Editorials
Although the authors have done an admirable job of assembling a large cohort to study, their findings emphasize the need for multi-institutional, multinational collaboration to study this uncommon disease process in order to better understand risk factors, pathophysiology, and possible therapies that the high mortality demands. Fortunately, a start in this direction has already occurred with the European Registry of Severe Cutaneous Adverse Drug Reactions (severe cutaneous adverse drug reaction) Project, a multinational database. Thus, de Prost et al have identified the complex nature of epidermal necrolysis; it is a challenge to us now to improve care.
REFERENCES
1. de Prost N, Mekontso-Dessap A, Valeryie-Allanore L, et al: Acute Respiratory Failure in Patients With Toxic Epidermal Necrolysis: Clinical Features and Factors Associated With Mechanical Ventilation. Crit Care Med 2014; 42:118–128 2. The Acute Respiratory Distress Syndrome Network: Ventilation with lower tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000; 342:1301–1308 3. Guérin C, Reignier J, Richard JC, et al; PROSEVA Study Group: Prone positioning in severe acute respiratory distress syndrome. N Engl J Med 2013; 368:2159–2168
4. Lebargy F, Wolkenstein P, Gisselbrecht M, et al: Pulmonary complications in toxic epidermal necrolysis: A prospective clinical study. Intensive Care Med 1997; 23:1237–1244 5. Bastuji-Garin S, Fouchard N, Bertocchi M, et al: SCORTEN: A severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol 2000; 115:149–153 6. Revuz J, Penso D, Roujeau JC, et al: Toxic epidermal necrolysis. Clinical findings and prognosis factors in 87 patients. Arch Dermatol 1987; 123:1160–1165 7. de Prost N, Ingen-Housz-Oro S, Duong TA, et al: Bacteremia in StevensJohnson syndrome and toxic epidermal necrolysis: Epidemiology, risk factors, and predictive value of skin cultures. Medicine (Baltimore) 2010; 89:28–36 8. Garcia-Doval I, LeCleach L, Bocquet H, et al: Toxic epidermal necrolysis and Stevens-Johnson syndrome: Does early withdrawal of causative drugs decrease the risk of death? Arch Dermatol 2000; 136:323–327 9. Palmieri TL, Greenhalgh DG, Saffle JR, et al: A multicenter review of toxic epidermal necrolysis treated in U.S. burn centers at the end of the twentieth century. J Burn Care Rehabil 2002; 23:87–96 10. Chung WH, Hung SI, Hong HS, et al: Medical genetics: A marker for Stevens-Johnson syndrome. Nature 2004; 428:486 11. Hung SI, Chung WH, Liou LB, et al: HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A 2005; 102:4134–4139 12. Chung WH, Hung SI, Chen YT: Genetic predisposition of life-threatening antiepileptic-induced skin reactions. Expert Opin Drug Saf 2010; 9:15–21
Are We Offtrack Using Propofol for Sedation After Traumatic Brain Injury?* Mark Coburn, MD Department of Anesthesiology University Hospital RWTH Aachen Aachen, Germany Pratik P. Pandharipande, MD, MSCI, FCCM Department of Anesthesiology Division of Critical Care Vanderbilt University Medical Center Nashville, TN
*See also p. 129. Key Words: mortality; neurogenesis; propofol; sedatives; traumatic brain injury Dr. Coburn consulted for Air Liquide Sante International, his institution received grant support from Deutsche Forschungsgemeinschaft and Air Liquide Sante International. Dr. Pandharipande’s institution received grant support from Hospira (cosupport with the National Institutes of Health). Dr. Sanders consulted for Air Liquide (consultancy on the development of medical gases) and lectured for Orion. Dr. Sanders and his institution received grant support from Orion (unrestricted grant for electroencephalography/functional MRI study of dexmedetomidine in healthy volunteers). Copyright © 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097CCM.0000000000000009
Critical Care Medicine
Robert D. Sanders, BSc, MBBS, PhD, FRCA Department of Anaesthesia and Surgical Outcomes Research Centre University College London Hospital; and Wellcome Department of Imaging Neuroscience University College London London, United Kingdom
P
ropofol is widely used for sedation in ICU patients, including sedation after traumatic brain injury. The gamma-aminobutyric acid type A (GABAA) receptor has been identified as a molecular target for propofol underlying general anesthesia and sedation (1). Interestingly, the neurotransmitter, GABA, serves as a key mediator in adult neurogenesis (2). Neurogenesis occurs throughout life in mammals, including humans (3, 4), and plays a restorative role after brain injury. Despite overlapping receptor targets, limited data exist on the influence of propofol on endogenous neurogenesis after traumatic brain injury, hence the importance of the work carried out by Thal et al (5). In this issue of Critical Care Medicine, Thal et al (5) assessed, in a well-established adult rat model of traumatic brain injury, the effects of propofol on mortality rate, neurological function, and neurogenesis. A mechanical www.ccmjournal.org
211
Editorials
brain lesion was induced by controlled cortical impact and propofol was applied in two concentrations (36 or 72 mg/kg/hr) peri- and posttraumatically with a 2 hours delay. The authors demonstrated that 2 hours delayed propofol sedation is associated with an increased 28-day mortality rate. The application of high doses of propofol (72 mg/kg/hr) resulted in an aggravation of the motor function assessed by the Beam Balance Test. Thal et al (5) are the first to hint that propofol impaired neurogenesis assessed by the detection of proliferating cells via bromodeoxyuridine and by labeling neurons with neuronal nuclear antigen–positive cells. This finding has important implications on the use of sedatives in neurocritical care. However, some limitations require discussion. The rationale to select 36 and 72 mg/kg/hr by Thal et al (5) was based on previous publications by Eberspächer et al (6), who showed in rats with controlled cortical impact injury via electroencephalogram a burst suppression ratio of 1–5% with 36 mg/kg/hr and a burst suppression ratio of 30–40% with 72 mg/kg/hr. However, it remains unclear how these propofol dosages may translate to clinical practice. In the first experimental set, Thal et al (5) applied propofol during the traumatic brain injury—a situation that rarely occurs in the critical care arena. However, Thal et al (5) chose a second more realistic approach, applying propofol with a 2-hour delay. Yet, the application of propofol was limited to a total of 3 hours. This might be one of the reasons why the neuroprotective effects of propofol observed in an in vitro model of traumatic brain injury (7) were not seen in the work performed by Thal et al (5). There is also a difference in the propofol concentrations used and the point of administration, which was inside the blood-brain barrier in the study performed by Rossaint et al (7). Based on the work performed by Thal et al (5), many more questions are stimulated. In consideration of the fact that GABA acts as a trophic factor that regulates neuronal stem cell proliferation, differentiation, and migration (2), it might be worthwhile to assess the effect of propofol on neuronal stem cells. This is underlined by the fact that Culley et al (8) demonstrated that isoflurane reduced proliferation of cultured rat embryonic neuronal stem cells. Having said this, GABAergic drugs other than propofol, such as benzodiazepines, might also have an effect on neurogenesis and stem cell proliferation. This inevitably leads to the fact that the study by Thal et al (5) is lacking a control sedative group. It would have been of paramount interest to compare the effect of other frequently used sedatives such as benzodiazepines and α2 agonists on neurogenesis in the aforementioned setting of traumatic brain injury. Indeed α2 agonist neuroprotection has been observed in in vitro models of traumatic brain injury (9). Further studies are required to clarify the role on neurogenesis afforded by the differing classes of sedative agents. Thal et al (5) have stimulated to undertake further experiments to determine the role of propofol and other sedatives on neurogenesis and stem cell proliferation.
212
www.ccmjournal.org
Perhaps the most important finding is that a brief exposure to propofol may increase mortality following traumatic brain injury. Although the lack of sedative control group makes interpretation of this finding difficult, several clinical and scientific observations are consistent with the observation by Thal et al (5). For example, similar to the animals, sedation to burst suppression leads to increased mortality in critically ill patients (10). Sedatives also contribute to delirium (11), which is both associated with increased mortality (12) and GABAA signaling (13), consistent with poor neurological function in the deeply sedated animals. Finally, the immune effects of propofol may be profound (14) as propofol impairs neutrophil function and could interfere with immune responses through GABAergic signaling as well (15). Because infection is an important complication of traumatic brain injury, it is plausible that propofol contributed to adverse outcomes. There is a sense of urgency to undertake further experiments to determine the sedative regime we use in treating patients after traumatic brain injury.
REFERENCES
1. Franks NP: Molecular targets underlying general anaesthesia. Br J Pharmacol 2006; 147(Suppl 1):S72–S81 2. Ge S, Pradhan DA, Ming GL, et al: GABA sets the tempo for activitydependent adult neurogenesis. Trends Neurosci 2007; 30:1–8 3. Ming GL, Song H: Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci 2005; 28:223–250 4. Lledo PM, Alonso M, Grubb MS: Adult neurogenesis and functional plasticity in neuronal circuits. Nat Rev Neurosci 2006; 7:179–193 5. Thal SC, Timaru-Kast R, Wilde F, et al: Propofol Impairs Neurogenesis and Neurological Recovery and Increases Mortality Rate in Adult Rats After Traumatic Brain Injury. Crit Care Med 2014; 42:129–141 6. Eberspächer E, Heimann K, Hollweck R, et al: The effect of electroencephalogram-targeted high- and low-dose propofol infusion on histopathological damage after traumatic brain injury in the rat. Anesth Analg 2006; 103:1527–1533 7. Rossaint J, Rossaint R, Weis J, et al: Propofol: Neuroprotection in an in vitro model of traumatic brain injury. Crit Care 2009; 13:R61 8. Culley DJ, Boyd JD, Palanisamy A, et al: Isoflurane decreases selfrenewal capacity of rat cultured neural stem cells. Anesthesiology 2011; 115:754–763 9. Schoeler M, Loetscher PD, Rossaint R, et al: Dexmedetomidine is neuroprotective in an in vitro model for traumatic brain injury. BMC Neurol 2012; 12:20 10. Watson PL, Shintani AK, Tyson R, et al: Presence of electroencephalogram burst suppression in sedated, critically ill patients is associated with increased mortality. Crit Care Med 2008; 36:3171–3177 11. Pandharipande P, Shintani A, Peterson J, et al: Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients. Anesthesiology 2006; 104:21–26 12. Ely EW, Shintani A, Truman B, et al: Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA 2004; 291:1753–1762 13. Sanders RD: Hypothesis for the pathophysiology of delirium: Role of baseline brain network connectivity and changes in inhibitory tone. Med Hypotheses 2011; 77:140–143 14. Sanders RD, Hussell T, Maze M: Sedation & immunomodulation. Crit Care Clin 2009; 25:551–570 15. Sanders RD, Godlee A, Fujimori T, et al: Benzodiazepine augmented γ-amino-butyric acid signaling increases mortality from pneumonia in mice. Crit Care Med 2013; 41:1627–1636
January 2014 • Volume 42 • Number 1
Although the authors have done an admirable job of assembling a large cohort to study, their findings emphasize the need for multi-institutional, multinational collaboration to study this uncommon disease process in order to better understand risk factors, pathophysiology, and possible therapies that the high mortality demands. Fortunately, a start in this direction has already occurred with the European Registry of Severe Cutaneous Adverse Drug Reactions (severe cutaneous adverse drug reaction) Project, a multinational database. Thus, de Prost et al have identified the complex nature of epidermal necrolysis; it is a challenge to us now to improve care.
REFERENCES
1. de Prost N, Mekontso-Dessap A, Valeryie-Allanore L, et al: Acute Respiratory Failure in Patients With Toxic Epidermal Necrolysis: Clinical Features and Factors Associated With Mechanical Ventilation. Crit Care Med 2014; 42:118–128 2. The Acute Respiratory Distress Syndrome Network: Ventilation with lower tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000; 342:1301–1308 3. Guérin C, Reignier J, Richard JC, et al; PROSEVA Study Group: Prone positioning in severe acute respiratory distress syndrome. N Engl J Med 2013; 368:2159–2168
4. Lebargy F, Wolkenstein P, Gisselbrecht M, et al: Pulmonary complications in toxic epidermal necrolysis: A prospective clinical study. Intensive Care Med 1997; 23:1237–1244 5. Bastuji-Garin S, Fouchard N, Bertocchi M, et al: SCORTEN: A severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol 2000; 115:149–153 6. Revuz J, Penso D, Roujeau JC, et al: Toxic epidermal necrolysis. Clinical findings and prognosis factors in 87 patients. Arch Dermatol 1987; 123:1160–1165 7. de Prost N, Ingen-Housz-Oro S, Duong TA, et al: Bacteremia in StevensJohnson syndrome and toxic epidermal necrolysis: Epidemiology, risk factors, and predictive value of skin cultures. Medicine (Baltimore) 2010; 89:28–36 8. Garcia-Doval I, LeCleach L, Bocquet H, et al: Toxic epidermal necrolysis and Stevens-Johnson syndrome: Does early withdrawal of causative drugs decrease the risk of death? Arch Dermatol 2000; 136:323–327 9. Palmieri TL, Greenhalgh DG, Saffle JR, et al: A multicenter review of toxic epidermal necrolysis treated in U.S. burn centers at the end of the twentieth century. J Burn Care Rehabil 2002; 23:87–96 10. Chung WH, Hung SI, Hong HS, et al: Medical genetics: A marker for Stevens-Johnson syndrome. Nature 2004; 428:486 11. Hung SI, Chung WH, Liou LB, et al: HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A 2005; 102:4134–4139 12. Chung WH, Hung SI, Chen YT: Genetic predisposition of life-threatening antiepileptic-induced skin reactions. Expert Opin Drug Saf 2010; 9:15–21
Are We Offtrack Using Propofol for Sedation After Traumatic Brain Injury?* Mark Coburn, MD Department of Anesthesiology University Hospital RWTH Aachen Aachen, Germany Pratik P. Pandharipande, MD, MSCI, FCCM Department of Anesthesiology Division of Critical Care Vanderbilt University Medical Center Nashville, TN
*See also p. 129. Key Words: mortality; neurogenesis; propofol; sedatives; traumatic brain injury Dr. Coburn consulted for Air Liquide Sante International, his institution received grant support from Deutsche Forschungsgemeinschaft and Air Liquide Sante International. Dr. Pandharipande’s institution received grant support from Hospira (cosupport with the National Institutes of Health). Dr. Sanders consulted for Air Liquide (consultancy on the development of medical gases) and lectured for Orion. Dr. Sanders and his institution received grant support from Orion (unrestricted grant for electroencephalography/functional MRI study of dexmedetomidine in healthy volunteers). Copyright © 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097CCM.0000000000000009
Critical Care Medicine
Robert D. Sanders, BSc, MBBS, PhD, FRCA Department of Anaesthesia and Surgical Outcomes Research Centre University College London Hospital; and Wellcome Department of Imaging Neuroscience University College London London, United Kingdom
P
ropofol is widely used for sedation in ICU patients, including sedation after traumatic brain injury. The gamma-aminobutyric acid type A (GABAA) receptor has been identified as a molecular target for propofol underlying general anesthesia and sedation (1). Interestingly, the neurotransmitter, GABA, serves as a key mediator in adult neurogenesis (2). Neurogenesis occurs throughout life in mammals, including humans (3, 4), and plays a restorative role after brain injury. Despite overlapping receptor targets, limited data exist on the influence of propofol on endogenous neurogenesis after traumatic brain injury, hence the importance of the work carried out by Thal et al (5). In this issue of Critical Care Medicine, Thal et al (5) assessed, in a well-established adult rat model of traumatic brain injury, the effects of propofol on mortality rate, neurological function, and neurogenesis. A mechanical www.ccmjournal.org
211
Editorials
brain lesion was induced by controlled cortical impact and propofol was applied in two concentrations (36 or 72 mg/kg/hr) peri- and posttraumatically with a 2 hours delay. The authors demonstrated that 2 hours delayed propofol sedation is associated with an increased 28-day mortality rate. The application of high doses of propofol (72 mg/kg/hr) resulted in an aggravation of the motor function assessed by the Beam Balance Test. Thal et al (5) are the first to hint that propofol impaired neurogenesis assessed by the detection of proliferating cells via bromodeoxyuridine and by labeling neurons with neuronal nuclear antigen–positive cells. This finding has important implications on the use of sedatives in neurocritical care. However, some limitations require discussion. The rationale to select 36 and 72 mg/kg/hr by Thal et al (5) was based on previous publications by Eberspächer et al (6), who showed in rats with controlled cortical impact injury via electroencephalogram a burst suppression ratio of 1–5% with 36 mg/kg/hr and a burst suppression ratio of 30–40% with 72 mg/kg/hr. However, it remains unclear how these propofol dosages may translate to clinical practice. In the first experimental set, Thal et al (5) applied propofol during the traumatic brain injury—a situation that rarely occurs in the critical care arena. However, Thal et al (5) chose a second more realistic approach, applying propofol with a 2-hour delay. Yet, the application of propofol was limited to a total of 3 hours. This might be one of the reasons why the neuroprotective effects of propofol observed in an in vitro model of traumatic brain injury (7) were not seen in the work performed by Thal et al (5). There is also a difference in the propofol concentrations used and the point of administration, which was inside the blood-brain barrier in the study performed by Rossaint et al (7). Based on the work performed by Thal et al (5), many more questions are stimulated. In consideration of the fact that GABA acts as a trophic factor that regulates neuronal stem cell proliferation, differentiation, and migration (2), it might be worthwhile to assess the effect of propofol on neuronal stem cells. This is underlined by the fact that Culley et al (8) demonstrated that isoflurane reduced proliferation of cultured rat embryonic neuronal stem cells. Having said this, GABAergic drugs other than propofol, such as benzodiazepines, might also have an effect on neurogenesis and stem cell proliferation. This inevitably leads to the fact that the study by Thal et al (5) is lacking a control sedative group. It would have been of paramount interest to compare the effect of other frequently used sedatives such as benzodiazepines and α2 agonists on neurogenesis in the aforementioned setting of traumatic brain injury. Indeed α2 agonist neuroprotection has been observed in in vitro models of traumatic brain injury (9). Further studies are required to clarify the role on neurogenesis afforded by the differing classes of sedative agents. Thal et al (5) have stimulated to undertake further experiments to determine the role of propofol and other sedatives on neurogenesis and stem cell proliferation.
212
www.ccmjournal.org
Perhaps the most important finding is that a brief exposure to propofol may increase mortality following traumatic brain injury. Although the lack of sedative control group makes interpretation of this finding difficult, several clinical and scientific observations are consistent with the observation by Thal et al (5). For example, similar to the animals, sedation to burst suppression leads to increased mortality in critically ill patients (10). Sedatives also contribute to delirium (11), which is both associated with increased mortality (12) and GABAA signaling (13), consistent with poor neurological function in the deeply sedated animals. Finally, the immune effects of propofol may be profound (14) as propofol impairs neutrophil function and could interfere with immune responses through GABAergic signaling as well (15). Because infection is an important complication of traumatic brain injury, it is plausible that propofol contributed to adverse outcomes. There is a sense of urgency to undertake further experiments to determine the sedative regime we use in treating patients after traumatic brain injury.
REFERENCES
1. Franks NP: Molecular targets underlying general anaesthesia. Br J Pharmacol 2006; 147(Suppl 1):S72–S81 2. Ge S, Pradhan DA, Ming GL, et al: GABA sets the tempo for activitydependent adult neurogenesis. Trends Neurosci 2007; 30:1–8 3. Ming GL, Song H: Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci 2005; 28:223–250 4. Lledo PM, Alonso M, Grubb MS: Adult neurogenesis and functional plasticity in neuronal circuits. Nat Rev Neurosci 2006; 7:179–193 5. Thal SC, Timaru-Kast R, Wilde F, et al: Propofol Impairs Neurogenesis and Neurological Recovery and Increases Mortality Rate in Adult Rats After Traumatic Brain Injury. Crit Care Med 2014; 42:129–141 6. Eberspächer E, Heimann K, Hollweck R, et al: The effect of electroencephalogram-targeted high- and low-dose propofol infusion on histopathological damage after traumatic brain injury in the rat. Anesth Analg 2006; 103:1527–1533 7. Rossaint J, Rossaint R, Weis J, et al: Propofol: Neuroprotection in an in vitro model of traumatic brain injury. Crit Care 2009; 13:R61 8. Culley DJ, Boyd JD, Palanisamy A, et al: Isoflurane decreases selfrenewal capacity of rat cultured neural stem cells. Anesthesiology 2011; 115:754–763 9. Schoeler M, Loetscher PD, Rossaint R, et al: Dexmedetomidine is neuroprotective in an in vitro model for traumatic brain injury. BMC Neurol 2012; 12:20 10. Watson PL, Shintani AK, Tyson R, et al: Presence of electroencephalogram burst suppression in sedated, critically ill patients is associated with increased mortality. Crit Care Med 2008; 36:3171–3177 11. Pandharipande P, Shintani A, Peterson J, et al: Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients. Anesthesiology 2006; 104:21–26 12. Ely EW, Shintani A, Truman B, et al: Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA 2004; 291:1753–1762 13. Sanders RD: Hypothesis for the pathophysiology of delirium: Role of baseline brain network connectivity and changes in inhibitory tone. Med Hypotheses 2011; 77:140–143 14. Sanders RD, Hussell T, Maze M: Sedation & immunomodulation. Crit Care Clin 2009; 25:551–570 15. Sanders RD, Godlee A, Fujimori T, et al: Benzodiazepine augmented γ-amino-butyric acid signaling increases mortality from pneumonia in mice. Crit Care Med 2013; 41:1627–1636
January 2014 • Volume 42 • Number 1
