investigated here, the infant microbiome may also influence lower airway infections of infants and toddlers. Pneumonia is the leading cause of childhood death globally and the leading cause of hospitalization for U.S. children (4). Prior colonization of the upper airway with respiratory pathogens typically precedes lower respiratory
American Journal of Respiratory and Critical Care Medicine Volume 190 Number 11 | December 1 2014
Goal-directed Cardiopulmonary Resuscitation for Patients in Intensive Care Units The fundamental elements of cardiopulmonary resuscitation (CPR)— combining closed-chest cardiac massage and defibrillation—were first described and then promoted in guidelines during the 1950s and 1960s (1–3). Subsequent recommendations have focused on improving the delivery of effective CPR, for example optimizing the depth and rate of compressions, minimizing interruptions of chest compressions, and avoiding hyperventilation (4, 5). The impact has been transformative: modern CPR has improved survival rates after cardiac arrest, has become a mandatory element of clinical training, and is now provided by default to all in-hospital cardiac arrest cases unless there exist explicit directives to withhold it. However, CPR as recommended by current guidelines is largely a “one-size-fits-all” approach. All patients—regardless of size, precipitating rhythm, or underlying acute physiology—receive a standard algorithm for CPR including compression depth and rate. Improved adherence to these guidelines has been associated with better outcomes (6), but many clinicians may prefer a more nuanced approach for their individual patients. After all, we dose drugs according to renal function, adjust tidal volume to predicted body weight in patients with acute respiratory distress syndrome, and titrate vasopressors to desired blood pressure targets. Why wouldn’t we also provide CPR targeting specific physiological goals, rather than delivering the same resuscitation approach to all patients? In this issue of the Journal, Sutton and colleagues (pp. 1255– 1262) address this question directly by testing an approach that seeks to tailor CPR to an individual’s hemodynamic parameters (7). Using a swine model of cardiac arrest, they evaluated a more “patientcentric” resuscitation, in which CPR compression depth was titrated to achieve a systolic blood pressure of at least 100 mm Hg and vasopressors were adjusted to maintain coronary perfusion pressures greater than 20 mm Hg. They randomly assigned 20 pigs to receive blood pressure–targeted CPR versus resuscitation using standard CPR compression depth and repeated epinephrine dosing as recommended by American Heart Association guidelines. The differences in outcomes between the groups were dramatic: 80% of the pigs in the blood pressure–targeted CPR group survived to 24 hours, whereas no pigs survived in the standard CPR group. Most of this survival benefit was already apparent when they compared rates of successful return of spontaneous circulation after the arrest. Surprisingly, the mean compression depth and total number of vasopressor doses were actually lower among pigs in the blood pressure–targeted CPR group. The importance of the Sutton trial is that it represents a carefully controlled animal experiment that may lead to important changes in the current approach to providing CPR to some patients. Their results have biological plausibility and face validity: it makes sense that targeting CPR to deliver adequate coronary and systemic arterial pressures should work better than a more generic approach. Their findings are also concordant with those from earlier observational data in humans showing that successful return of spontaneous circulation is more likely in the setting of higher coronary perfusion pressures during CPR (8). In particular, providing blood pressure–targeted CPR may have clinical relevance to patients in intensive care units (ICUs) or Editorials
coronary care units. These patients frequently already have arterial and central venous catheters in situ during CPR, allowing for direct and immediate measurement of systemic arterial pressures and estimation of coronary perfusion pressures (calculated as the mathematical difference between arterial and right atrial diastolic pressures). The findings of this study are less likely to lead to changes in the approach to CPR in patients suffering out-of-hospital cardiac arrests, since the required hemodynamic measurements are seldom feasible. Clinicians should of course be wary of translating findings from animal research directly to the bedside. The swine cardiac arrest model that was used in this experiment has anatomical similarities to humans, including anterior–posterior chest depth and compression characteristics, but confirmatory human clinical research is required. Nevertheless, the potential benefits of CPR were first elucidated in animal experiments, and the treatment was quickly adopted into clinical practice because of a lack of alternative therapies for otherwise dire situations. In the same tradition, delivering CPR that targets a patient’s hemodynamics is an appealing approach for ICU patients who already have arterial and central venous catheters inserted—and for whom outcomes with conventional CPR remain very poor (9). Conducting randomized controlled trials to evaluate such an approach is not impossible but does present a daunting task: the incidence of cardiac arrest in ICU patients is less than 2% (10). Until such higher-level evidence becomes available, intensivists may choose to monitor—and titrate— systolic blood pressure and coronary perfusion pressure to ensure that goal-directed CPR is delivered when ICU patients develop cardiac arrest. n Author disclosures are available with the text of this article at www.atsjournals.org. Damon C. Scales, M.D., Ph.D. Department of Critical Care Medicine Sunnybrook Health Sciences Centre Toronto, Ontario, Canada and Interdepartmental Division of Critical Care Department of Medicine and Institute of Health Policy, Management and Evaluation University of Toronto Toronto, Ontario, Canada
References 1. Kouwenhoven WB, Jude JR, Knickerbocker GG. Closed-chest cardiac massage. JAMA 1960;173:1064–1067. 2. Ad Hoc Committee on Cardiopulmonary Resuscitation of the Division of Medical Sciences, National Academy of Sciences—National Research Council. Cardiopulmonary resuscitation. JAMA 1966;198: 372–379. 3. Cooper JA, Cooper JD, Cooper JM. Cardiopulmonary resuscitation: history, current practice, and future direction. Circulation 2006;114: 2839–2849. 4. Sayre MR, Koster RW, Botha M, Cave DM, Cudnik MT, Handley AJ, Hatanaka T, Hazinski MF, Jacobs I, Monsieurs K, et al.; Adult Basic
1205
EDITORIALS Life Support Chapter Collaborators. Part 5: Adult basic life support: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Circulation 2010;122:S298–S324. 5. Meaney PA, Bobrow BJ, Mancini ME, Christenson J, de Caen AR, Bhanji F, Abella BS, Kleinman ME, Edelson DP, Berg RA, et al.; CPR Quality Summit Investigators, the American Heart Association Emergency Cardiovascular Care Committee, and the Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation. Cardiopulmonary resuscitation quality: [corrected] improving cardiac resuscitation outcomes both inside and outside the hospital: a consensus statement from the American Heart Association. Circulation 2013; 128:417–435. 6. Wissenberg M, Lippert FK, Folke F, Weeke P, Hansen CM, Christensen EF, Jans H, Hansen PA, Lang-Jensen T, Olesen JB, et al. Association of national initiatives to improve cardiac arrest management with rates of bystander intervention and patient survival after out-ofhospital cardiac arrest. JAMA 2013;310:1377–1384.
7. Sutton RM, Friess SH, Naim MY, Lampe JW, Bratinov G, Weiland TR III, Garuccio M, Nadkarni VM, Becker LB, Berg RA. Patient-centric blood pressure–targeted cardiopulmonary resuscitation improves survival from cardiac arrest. Am J Respir Crit Care Med 2014;190:1255–1262. 8. Paradis NA, Martin GB, Rivers EP, Goetting MG, Appleton TJ, Feingold M, Nowak RM. Coronary perfusion pressure and the return of spontaneous circulation in human cardiopulmonary resuscitation. JAMA 1990;263: 1106–1113. 9. Tian J, Kaufman DA, Zarich S, Chan PS, Ong P, Amoateng-Adjepong Y, Manthous CA; American Heart Association National Registry for Cardiopulmonary Resuscitation Investigators. Outcomes of critically ill patients who received cardiopulmonary resuscitation. Am J Respir Crit Care Med 2010;182:501–506. 10. Gershengorn HB, Li G, Kramer A, Wunsch H. Survival and functional outcomes after cardiopulmonary resuscitation in the intensive care unit. J Crit Care 2012;27:421.e9–17.
Copyright © 2014 by the American Thoracic Society
The Infant Nose Introducing the Respiratory Tract to the World The nasopharynx is extraordinarily hospitable to bacteria. These upper airway microbes form an interface between the outside world and our lower respiratory tract, and as such, they have many implications for pulmonary biology and respiratory disease. Thanks to recent improvements in sequencing technologies, our appreciation of the upper airway bacteria is progressing rapidly. While in the womb, the airways are sterile and free of microbial exposures. With birth, however, these tissues are abruptly and ever-after exposed to a vast panoply of microbes, many of which thrive in the nasopharyngeal niche. The dynamics of nasopharyngeal colonization during these young ages was almost completely mysterious before a contribution in this issue of the Journal by Biesbroek and colleagues (pp. 1283–1292) (1). These investigators profiled nasopharyngeal samples serially collected from healthy children beginning at 1.5 months of age and continuing until 2 years of age. They used deep sequencing of 16S rRNA genes to characterize the microbial communities in these samples and machine learning algorithms to search for patterns within these communities and their changes over time. In some children, the microbiome observed at 1.5 months of age remained largely consistent throughout the examination period, suggesting early establishment of a stable microbiome structure that persisted during infancy and the toddler years. In contrast, other children had upper airway microbiomes that were less stable, changing markedly over time. Several factors were associated with the greater stability of the infant upper airway microbiome, including the types of bacteria predominating (in particular, an early colonization with Moraxella), breastfeeding, and fewer upper respiratory tract infections (URTIs). A major strength of these studies is the serial sampling of a cohort during this pivotal and interesting age range. These are first insights into the dynamics of nasopharyngeal microbiomes during infancy. Another strength of this work is the sophisticated approaches to resolving patterns among these large and complex data sets involving time series. Important limitations include the rather small size and narrow composition of the 1206
population studied and the reliance on parental reporting for outcomes of interest beyond microbiome data (e.g., URTIs were based on parental reports). Associations based on small numbers of participants with crude clinical information deserve caution. Another limitation is that the microbiome characterization was restricted entirely to bacterial inferences from 16S rRNA sequencing, so components of these microbial communities other than the relative composition of bacterial members were unexamined. This combination of strengths and limitations in the study design enabled the investigators to conclude that stable bacterial microbiomes are established quite early in the nasopharynges of some, but not all, infants and suggest that unstable nasopharyngeal microbiomes may associate positively with URTIs and negatively with Moraxella and breastfeeding. The association of nasopharyngeal microbiome instability with increased URTIs is intriguing. Does a stable microbiome help prevent infection? Do underlying host factors such as immunity parameters independently drive both outcomes, making microbiomes less stable and infections more likely? Do infections (e.g., by respiratory viruses) disrupt the nasopharyngeal microbiome and make it less stable? All seem reasonable possibilities, and they may be interacting (2). An experimental rhinovirus infection in adults is sufficient to alter the lower airway microbiome in patients with chronic obstructive pulmonary disease, but not healthy participants (3), suggesting that the relationships among URTIs, host factors, and airway microbiota are not linear, one-way relationships. The present publication does not shed light on mechanistic or causal relationships between microbiome stability and URTIs in young children, but by forwarding these relationships, it inspires future lines of investigation. In addition to the URTIs investigated here, the infant microbiome may also influence lower airway infections of infants and toddlers. Pneumonia is the leading cause of childhood death globally and the leading cause of hospitalization for U.S. children (4). Prior colonization of the upper airway with respiratory pathogens typically precedes lower respiratory
American Journal of Respiratory and Critical Care Medicine Volume 190 Number 11 | December 1 2014
