EDITORIALS Under Pressure: Reduced Cerebral Perfusion as a Risk Factor for Postoperative Delirium in Lung Transplant Recipients Brian J. Anderson1 and Joshua M. Diamond1,2 1
Division of Pulmonary, Allergy, and Critical Care Medicine, and 2Penn Lung Transplant Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
Delirium is common in the intensive care unit (ICU) (1) and is particularly common in patients recovering from lung transplantation (2, 3). The emergence of delirium is frightening to patients and family members. Delirium complicates patient care and is associated with prolonged mechanical ventilation (4, 5), longer hospital stays (3–6), and increased mortality (5–7). In addition, delirium is associated with significant long-term morbidity in ICU survivors, including long-term cognitive impairment (1, 2, 8). Importantly, growing evidence also suggests delirium is associated with potentially permanent brain injury. Imaging studies comparing ICU survivors with matched controls reveal significant volume loss in the frontal lobes and hippocampus, the severity of which is closely linked to the duration of delirium and the degree of long-term cognitive impairment (9, 10). The pathophysiology of delirium and how it may lead to subsequent cognitive impairment remains poorly understood. Few studies have investigated hypoperfusion as a mechanism leading delirium. One study by Wijdicks and colleagues demonstrated that cardiovascular failure was a risk factor for septic encephalopathy in 84 postoperative patients (11), but to our knowledge, the study in this month’s issue of AnnalsATS by Smith and colleagues (pp. 180–187) is the only human study linking hypoperfusion to delirium (12). Using a prospective cohort design, the authors obtained detailed hemodynamic
measurements on 63 patients who underwent lung transplantation. They defined cerebral perfusion pressure (CPP) as the difference between mean arterial pressure (MAP), measured by a femoral or radial arterial catheter, and central venous pressure (CVP), measured by a pulmonary artery catheter (CPP = MAP – CVP). Patients were assessed daily for delirium, using the Confusion Assessment Method, and were also assessed for delirium severity, using the Delirium Rating Scale. Using logistic regression adjusting for native lung disease and primary graft dysfunction, the authors demonstrated that every 10 mm Hg decrease in CPP was associated with a doubling of the odds of developing postoperative delirium (odds ratio, 2.08; 95% confidence interval, 1.08–4.24; P = 0.043). Next, in a negative binomial regression model adjusting for native lung disease and primary graft dysfunction, they showed that lower CPP was associated with longer duration of delirium (b = 20.54; 95% confidence interval, 21.00 to 20.08; P = 0.22), such that every 10 mm Hg decrease in CPP was associated with a 1.7-day increase in delirium duration. Finally, they identified an association of lower CPP with higher delirium severity, as well as associations of primary graft dysfunction with both odds of delirium and delirium duration. The study by Smith and colleagues has several strengths. First, the authors rigorously investigated an important topic that continues to challenge the critical care community. Second, the authors employed sound methodology, including a well-
defined exposure variable and use of a wellvalidated screening tool for delirium. Third, the statistical techniques were appropriately chosen and the authors assessed their models for overfitting, given the small number of outcomes relative to the potential numbers of covariates. Several potential limitations of the study should be noted. The study was performed at a single center and thus may not be generalizable. This remains the primary limitation to the majority of studies evaluating delirium and neurocognition in lung transplant recipients. Although the authors adjusted for native lung disease and subsequent development of primary graft dysfunction, the association of CPP with delirium may be subject to residual confounding by additional covariates such as pretransplant cognitive function, severity of illness (e.g., mechanical ventilation and/ or extracorporeal membrane oxygenation as a bridge to transplant), age, chronic history of hypertension, and benzodiazepine or opiate use (3, 13). One prior study identified graft ischemic time as an independent risk factor of worse posttransplant cognitive function (14); thus, it would be interesting to investigate graft ischemic time as a potential confounder. A particular challenge in investigating mechanisms of delirium in patients with end-stage lung disease who undergo lung transplantation is accounting for the effects of hypoxemia on cognitive function. The authors note that reduced cerebral oxygenation has been associated with postoperative neurocognitive dysfunction (12), and additional studies have shown
(Received in original form December 3, 2015; accepted in final form December 4, 2015 ) Supported in part by National Institutes of Health grant K23-HL121406. Correspondence and requests for reprints should be addressed to Brian J. Anderson, M.D., M.S., Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, 5048 Gates Building, Philadelphia, PA 19104. E-mail: [email protected] Ann Am Thorac Soc Vol 13, No 2, pp 156–157, Feb 2016 Copyright © 2016 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201512-796ED Internet address: www.atsjournals.org
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EDITORIALS that low arterial partial pressure of oxygen and low peripheral oxygen saturation measurements are associated with poor cognitive outcomes in survivors of Acute Respiratory Distress Syndrome (15, 16). Because decreased cerebral perfusion and decreased arterial oxygen saturation both ultimately result in reduced cerebral oxygen delivery, it is likely that both mechanisms can lead to brain injury and manifest as delirium and/or cognitive impairment. Although Smith and colleagues did not investigate hypoxemia in the present study, their well-phenotyped cohort presents a unique opportunity to explore the individual and combined effects of poor cerebral perfusion and reduced arterial oxygen saturation on
postoperative delirium and cognitive function. Despite potential limitations, the present study by Smith and colleagues suggests reduced cerebral perfusion is a potentially modifiable risk factor associated with risk, duration, and severity of postoperative delirium. A major question moving forward is whether reduced cerebral perfusion is associated with longer-term outcomes, such as long-term cognitive impairment and diminished executive function, and whether reduced cerebral perfusion pressure results in delirium simply through neuronal dysfunction or by causing more permanent brain injury. Studies employing systemic biomarkers of brain injury may be useful as a
References 1 Pandharipande PP, Girard TD, Jackson JC, Morandi A, Thompson JL, Pun BT, Brummel NE, Hughes CG, Vasilevskis EE, Shintani AK, et al.; BRAIN-ICU Study Investigators. Long-term cognitive impairment after critical illness. N Engl J Med 2013;369:1306–1316. 2 Smith PJ, Rivelli S, Waters A, Reynolds J, Hoyle A, Flowers M, Davis RD, Palmer SM, Mathew J, Durheim M, et al. Neurocognitive changes after lung transplantation. Ann Am Thorac Soc 2014;11: 1520–1527. 3 Smith PJ, Rivelli SK, Waters AM, Hoyle A, Durheim MT, Reynolds JM, Flowers M, Davis RD, Palmer SM, Mathew JP, et al. Delirium affects length of hospital stay after lung transplantation. J Crit Care 2015;30: 126–129. 4 Lat I, McMillian W, Taylor S, Janzen JM, Papadopoulos S, Korth L, Ehtisham A, Nold J, Agarwal S, Azocar R, et al. The impact of delirium on clinical outcomes in mechanically ventilated surgical and trauma patients. Crit Care Med 2009;37:1898–1905. 5 Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, Harrell FE Jr, Inouye SK, Bernard GR, Dittus RS. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA 2004;291:1753–1762. 6 Ouimet S, Kavanagh BP, Gottfried SB, Skrobik Y. Incidence, risk factors and consequences of ICU delirium. Intensive Care Med 2007;33:66–73. 7 Lin SM, Liu CY, Wang CH, Lin HC, Huang CD, Huang PY, Fang YF, Shieh MH, Kuo HP. The impact of delirium on the survival of mechanically ventilated patients. Crit Care Med 2004;32:2254–2259. 8 Girard TD, Jackson JC, Pandharipande PP, Pun BT, Thompson JL, Shintani AK, Gordon SM, Canonico AE, Dittus RS, Bernard GR, et al. Delirium as a predictor of long-term cognitive impairment in survivors of critical illness. Crit Care Med 2010;38:1513–1520.
Editorials
quantitative trait for assessing the degree of brain injury in critically ill patients. Biomarkers may also serve as surrogates when formal delirium testing is not possible in the setting of prolonged mechanical ventilation and significant sedation requirements. Detailed serial neuroimaging and longer-term follow-up of transplant recipient cognitive function may ultimately lead to a better understanding of the lasting effects of early posttransplant brain injury and give insight into how we can intervene to improve both short- and long-term neurocognitive outcomes after lung transplantation. n Author disclosures are available with the text of this article at www.atsjournals.org.
9 Gunther ML, Morandi A, Krauskopf E, Pandharipande P, Girard TD, Jackson JC, Thompson J, Shintani AK, Geevarghese S, Miller RR III, et al.; VISIONS Investigation, VISualizing Icu SurvivOrs Neuroradiological Sequelae. The association between brain volumes, delirium duration, and cognitive outcomes in intensive care unit survivors: the VISIONS cohort magnetic resonance imaging study*. Crit Care Med 2012;40:2022–2032. 10 Semmler A, Widmann CN, Okulla T, Urbach H, Kaiser M, Widman G, Mormann F, Weide J, Fliessbach K, Hoeft A, et al. Persistent cognitive impairment, hippocampal atrophy and EEG changes in sepsis survivors. J Neurol Neurosurg Psychiatry 2013;84:62–69. 11 Wijdicks EF, Stevens M. The role of hypotension in septic encephalopathy following surgical procedures. Arch Neurol 1992;49: 653–656. 12 Smith PJ, Blumenthal JA, Hoffman BM, Rivelli S, Palmer SM, Davis RD, Mathew J. Reduced cerebral perfusion pressure worsens delirium outcomes following lung transplantation. Ann Am Thorac Soc 2016; 13:180–187. 13 Zaal IJ, Devlin JW, Peelen LM, Slooter AJ. A systematic review of risk factors for delirium in the ICU. Crit Care Med 2015;43:40–47. 14 Cohen DG, Christie JD, Anderson BJ, Diamond JM, Judy RP, Shah RJ, Cantu E, Bellamy SL, Blumenthal NP, Demissie E, et al. Cognitive function, mental health, and health-related quality of life after lung transplantation. Ann Am Thorac Soc 2014;11:522–530. 15 Mikkelsen ME, Christie JD, Lanken PN, Biester RC, Thompson BT, Bellamy SL, Localio AR, Demissie E, Hopkins RO, Angus DC. The adult respiratory distress syndrome cognitive outcomes study: longterm neuropsychological function in survivors of acute lung injury. Am J Respir Crit Care Med 2012;185:1307–1315. 16 Hopkins RO, Weaver LK, Pope D, Orme JF, Bigler ED, Larson-LOHR V. Neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome. Am J Respir Crit Care Med 1999;160:50–56.
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Division of Pulmonary, Allergy, and Critical Care Medicine, and 2Penn Lung Transplant Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
Delirium is common in the intensive care unit (ICU) (1) and is particularly common in patients recovering from lung transplantation (2, 3). The emergence of delirium is frightening to patients and family members. Delirium complicates patient care and is associated with prolonged mechanical ventilation (4, 5), longer hospital stays (3–6), and increased mortality (5–7). In addition, delirium is associated with significant long-term morbidity in ICU survivors, including long-term cognitive impairment (1, 2, 8). Importantly, growing evidence also suggests delirium is associated with potentially permanent brain injury. Imaging studies comparing ICU survivors with matched controls reveal significant volume loss in the frontal lobes and hippocampus, the severity of which is closely linked to the duration of delirium and the degree of long-term cognitive impairment (9, 10). The pathophysiology of delirium and how it may lead to subsequent cognitive impairment remains poorly understood. Few studies have investigated hypoperfusion as a mechanism leading delirium. One study by Wijdicks and colleagues demonstrated that cardiovascular failure was a risk factor for septic encephalopathy in 84 postoperative patients (11), but to our knowledge, the study in this month’s issue of AnnalsATS by Smith and colleagues (pp. 180–187) is the only human study linking hypoperfusion to delirium (12). Using a prospective cohort design, the authors obtained detailed hemodynamic
measurements on 63 patients who underwent lung transplantation. They defined cerebral perfusion pressure (CPP) as the difference between mean arterial pressure (MAP), measured by a femoral or radial arterial catheter, and central venous pressure (CVP), measured by a pulmonary artery catheter (CPP = MAP – CVP). Patients were assessed daily for delirium, using the Confusion Assessment Method, and were also assessed for delirium severity, using the Delirium Rating Scale. Using logistic regression adjusting for native lung disease and primary graft dysfunction, the authors demonstrated that every 10 mm Hg decrease in CPP was associated with a doubling of the odds of developing postoperative delirium (odds ratio, 2.08; 95% confidence interval, 1.08–4.24; P = 0.043). Next, in a negative binomial regression model adjusting for native lung disease and primary graft dysfunction, they showed that lower CPP was associated with longer duration of delirium (b = 20.54; 95% confidence interval, 21.00 to 20.08; P = 0.22), such that every 10 mm Hg decrease in CPP was associated with a 1.7-day increase in delirium duration. Finally, they identified an association of lower CPP with higher delirium severity, as well as associations of primary graft dysfunction with both odds of delirium and delirium duration. The study by Smith and colleagues has several strengths. First, the authors rigorously investigated an important topic that continues to challenge the critical care community. Second, the authors employed sound methodology, including a well-
defined exposure variable and use of a wellvalidated screening tool for delirium. Third, the statistical techniques were appropriately chosen and the authors assessed their models for overfitting, given the small number of outcomes relative to the potential numbers of covariates. Several potential limitations of the study should be noted. The study was performed at a single center and thus may not be generalizable. This remains the primary limitation to the majority of studies evaluating delirium and neurocognition in lung transplant recipients. Although the authors adjusted for native lung disease and subsequent development of primary graft dysfunction, the association of CPP with delirium may be subject to residual confounding by additional covariates such as pretransplant cognitive function, severity of illness (e.g., mechanical ventilation and/ or extracorporeal membrane oxygenation as a bridge to transplant), age, chronic history of hypertension, and benzodiazepine or opiate use (3, 13). One prior study identified graft ischemic time as an independent risk factor of worse posttransplant cognitive function (14); thus, it would be interesting to investigate graft ischemic time as a potential confounder. A particular challenge in investigating mechanisms of delirium in patients with end-stage lung disease who undergo lung transplantation is accounting for the effects of hypoxemia on cognitive function. The authors note that reduced cerebral oxygenation has been associated with postoperative neurocognitive dysfunction (12), and additional studies have shown
(Received in original form December 3, 2015; accepted in final form December 4, 2015 ) Supported in part by National Institutes of Health grant K23-HL121406. Correspondence and requests for reprints should be addressed to Brian J. Anderson, M.D., M.S., Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, 5048 Gates Building, Philadelphia, PA 19104. E-mail: [email protected] Ann Am Thorac Soc Vol 13, No 2, pp 156–157, Feb 2016 Copyright © 2016 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201512-796ED Internet address: www.atsjournals.org
156
AnnalsATS Volume 13 Number 2 | February 2016
EDITORIALS that low arterial partial pressure of oxygen and low peripheral oxygen saturation measurements are associated with poor cognitive outcomes in survivors of Acute Respiratory Distress Syndrome (15, 16). Because decreased cerebral perfusion and decreased arterial oxygen saturation both ultimately result in reduced cerebral oxygen delivery, it is likely that both mechanisms can lead to brain injury and manifest as delirium and/or cognitive impairment. Although Smith and colleagues did not investigate hypoxemia in the present study, their well-phenotyped cohort presents a unique opportunity to explore the individual and combined effects of poor cerebral perfusion and reduced arterial oxygen saturation on
postoperative delirium and cognitive function. Despite potential limitations, the present study by Smith and colleagues suggests reduced cerebral perfusion is a potentially modifiable risk factor associated with risk, duration, and severity of postoperative delirium. A major question moving forward is whether reduced cerebral perfusion is associated with longer-term outcomes, such as long-term cognitive impairment and diminished executive function, and whether reduced cerebral perfusion pressure results in delirium simply through neuronal dysfunction or by causing more permanent brain injury. Studies employing systemic biomarkers of brain injury may be useful as a
References 1 Pandharipande PP, Girard TD, Jackson JC, Morandi A, Thompson JL, Pun BT, Brummel NE, Hughes CG, Vasilevskis EE, Shintani AK, et al.; BRAIN-ICU Study Investigators. Long-term cognitive impairment after critical illness. N Engl J Med 2013;369:1306–1316. 2 Smith PJ, Rivelli S, Waters A, Reynolds J, Hoyle A, Flowers M, Davis RD, Palmer SM, Mathew J, Durheim M, et al. Neurocognitive changes after lung transplantation. Ann Am Thorac Soc 2014;11: 1520–1527. 3 Smith PJ, Rivelli SK, Waters AM, Hoyle A, Durheim MT, Reynolds JM, Flowers M, Davis RD, Palmer SM, Mathew JP, et al. Delirium affects length of hospital stay after lung transplantation. J Crit Care 2015;30: 126–129. 4 Lat I, McMillian W, Taylor S, Janzen JM, Papadopoulos S, Korth L, Ehtisham A, Nold J, Agarwal S, Azocar R, et al. The impact of delirium on clinical outcomes in mechanically ventilated surgical and trauma patients. Crit Care Med 2009;37:1898–1905. 5 Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, Harrell FE Jr, Inouye SK, Bernard GR, Dittus RS. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA 2004;291:1753–1762. 6 Ouimet S, Kavanagh BP, Gottfried SB, Skrobik Y. Incidence, risk factors and consequences of ICU delirium. Intensive Care Med 2007;33:66–73. 7 Lin SM, Liu CY, Wang CH, Lin HC, Huang CD, Huang PY, Fang YF, Shieh MH, Kuo HP. The impact of delirium on the survival of mechanically ventilated patients. Crit Care Med 2004;32:2254–2259. 8 Girard TD, Jackson JC, Pandharipande PP, Pun BT, Thompson JL, Shintani AK, Gordon SM, Canonico AE, Dittus RS, Bernard GR, et al. Delirium as a predictor of long-term cognitive impairment in survivors of critical illness. Crit Care Med 2010;38:1513–1520.
Editorials
quantitative trait for assessing the degree of brain injury in critically ill patients. Biomarkers may also serve as surrogates when formal delirium testing is not possible in the setting of prolonged mechanical ventilation and significant sedation requirements. Detailed serial neuroimaging and longer-term follow-up of transplant recipient cognitive function may ultimately lead to a better understanding of the lasting effects of early posttransplant brain injury and give insight into how we can intervene to improve both short- and long-term neurocognitive outcomes after lung transplantation. n Author disclosures are available with the text of this article at www.atsjournals.org.
9 Gunther ML, Morandi A, Krauskopf E, Pandharipande P, Girard TD, Jackson JC, Thompson J, Shintani AK, Geevarghese S, Miller RR III, et al.; VISIONS Investigation, VISualizing Icu SurvivOrs Neuroradiological Sequelae. The association between brain volumes, delirium duration, and cognitive outcomes in intensive care unit survivors: the VISIONS cohort magnetic resonance imaging study*. Crit Care Med 2012;40:2022–2032. 10 Semmler A, Widmann CN, Okulla T, Urbach H, Kaiser M, Widman G, Mormann F, Weide J, Fliessbach K, Hoeft A, et al. Persistent cognitive impairment, hippocampal atrophy and EEG changes in sepsis survivors. J Neurol Neurosurg Psychiatry 2013;84:62–69. 11 Wijdicks EF, Stevens M. The role of hypotension in septic encephalopathy following surgical procedures. Arch Neurol 1992;49: 653–656. 12 Smith PJ, Blumenthal JA, Hoffman BM, Rivelli S, Palmer SM, Davis RD, Mathew J. Reduced cerebral perfusion pressure worsens delirium outcomes following lung transplantation. Ann Am Thorac Soc 2016; 13:180–187. 13 Zaal IJ, Devlin JW, Peelen LM, Slooter AJ. A systematic review of risk factors for delirium in the ICU. Crit Care Med 2015;43:40–47. 14 Cohen DG, Christie JD, Anderson BJ, Diamond JM, Judy RP, Shah RJ, Cantu E, Bellamy SL, Blumenthal NP, Demissie E, et al. Cognitive function, mental health, and health-related quality of life after lung transplantation. Ann Am Thorac Soc 2014;11:522–530. 15 Mikkelsen ME, Christie JD, Lanken PN, Biester RC, Thompson BT, Bellamy SL, Localio AR, Demissie E, Hopkins RO, Angus DC. The adult respiratory distress syndrome cognitive outcomes study: longterm neuropsychological function in survivors of acute lung injury. Am J Respir Crit Care Med 2012;185:1307–1315. 16 Hopkins RO, Weaver LK, Pope D, Orme JF, Bigler ED, Larson-LOHR V. Neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome. Am J Respir Crit Care Med 1999;160:50–56.
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