- Email: [email protected]
Sepsis-Associated Neurologic Dysfunction
Abstract: Sepsis is a leading cause of morbidity and mortality for infants and children in the United States and is associated with peripheral and central nervous system dysfunction including encephalopathy and paresis. Sepsisassociated encephalopathy (SAE) may be underdiagnosed in children, but the exact incidence is not known because of variable criteria for its diagnosis, which require a high index of suspicion and exclusion of other confounding factors. Neuroimaging and cerebrospinal fluid analysis are often normal. Electroencephalography may correlate with the severity of encephalopathy. Intensive care unit– acquired weakness due to critical illness neuropathy or myopathy develops later, and resolution of weakness is gradual. Difficulty weaning from the ventilator is an early sign. Electroencephalography may be helpful in identifying SAE once other causes of encephalopathy have been ruled out. However, the lack of consensus on the definition of SAE and sparse pediatric data limit the specific evidence-based recommendations, which can be made for the assessment and treatment of this disorder in the emergency department.
Sepsis-Associated Neurologic Dysfunction Mashael F. Alqahtani, MBBS*, Mark S. Wainwright, MD, PhD†
S
epsis is a leading cause of morbidity and mortality for infants and children in the United States. Bacterial sepsis of the newborn and septicemia has remained among the top 10 leading causes of death in children aged 0 to 14 years. 1 Recent epidemiological data show that the prevalence of severe sepsis in children has increased over the past decade. Although mortality has decreased, the prevalence of comorbidities associated with sepsis in children has increased. 2 The International Pediatric Sepsis consensus conference definition of sepsis and organ dysfunction in pediatrics is illustrated in Tables 1 and 2. 3 Here, we review the pediatric data on sepsis-associated encephalopathy (SAE) and acquired weakness. The lack of consensus on the definition of SAE and sparse pediatric data limit the specific recommendations, which can be made for the assessment and treatment of this disorder in the emergency department (ED).
Keywords: encephalopathy; sepsis; sepsis-associated encephalopathy; critical illness polyneuropathy; critical illness myopathy *Department of Pediatrics, Division of Critical Care Medicine, Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL; †Department of Pediatrics, Divisions of Neurology and Critical Care, Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL.
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SEPSIS-ASSOCIATED ENCEPHALOPATHY Definition The syndrome of SAE is defined as “diffuse cerebral dysfunction that accompanies sepsis in the absence of direct central nervous system (CNS) infection, structural abnormality, or other types of encephalopathy (eg, hepatic or renal encephalopathy) as detected by clinical or standard laboratory tests. 4 The reported frequency of SAE in adults with sepsis ranges from 8 to 70%. 4 This range is most likely due to the variety of definitions used in different studies. In children, there are limited data on SAE from case reports 5,6 and only 1 prospective study. 7 The definition of SAE in the case reports was quite similar, where it was characterized by brain dysfunction as a result of the systemic process of infection/sepsis
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Reprint requests and correspondence: Mashael F. Alqahtani, MBBS, Department of Pediatrics, Division of Critical Care Medicine, Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, 225 E Chicago Ave, Chicago, IL 60611. E-mail: [email protected] (M.F. Alqahtani), [email protected] (M.S. Wainwright) 1522-8401 © 2015 Elsevier Inc. All rights reserved.
without a direct infectious process to the brain. 5,6 The prospective pediatric study included 2 cohorts of patients who met the study inclusion for septic shock. Continuous electroencephalography (EEG) was used in the second cohort to identify patients with SAE. Encephalopathy was classified as mild, moderate, and severe based on the continuous EEG findings, which ranged from slowing (mild) to the presence of epileptiform discharges and loss of background waveforms in severe SAE. All patients in the second cohort had moderate-to-severe encephalopathy. Notably, there were no abnormalities on the neurologic examination in either cohort. These limited data and the limited contribution of the physical examination highlight the challenges in interpreting research in this area and in understanding the contribution of SAE to morbidity in sepsis.
Clinical Manifestations Sepsis-associated encephalopathy clinical characteristics have been described most extensively in adults and include acute changes in mental status, cognition, alteration of sleep/wake cycle, disorientation, impaired attention, and disorganized thinking. Agitation and somnolence may also occur as well as other rare symptoms including paratonic rigidity, asterixis, tremor, and multifocal myoclonus (Table 3). At present, the detection of acute brain dysfunction in the septic patient relies primarily on the bedside neurologic examination.
Assessment Tools There is no standardized clinical assessment measure for the diagnosis of SAE in children or adults. Most data are from adult studies and use a scale validated for the detection of delirium. 8,9 The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) was used to diagnose delirium in adult mechanically ventilated ICU patients and was validated against evaluation by a psychiatrist or neuropsychologist using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criterion. The Intensive Care Delirium–Screening Checklist (ICDSC) is also used for adults and consists of 8 items based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria. A metaanalysis of 9 studies evaluating CAM-ICU and 4 evaluating ICDSC in adults showed that the CAM-ICU was superior to ICDSC, as it has excellent sensitivity and specificity. 10 Although the Glasgow Coma Scale has been used to assess patients with SAE, its value is limited in intubated and sedated patients. In pediatric patients, similar validated testing has been developed to assess delirium, including the pediatric CAM-ICU. The pediatric
CAM-ICU demonstrated a sensitivity of 83% (95% confidence interval, 66-93%), a specificity of 99% (95% confidence interval, 95-100%), and a high interrater reliability. 11
Diagnosis of Sepsis-Associated Encephalopathy Biomarkers Brain injury biomarkers, including S-100 calcium binding protein β (S-100β); neuron-specific enolase (NSE); and the astrocyte protein, glial fibrillary acidic protein (GFAP), have been studied as biomarkers for the detection of SAE. 7,12 In a single-center study, NSE and S-100β were measured daily in sedated adult patients with severe sepsis and septic shock. High NSE and S-100β levels were associated with the maximum sequential organ failure assessment scores, and the highest values in the first 48 hours were found in patients who died early, within 4 days of study inclusion. 12 A recent prospective, observational study, which included 112 septic adult patients (48 with SAE and 64 with no SAE), suggested that serum S-100β is a more sensitive biomarker than NSE for detection of SAE. 13,14 In a prospective, observational study of children with septic shock, serum (S-100β, NSE, and GFAP) and urinary (S-100β and GFAP) markers were collected daily for 7 days. Septic patients had higher S-100β and NSE measured daily during the study period with the highest levels in comparison with control on days 5 to 7. 7 Glial fibrillary acidic protein has been shown to be a predictor for neurologic injury and outcomes after acute stroke, cardiac arrest, and traumatic brain injury. This is the only pediatric study that has measured serum and urinary GFAP in septic patients and showed that
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TABLE 1. Definitions of systemic inflammatory response syndrome, infection, sepsis, severe sepsis, and septic shock. 3 Systemic inflammatory response syndrome (SIRS) The presence of 2 of the following 4 criteria, one of which must be abnormal temperature or leukocyte count: &Core temperature of N 38.5°C or b 36°C. &Tachycardia, defined as a mean heart rate N 2 SDs above normal for age in the absence of external stimulus, chronic drugs, or painful stimuli or otherwise unexplained persistent elevation over a 0.5- to 4-hour period or for children b 1 year old; bradycardia, defined as a mean heart rate b 10th percentile for age in the absence of external vagal stimulus, β-blocker drugs, or congenital heart disease or otherwise unexplained persistent depression over a 0.5-hour period. &Mean respiratory rate N 2 SD above normal for age or mechanical ventilation for an acute process not related to underlying neuromuscular disease or the receipt of general anesthesia. &Leukocyte count elevated or depressed for age (not secondary to chemotherapy-induced leukopenia) or N 10% immature neutrophils. Infection A suspected or proven (by positive culture, tissue stain, or polymerase chain reaction test) infection caused by any pathogen or a clinical syndrome associated with a high probability of infection. Evidence of infection includes positive findings on clinical examination, imaging, or laboratory tests (eg, white blood cells in a normally sterile body fluid, perforated viscus, chest radiograph consistent with pneumonia, petechial or purpuric rash, or purpura fulminans). Sepsis SIRS in the presence of or as a result of suspected or proven infection. Severe sepsis Sepsis plus one of the following: cardiovascular organ dysfunction or acute respiratory distress syndrome or 2 other organ dysfunctions. Organ dysfunctions are defined in Table 2. Septic shock Sepsis and cardiovascular organ dysfunction as defined in Table 2. Abbreviations: SD, standard deviation.
serum GFAP was detected in patients with septic shock but not controls. 7
Transcranial Doppler and Near-Infrared Spectroscopy Near-infrared spectroscopy (NIRS) and transcranial Doppler (TCD) have been used as surrogate measures for quantification of cerebral blood flow and autoregulation. 15 -18 Again, most studies using these measures in sepsis have been performed in adults. In a prospective study of 8 adults with severe sepsis and septic shock, NIRS was used as a method
TABLE 2. Organ dysfunction criteria. Cardiovascular Despite administration of isotonic intravenous fluid bolus N 40 mL/kg over 1 h Decrease in BP (hypotension) b 5th percentile for age or systolic BP b 2 SD below normal for age or Need for vasoactive drug to maintain BP in reference range (dopamine N 5 μg/kg per minute or dobutamine, epinephrine, or norepinephrine at any dose) or Two of the following: Unexplained metabolic acidosis: base deficit N 5.0 mEq/L Increased arterial lactate N 2 times upper limit of normal Oliguria: urine output b 0.5 mL/kg per hour Prolonged capillary refill: N 5 s Core to peripheral temperature gap N 3°C Respiratory PaO2/FiO2 b 300 in absence of cyanotic heart disease or preexisting lung disease or PaCO2 N 65 or 20 mm Hg over baseline PaCO2 or Proven need or N 50% FiO2 to maintain saturation z 92% or Need for nonelective invasive or noninvasive mechanical ventilation Neurologic Glasgow Coma Score b 11 or Acute change in mental status with a decrease in Glasgow Coma Score 3 points from abnormal baseline Hematologic Platelet count b 80 000/mm 3 or a decline of 50% in platelet count from highest value recorded over the past 3 d (for chronic hematology/oncology patients) or International normalized ratio N 2 Renal Serum creatinine 2 times upper limit of normal for age or 2-fold increase in baseline creatinine Hepatic Total bilirubin z 4 mg/dL (not applicable for newborn) or ALT, 2 times upper limit of normal for age Abbreviations: BP, blood pressure; FiO2, fraction of inspired oxygen; ALT, alanine transaminase PaO2, partial pressure of arterial oxygen; PaCO2, partial pressure of arterial carbon dioxide.
for testing of reduced carbon dioxide–induced vasomotor reactivity (VMR), calculated by TCD and NIRS in sepsis. 15 Interestingly, NIRS reactivity was significantly related to VMR; also, NIRS and VMR were highly reduced during severe sepsis and
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TABLE 3. Clinical symptoms of sepsis-associated encephalopathy. Common Symptoms
Rare Symptoms
Acute changes in mental status Cognition impairment Alteration of sleep/wake cycle Disorientation Impaired attention Disorganized thinking
Paratonic rigidity Tremor Multifocal myoclonus
septic shock. 15 In another prospective adult study, tissue oxygenation index, recorded with NIRS, and blood flow velocity, measured using TCD, were strongly correlated, indicating that NIRS is a promising tool for the continuous assessment of cerebral autoregulation in adults. 16 Results from adult studies suggest that cerebral autoregulation is compromised during sepsis. 17,18 Transcranial Doppler velocities at rest and after intravenous administration of acetazolamide showed reduced reactivity in the patients with SAE, suggesting a diminished capacity for vasodilatation after acetazolamide administration. 17 In a study of 30 adults with severe sepsis, SAE was clinically diagnosed using the CAM-ICU at day 4, and, in most of these patients, autoregulation assessed by TCD was impaired. 18 However, there are no pediatric studies assessing cerebral autoregulation using TCD and NIRS in sepsis.
Brain Imaging There are no specific imaging findings for the diagnosis of SAE. Several changes have been described in adult septic patients (Table 4). In the acute phase of SAE in adults, cytotoxic and vasogenic edema may occur 19,20 as well as ischemic lesions and imaging evidence of leukoencephalopathy. 19,20 Posterior reversible encephalopathy syndrome was reported in 23% in association with sepsis. Accordingly, the optimum imaging study for the patient with sepsis and an abnormal neurologic examination is magnetic resonance imaging (MRI) with diffusion weighted imaging, gradient echo sequences, and contrast. This study will evaluate for other complications of sepsis including CNS infection, cerebral edema, and arterial and venous stroke that must be excluded before considering a diagnosis of SAE. Imaging studies performed in critically ill patients may help guide the assessment of prognosis for
TABLE 4. Magnetic resonance imaging findings in sepsis-associated encephalopathy. Acute MRI Findings Cytotoxic edema Vasogenic edema
Chronic MRI Findings Cytotoxic edema Brain atrophy (hippocampus and frontal region)
Ischemic lesions Leukoencephalopathy PRES PRES indicates posterior reversible encephalopathy syndrome.
neurologic recovery. Sepsis-associated encephalopathy may lead to long-term imaging findings in adults, including white matter lesions. 19 In a 2-center study including 47 critically ill adult patients of which 30% had sepsis, patients with white matter disruption at discharge or 3 months after discharge were associated with worse cognitive scores up to 12 months later. 21 In addition, greater brain atrophy (higher ventricle-to-brain ratio) at 3 months was associated with worse cognitive performances at 12 months. In addition, smaller superior frontal lobes, thalamus, and cerebellar volumes at 3 months were associated with worse executive functioning and visual attention at 12 months. 22 In another similar study, adult patients from 2 ICUs (25 septic and 19 nonseptic patients) were followed up for 6 to 24 months; left-sided hippocampal atrophy was found in adult sepsis survival patients compared with healthy controls. 23 Again, there are no comparable data for children.
Electrophysiology In adults diagnosed with SAE, EEG may be normal or may show excessive theta, predominantly delta, and triphasic waves/burst suppression according to the severity of encephalopathy. 24 Sepsis can also be associated with electrographic seizures or periodic epileptiform discharges. 25 Generalized periodic discharges were strongly associated with nonconvulsive seizures and nonconvulsive status epilepticus. 26 In pediatric case reports, the EEG varied to show excessive beta, predominantly delta, or burst suppression. 5,7 In the pediatric prospective study, all patients with SAE had a background abnormality on their EEG. 7 Sensory evoked potentials (SEPs) detect the integrity of somatosensory pathways from the peripheral to the CNS. Measurement of SEP in 68
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adult patients with severe sepsis and septic shock showed impairment of subcortical and cortical pathways within 48 hours of the development of severe sepsis and septic shock. There were no differences found in SEP between patients with severe sepsis and those with septic shock. 27
Management Advances in the treatment of SAE have been limited by lack of consensus on the definition, limited data on the incidence, and lack of data on mechanisms of SAE with no clearly defined treatment targets. The mainstays of therapy are early consideration of the diagnosis, exclusion of other causes of encephalopathy in the septic patient (CNS infection, arterial and venous stroke, cerebral edema, and nonconvulsive seizures), and supportive care. The use of sedating medications should be limited in patients with suspected SAE, as gamma-aminobutyric acid (GABA), which acts as an inhibitory neurotransmitter in the CNS, was found to increase in plasma from septic encephalopathy patients. 28 In general, benzodiazepines and propofol, which have high affinity to GABA receptors, should be avoided if possible. 29 A double-blind, randomized, controlled trial of adult mechanically ventilated medical and surgical ICU patients showed that sedation with dexmedetomidine resulted in more days alive without delirium or coma compared with sedation with lorazepam. Among this cohort, 63 patients were admitted with sepsis. The septic patients treated with dexmedetomidine had more days free of brain dysfunction and were less likely to die than those who received a lorazepam-based sedation regimen. 30,31
CRITICAL ILLNESS POLYNEUROPATHY AND MYOPATHY Critical illness neuropathy (CIP) and critical illness myopathy (CIM) have a similar clinical picture and are hard to differentiate, as both clinical syndromes coexist simultaneously in most cases. Critical illness neuropathy is a primary axonal polyneuropathy that is well recognized in adult ICU patients with sepsis and multiple organ dysfunction. The true prevalence of ICU-acquired weakness is not exactly known, but it may occur in up to 50% of adult patients with severe sepsis. 32 Critical illness neuropathy and CIM are clinically characterized by a flaccid and symmetrical muscle weakness of the extremities, loss of deep tendon reflexes, and atrophy of the muscles. Although distal muscles are usually affected more than proximal
muscles, facial muscles can be involved rarely (eg, ophthalmoplegia). Failure of weaning from the ventilator may be a first sign, when weakness involves thoracic or phrenic nerves. Although motor failure often predominates, distal loss of sensitivity to light touch, pain, temperature, and vibration may also be apparent in CIP. 33 There are many risk factors for CIP and CIM that have been identified in adults including glucocorticoids and neuromuscular blocking agents, female sex, severity of illness, duration of organ dysfunction, renal failure and renal replacement therapy, hyperosmolality, parenteral nutrition, low serum albumin, duration of ICU stay, vasopressor/catecholamine support, and central neurologic failure. 33-36 In the largest pediatric study of acquired weakness in critically ill children, the incidence was 1.7%. 37 This single-center, prospective study included 830 children admitted to the ICU. Risk factors were congruent with results of adult studies and included mechanical ventilation longer than 5 days, multiorgan dysfunction, sepsis, neuromuscular blockade, use of steroids, need for inotropic support, and solid organ/bone marrow transplant. In addition, asthma has been documented as a risk factor in many pediatric case reports. 38
Diagnosis The diagnosis can be established on clinical grounds in the ED once other potential causes of weakness in the septic patient are ruled out. Typically, in the first presentation of the septic patient to the ED, the presence of multifocal weakness and areflexia should raise concerns for a spinal cord injury (if a level is present on examination), Guillain-Barre syndrome, or inflammatory myopathy. Given the duration of exposure to risk factors required to produce this syndrome, CIP or CIM rarely needs to be diagnosed in the ED. If needed, electromyography and nerve conduction studies can be obtained to confirm the clinical diagnosis. 39 In children, treatment is mostly supportive care with a focus on physical therapy.
Long-Term CNS Complications of Sepsis Pediatric survivors of critical illness and sepsis in particular may experience significant compromise of cognitive function, including deficits in attention and memory. 40,41 In a follow-up study, children admitted to pediatric ICUs significantly underperformed on neuropsychologic measures in comparison with healthy controls. 4 0 Memory and teacher-rated academic performance were most reduced in children with meningoencephalitis and
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septic illness. 42 Lower performance on a composite score of neuropsychologic impairment was more prevalent when children were younger, from a lower social class, and had experienced seizures during their admission. In another pediatric study years after surviving sepsis, cognitive function was significantly lower than that in the normal population in 44% of the survivors. Again, young age at the time of ICU admission was predictive of cognitive problems, and cognitive problems were associated with lower emotional function. 41
SUMMARY Encephalopathy may be underdiagnosed in children with sepsis. The limited pediatric data and extrapolation from adult studies suggest that SAE may contribute to long-term cognitive and behavioral sequelae in survivors of critical illness. The physical examination is of limited use in making this diagnosis, and interpretation of the pediatric literature is confounded by differences in criteria used to assign the diagnosis of SAE. Neuropathy and myopathy may also add to the morbidity of critical illness and sepsis in children and can be diagnosed using the clinical examination. Clearly in the ED, encephalopathy in the septic patient should raise concerns for direct CNS infection requiring brain imaging and lumbar puncture. Electroencephalography may be helpful in identifying SAE once other causes of encephalopathy have been ruled out. However, the current lack of consensus on the definition of SAE and sparse pediatric data limit the specific recommendations, which can be made for the assessment and treatment of this disorder in the ED setting.
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7. Hsu AA, Fenton K, Weinstein S, et al. Neurological injury markers in children with septic shock. Pediatr Crit Care Med 2008;9:245–51. 8. Ely EW, Inouye SK, Bernard GR, et al. Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA 2001;286:2703–10. 9. Ritter C, Tomasi CD, Dal-Pizzol F, et al. Inflammation biomarkers and delirium in critically ill patients. Crit Care 2014;18:R106. http://dx.doi.org/10.1186/cc13887. 10. Gusmao-Flores D, Salluh JI, Chalhub RA, et al. The confusion assessment method for the intensive care unit (CAM-ICU) and intensive care delirium screening checklist (ICDSC) for the diagnosis of delirium: a systematic review and metaanalysis of clinical studies. Crit Care 2012;16:R115. http://dx. doi.org/10.1186/cc11407. 11. Smith HA, Boyd J, Fuchs DC, et al. Diagnosing delirium in critically ill children: validity and reliability of the pediatric confusion assessment method for the intensive care unit. Crit Care Med 2011;39:150–7. 12. Nguyen DN, Spapen H, Su F, et al. Elevated serum levels of S100beta protein and neuron-specific enolase are associated with brain injury in patients with severe sepsis and septic shock. Crit Care Med 2006;34:1967–74. 13. Yao B, Zhang LN, Ai YH, et al. Serum S100beta is a better biomarker than neuron-specific enolase for sepsis-associated encephalopathy and determining its prognosis: a prospective and observational study. Neurochem Res 2014;39:1263–9. 14. Su CM, Cheng HH, Tsai TC, et al. Elevated serum vascular cell adhesion molecule-1 is associated with septic encephalopathy in adult community-onset severe sepsis patients. Biomed Res Int 2014;2014:598762. http://dx.doi.org/10.1155/2014/598762. 15. Terborg C, Schummer W, Albrecht M, et al. Dysfunction of vasomotor reactivity in severe sepsis and septic shock. Intensive Care Med 2001;27:1231–4. 16. Steiner LA, Pfister D, Strebel SP, et al. Near-infrared spectroscopy can monitor dynamic cerebral autoregulation in adults. Neurocrit Care 2009;10:122–8. 17. Zatmari S, Vegh T, Csomos A, et al. Impaired cerebrovascular reactivity in sepsis-associated encephalopathy studied by acetazolamide test. Crit Care 2010;14:R50. http://dx.doi.org/ 10.1186/cc8939. Epub 2010 Mar 31. 18. Schramm P, Klein KU, Falkenberg L, et al. Impaired cerebrovascular autoregulation in patients with severe sepsis and sepsis-associated delirium. Crit Care 2012;16:R181. 19. Sharshar T, Carlier R, Bernard F, et al. Brain lesions in septic shock: a magnetic resonance imaging study. Intensive Care Med 2007;33:798–806. 20. Bozza FA, Garteiser P, Oliveira MF, et al. Sepsis-associated encephalopathy: a magnetic resonance imaging and spectroscopy study. J Cereb Blood Flow Metab 2010;30:440–8. 21. Morandi A, Rogers BP, Gunther M, et al. The relationship between delirium duration, white matter integrity, and cognitive impairment in intensive care unit survivors as determined by diffusion tensor imaging: the VISIONS prospective cohort magnetic resonance imaging study. Crit Care Med 2012;40:2182–9. 22. Gunther ML, Morandi A, Krauskopf E, et al. 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: 2022–32. 23. Semmler A, Widmann CN, Okulla T, et al. Persistent cognitive impairment, hippocampal atrophy and EEG changes in sepsis survivors. J Neurol Neurosurg Psychiatry 2013;84:62–9.
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24. Young GB, Bolton CF, Archibald YM, et al. The electroencephalogram in sepsis-associated encephalopathy. J Clin Neurophysiol 1992;9:145–52. 25. Oddo M, Carrera E, Claassen J, et al. Continuous electroencephalography in the medical intensive care unit. Crit Care Med 2009;37:2051–6. 26. Foreman B, Claassen J, Abou Khaled K, et al. Generalized periodic discharges in the critically ill: a case-control study of 200 patients. Neurology 2012;79:1951–60. 27. Zauner C, Gendo A, Kramer L, et al. Impaired subcortical and cortical sensory evoked potential pathways in septic patients. Crit Care Med 2002;30:1136–9. 28. Sprung CL, Cerra FB, Freund HR, et al. Amino acid alterations and encephalopathy in the sepsis syndrome. Crit Care Med 1991;19:753–7. 29. Kadoi Y, Saito S. An alteration in the gamma-aminobutyric acid receptor system in experimentally induced septic shock in rats. Crit Care Med 1996;24:298–305. 30. Pandharipande PP, Sanders RD, Girard TD, et al. Effect of dexmedetomidine versus lorazepam on outcome in patients with sepsis: an a priori-designed analysis of the MENDS randomized controlled trial. Crit Care 2010;14:R38. http:// dx.doi.org/10.1186/cc8916 Epub 2010 Mar 16. 31. Pandharipande PP, Pun BT, Herr DL, et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA 2007;298: 2644–53. 32. Garnacho-Montero J, Amaya-Villar R, Garcia-Garmendia JL, et al. Effect of critical illness polyneuropathy on the withdrawal from mechanical ventilation and the length of stay in septic patients. Crit Care Med 2005;33: 349–54.
33. Hermans G, De Jonghe B, Bruyninckx F, et al. Clinical review: critical illness polyneuropathy and myopathy. Crit Care 2008;12:238. http://dx.doi.org/10.1186/cc7100. 34. De Jonghe B, Sharshar T, Lefaucheur JP, et al. Paresis acquired in the intensive care unit: a prospective multicenter study. JAMA 2002;288:2859–67. 35. Bednarik J, Vondracek P, Dusek L, et al. Risk factors for critical illness polyneuromyopathy. J Neurol 2005;252:343–51. 36. Garnacho-Montero J, Madrazo-Osuna J, Garcia-Garmendia JL, et al. Critical illness polyneuropathy: risk factors and clinical consequences. A cohort study in septic patients. Intensive Care Med 2001;27:1288–96. 37. Banwell BL, Mildner RJ, Hassall AC, et al. Muscle weakness in critically ill children. Neurology 2003;61:1779–82. 38. Williams S, Horrocks IA, Ouvrier RA, et al. Critical illness polyneuropathy and myopathy in pediatric intensive care: a review. Pediatr Crit Care Med 2007;8:18–22. 39. Tennila A, Salmi T, Pettila V, et al. Early signs of critical illness polyneuropathy in ICU patients with systemic inflammatory response syndrome or sepsis. Intensive Care Med 2000;26:1360–3. 40. Als LC, Nadel S, Cooper M, et al. Neuropsychologic function three to six months following admission to the PICU with meningoencephalitis, sepsis, and other disorders: a prospective study of school-aged children. Crit Care Med 2013;41: 1094–103. http://dx.doi.org/10.1186/cc7694 Epub 2009 Jan 24. 41. Bronner MB, Knoester H, Sol JJ, et al. An explorative study on quality of life and psychological and cognitive function in pediatric survivors of septic shock. Pediatr Crit Care Med 2009;10:636–42. 42. Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008;358:25–39.
Sepsis-Associated Neurologic Dysfunction Mashael F. Alqahtani, MBBS*, Mark S. Wainwright, MD, PhD†
S
epsis is a leading cause of morbidity and mortality for infants and children in the United States. Bacterial sepsis of the newborn and septicemia has remained among the top 10 leading causes of death in children aged 0 to 14 years. 1 Recent epidemiological data show that the prevalence of severe sepsis in children has increased over the past decade. Although mortality has decreased, the prevalence of comorbidities associated with sepsis in children has increased. 2 The International Pediatric Sepsis consensus conference definition of sepsis and organ dysfunction in pediatrics is illustrated in Tables 1 and 2. 3 Here, we review the pediatric data on sepsis-associated encephalopathy (SAE) and acquired weakness. The lack of consensus on the definition of SAE and sparse pediatric data limit the specific recommendations, which can be made for the assessment and treatment of this disorder in the emergency department (ED).
Keywords: encephalopathy; sepsis; sepsis-associated encephalopathy; critical illness polyneuropathy; critical illness myopathy *Department of Pediatrics, Division of Critical Care Medicine, Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL; †Department of Pediatrics, Divisions of Neurology and Critical Care, Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL.
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SEPSIS-ASSOCIATED ENCEPHALOPATHY Definition The syndrome of SAE is defined as “diffuse cerebral dysfunction that accompanies sepsis in the absence of direct central nervous system (CNS) infection, structural abnormality, or other types of encephalopathy (eg, hepatic or renal encephalopathy) as detected by clinical or standard laboratory tests. 4 The reported frequency of SAE in adults with sepsis ranges from 8 to 70%. 4 This range is most likely due to the variety of definitions used in different studies. In children, there are limited data on SAE from case reports 5,6 and only 1 prospective study. 7 The definition of SAE in the case reports was quite similar, where it was characterized by brain dysfunction as a result of the systemic process of infection/sepsis
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Reprint requests and correspondence: Mashael F. Alqahtani, MBBS, Department of Pediatrics, Division of Critical Care Medicine, Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, 225 E Chicago Ave, Chicago, IL 60611. E-mail: [email protected] (M.F. Alqahtani), [email protected] (M.S. Wainwright) 1522-8401 © 2015 Elsevier Inc. All rights reserved.
without a direct infectious process to the brain. 5,6 The prospective pediatric study included 2 cohorts of patients who met the study inclusion for septic shock. Continuous electroencephalography (EEG) was used in the second cohort to identify patients with SAE. Encephalopathy was classified as mild, moderate, and severe based on the continuous EEG findings, which ranged from slowing (mild) to the presence of epileptiform discharges and loss of background waveforms in severe SAE. All patients in the second cohort had moderate-to-severe encephalopathy. Notably, there were no abnormalities on the neurologic examination in either cohort. These limited data and the limited contribution of the physical examination highlight the challenges in interpreting research in this area and in understanding the contribution of SAE to morbidity in sepsis.
Clinical Manifestations Sepsis-associated encephalopathy clinical characteristics have been described most extensively in adults and include acute changes in mental status, cognition, alteration of sleep/wake cycle, disorientation, impaired attention, and disorganized thinking. Agitation and somnolence may also occur as well as other rare symptoms including paratonic rigidity, asterixis, tremor, and multifocal myoclonus (Table 3). At present, the detection of acute brain dysfunction in the septic patient relies primarily on the bedside neurologic examination.
Assessment Tools There is no standardized clinical assessment measure for the diagnosis of SAE in children or adults. Most data are from adult studies and use a scale validated for the detection of delirium. 8,9 The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) was used to diagnose delirium in adult mechanically ventilated ICU patients and was validated against evaluation by a psychiatrist or neuropsychologist using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criterion. The Intensive Care Delirium–Screening Checklist (ICDSC) is also used for adults and consists of 8 items based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria. A metaanalysis of 9 studies evaluating CAM-ICU and 4 evaluating ICDSC in adults showed that the CAM-ICU was superior to ICDSC, as it has excellent sensitivity and specificity. 10 Although the Glasgow Coma Scale has been used to assess patients with SAE, its value is limited in intubated and sedated patients. In pediatric patients, similar validated testing has been developed to assess delirium, including the pediatric CAM-ICU. The pediatric
CAM-ICU demonstrated a sensitivity of 83% (95% confidence interval, 66-93%), a specificity of 99% (95% confidence interval, 95-100%), and a high interrater reliability. 11
Diagnosis of Sepsis-Associated Encephalopathy Biomarkers Brain injury biomarkers, including S-100 calcium binding protein β (S-100β); neuron-specific enolase (NSE); and the astrocyte protein, glial fibrillary acidic protein (GFAP), have been studied as biomarkers for the detection of SAE. 7,12 In a single-center study, NSE and S-100β were measured daily in sedated adult patients with severe sepsis and septic shock. High NSE and S-100β levels were associated with the maximum sequential organ failure assessment scores, and the highest values in the first 48 hours were found in patients who died early, within 4 days of study inclusion. 12 A recent prospective, observational study, which included 112 septic adult patients (48 with SAE and 64 with no SAE), suggested that serum S-100β is a more sensitive biomarker than NSE for detection of SAE. 13,14 In a prospective, observational study of children with septic shock, serum (S-100β, NSE, and GFAP) and urinary (S-100β and GFAP) markers were collected daily for 7 days. Septic patients had higher S-100β and NSE measured daily during the study period with the highest levels in comparison with control on days 5 to 7. 7 Glial fibrillary acidic protein has been shown to be a predictor for neurologic injury and outcomes after acute stroke, cardiac arrest, and traumatic brain injury. This is the only pediatric study that has measured serum and urinary GFAP in septic patients and showed that
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TABLE 1. Definitions of systemic inflammatory response syndrome, infection, sepsis, severe sepsis, and septic shock. 3 Systemic inflammatory response syndrome (SIRS) The presence of 2 of the following 4 criteria, one of which must be abnormal temperature or leukocyte count: &Core temperature of N 38.5°C or b 36°C. &Tachycardia, defined as a mean heart rate N 2 SDs above normal for age in the absence of external stimulus, chronic drugs, or painful stimuli or otherwise unexplained persistent elevation over a 0.5- to 4-hour period or for children b 1 year old; bradycardia, defined as a mean heart rate b 10th percentile for age in the absence of external vagal stimulus, β-blocker drugs, or congenital heart disease or otherwise unexplained persistent depression over a 0.5-hour period. &Mean respiratory rate N 2 SD above normal for age or mechanical ventilation for an acute process not related to underlying neuromuscular disease or the receipt of general anesthesia. &Leukocyte count elevated or depressed for age (not secondary to chemotherapy-induced leukopenia) or N 10% immature neutrophils. Infection A suspected or proven (by positive culture, tissue stain, or polymerase chain reaction test) infection caused by any pathogen or a clinical syndrome associated with a high probability of infection. Evidence of infection includes positive findings on clinical examination, imaging, or laboratory tests (eg, white blood cells in a normally sterile body fluid, perforated viscus, chest radiograph consistent with pneumonia, petechial or purpuric rash, or purpura fulminans). Sepsis SIRS in the presence of or as a result of suspected or proven infection. Severe sepsis Sepsis plus one of the following: cardiovascular organ dysfunction or acute respiratory distress syndrome or 2 other organ dysfunctions. Organ dysfunctions are defined in Table 2. Septic shock Sepsis and cardiovascular organ dysfunction as defined in Table 2. Abbreviations: SD, standard deviation.
serum GFAP was detected in patients with septic shock but not controls. 7
Transcranial Doppler and Near-Infrared Spectroscopy Near-infrared spectroscopy (NIRS) and transcranial Doppler (TCD) have been used as surrogate measures for quantification of cerebral blood flow and autoregulation. 15 -18 Again, most studies using these measures in sepsis have been performed in adults. In a prospective study of 8 adults with severe sepsis and septic shock, NIRS was used as a method
TABLE 2. Organ dysfunction criteria. Cardiovascular Despite administration of isotonic intravenous fluid bolus N 40 mL/kg over 1 h Decrease in BP (hypotension) b 5th percentile for age or systolic BP b 2 SD below normal for age or Need for vasoactive drug to maintain BP in reference range (dopamine N 5 μg/kg per minute or dobutamine, epinephrine, or norepinephrine at any dose) or Two of the following: Unexplained metabolic acidosis: base deficit N 5.0 mEq/L Increased arterial lactate N 2 times upper limit of normal Oliguria: urine output b 0.5 mL/kg per hour Prolonged capillary refill: N 5 s Core to peripheral temperature gap N 3°C Respiratory PaO2/FiO2 b 300 in absence of cyanotic heart disease or preexisting lung disease or PaCO2 N 65 or 20 mm Hg over baseline PaCO2 or Proven need or N 50% FiO2 to maintain saturation z 92% or Need for nonelective invasive or noninvasive mechanical ventilation Neurologic Glasgow Coma Score b 11 or Acute change in mental status with a decrease in Glasgow Coma Score 3 points from abnormal baseline Hematologic Platelet count b 80 000/mm 3 or a decline of 50% in platelet count from highest value recorded over the past 3 d (for chronic hematology/oncology patients) or International normalized ratio N 2 Renal Serum creatinine 2 times upper limit of normal for age or 2-fold increase in baseline creatinine Hepatic Total bilirubin z 4 mg/dL (not applicable for newborn) or ALT, 2 times upper limit of normal for age Abbreviations: BP, blood pressure; FiO2, fraction of inspired oxygen; ALT, alanine transaminase PaO2, partial pressure of arterial oxygen; PaCO2, partial pressure of arterial carbon dioxide.
for testing of reduced carbon dioxide–induced vasomotor reactivity (VMR), calculated by TCD and NIRS in sepsis. 15 Interestingly, NIRS reactivity was significantly related to VMR; also, NIRS and VMR were highly reduced during severe sepsis and
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TABLE 3. Clinical symptoms of sepsis-associated encephalopathy. Common Symptoms
Rare Symptoms
Acute changes in mental status Cognition impairment Alteration of sleep/wake cycle Disorientation Impaired attention Disorganized thinking
Paratonic rigidity Tremor Multifocal myoclonus
septic shock. 15 In another prospective adult study, tissue oxygenation index, recorded with NIRS, and blood flow velocity, measured using TCD, were strongly correlated, indicating that NIRS is a promising tool for the continuous assessment of cerebral autoregulation in adults. 16 Results from adult studies suggest that cerebral autoregulation is compromised during sepsis. 17,18 Transcranial Doppler velocities at rest and after intravenous administration of acetazolamide showed reduced reactivity in the patients with SAE, suggesting a diminished capacity for vasodilatation after acetazolamide administration. 17 In a study of 30 adults with severe sepsis, SAE was clinically diagnosed using the CAM-ICU at day 4, and, in most of these patients, autoregulation assessed by TCD was impaired. 18 However, there are no pediatric studies assessing cerebral autoregulation using TCD and NIRS in sepsis.
Brain Imaging There are no specific imaging findings for the diagnosis of SAE. Several changes have been described in adult septic patients (Table 4). In the acute phase of SAE in adults, cytotoxic and vasogenic edema may occur 19,20 as well as ischemic lesions and imaging evidence of leukoencephalopathy. 19,20 Posterior reversible encephalopathy syndrome was reported in 23% in association with sepsis. Accordingly, the optimum imaging study for the patient with sepsis and an abnormal neurologic examination is magnetic resonance imaging (MRI) with diffusion weighted imaging, gradient echo sequences, and contrast. This study will evaluate for other complications of sepsis including CNS infection, cerebral edema, and arterial and venous stroke that must be excluded before considering a diagnosis of SAE. Imaging studies performed in critically ill patients may help guide the assessment of prognosis for
TABLE 4. Magnetic resonance imaging findings in sepsis-associated encephalopathy. Acute MRI Findings Cytotoxic edema Vasogenic edema
Chronic MRI Findings Cytotoxic edema Brain atrophy (hippocampus and frontal region)
Ischemic lesions Leukoencephalopathy PRES PRES indicates posterior reversible encephalopathy syndrome.
neurologic recovery. Sepsis-associated encephalopathy may lead to long-term imaging findings in adults, including white matter lesions. 19 In a 2-center study including 47 critically ill adult patients of which 30% had sepsis, patients with white matter disruption at discharge or 3 months after discharge were associated with worse cognitive scores up to 12 months later. 21 In addition, greater brain atrophy (higher ventricle-to-brain ratio) at 3 months was associated with worse cognitive performances at 12 months. In addition, smaller superior frontal lobes, thalamus, and cerebellar volumes at 3 months were associated with worse executive functioning and visual attention at 12 months. 22 In another similar study, adult patients from 2 ICUs (25 septic and 19 nonseptic patients) were followed up for 6 to 24 months; left-sided hippocampal atrophy was found in adult sepsis survival patients compared with healthy controls. 23 Again, there are no comparable data for children.
Electrophysiology In adults diagnosed with SAE, EEG may be normal or may show excessive theta, predominantly delta, and triphasic waves/burst suppression according to the severity of encephalopathy. 24 Sepsis can also be associated with electrographic seizures or periodic epileptiform discharges. 25 Generalized periodic discharges were strongly associated with nonconvulsive seizures and nonconvulsive status epilepticus. 26 In pediatric case reports, the EEG varied to show excessive beta, predominantly delta, or burst suppression. 5,7 In the pediatric prospective study, all patients with SAE had a background abnormality on their EEG. 7 Sensory evoked potentials (SEPs) detect the integrity of somatosensory pathways from the peripheral to the CNS. Measurement of SEP in 68
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adult patients with severe sepsis and septic shock showed impairment of subcortical and cortical pathways within 48 hours of the development of severe sepsis and septic shock. There were no differences found in SEP between patients with severe sepsis and those with septic shock. 27
Management Advances in the treatment of SAE have been limited by lack of consensus on the definition, limited data on the incidence, and lack of data on mechanisms of SAE with no clearly defined treatment targets. The mainstays of therapy are early consideration of the diagnosis, exclusion of other causes of encephalopathy in the septic patient (CNS infection, arterial and venous stroke, cerebral edema, and nonconvulsive seizures), and supportive care. The use of sedating medications should be limited in patients with suspected SAE, as gamma-aminobutyric acid (GABA), which acts as an inhibitory neurotransmitter in the CNS, was found to increase in plasma from septic encephalopathy patients. 28 In general, benzodiazepines and propofol, which have high affinity to GABA receptors, should be avoided if possible. 29 A double-blind, randomized, controlled trial of adult mechanically ventilated medical and surgical ICU patients showed that sedation with dexmedetomidine resulted in more days alive without delirium or coma compared with sedation with lorazepam. Among this cohort, 63 patients were admitted with sepsis. The septic patients treated with dexmedetomidine had more days free of brain dysfunction and were less likely to die than those who received a lorazepam-based sedation regimen. 30,31
CRITICAL ILLNESS POLYNEUROPATHY AND MYOPATHY Critical illness neuropathy (CIP) and critical illness myopathy (CIM) have a similar clinical picture and are hard to differentiate, as both clinical syndromes coexist simultaneously in most cases. Critical illness neuropathy is a primary axonal polyneuropathy that is well recognized in adult ICU patients with sepsis and multiple organ dysfunction. The true prevalence of ICU-acquired weakness is not exactly known, but it may occur in up to 50% of adult patients with severe sepsis. 32 Critical illness neuropathy and CIM are clinically characterized by a flaccid and symmetrical muscle weakness of the extremities, loss of deep tendon reflexes, and atrophy of the muscles. Although distal muscles are usually affected more than proximal
muscles, facial muscles can be involved rarely (eg, ophthalmoplegia). Failure of weaning from the ventilator may be a first sign, when weakness involves thoracic or phrenic nerves. Although motor failure often predominates, distal loss of sensitivity to light touch, pain, temperature, and vibration may also be apparent in CIP. 33 There are many risk factors for CIP and CIM that have been identified in adults including glucocorticoids and neuromuscular blocking agents, female sex, severity of illness, duration of organ dysfunction, renal failure and renal replacement therapy, hyperosmolality, parenteral nutrition, low serum albumin, duration of ICU stay, vasopressor/catecholamine support, and central neurologic failure. 33-36 In the largest pediatric study of acquired weakness in critically ill children, the incidence was 1.7%. 37 This single-center, prospective study included 830 children admitted to the ICU. Risk factors were congruent with results of adult studies and included mechanical ventilation longer than 5 days, multiorgan dysfunction, sepsis, neuromuscular blockade, use of steroids, need for inotropic support, and solid organ/bone marrow transplant. In addition, asthma has been documented as a risk factor in many pediatric case reports. 38
Diagnosis The diagnosis can be established on clinical grounds in the ED once other potential causes of weakness in the septic patient are ruled out. Typically, in the first presentation of the septic patient to the ED, the presence of multifocal weakness and areflexia should raise concerns for a spinal cord injury (if a level is present on examination), Guillain-Barre syndrome, or inflammatory myopathy. Given the duration of exposure to risk factors required to produce this syndrome, CIP or CIM rarely needs to be diagnosed in the ED. If needed, electromyography and nerve conduction studies can be obtained to confirm the clinical diagnosis. 39 In children, treatment is mostly supportive care with a focus on physical therapy.
Long-Term CNS Complications of Sepsis Pediatric survivors of critical illness and sepsis in particular may experience significant compromise of cognitive function, including deficits in attention and memory. 40,41 In a follow-up study, children admitted to pediatric ICUs significantly underperformed on neuropsychologic measures in comparison with healthy controls. 4 0 Memory and teacher-rated academic performance were most reduced in children with meningoencephalitis and
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septic illness. 42 Lower performance on a composite score of neuropsychologic impairment was more prevalent when children were younger, from a lower social class, and had experienced seizures during their admission. In another pediatric study years after surviving sepsis, cognitive function was significantly lower than that in the normal population in 44% of the survivors. Again, young age at the time of ICU admission was predictive of cognitive problems, and cognitive problems were associated with lower emotional function. 41
SUMMARY Encephalopathy may be underdiagnosed in children with sepsis. The limited pediatric data and extrapolation from adult studies suggest that SAE may contribute to long-term cognitive and behavioral sequelae in survivors of critical illness. The physical examination is of limited use in making this diagnosis, and interpretation of the pediatric literature is confounded by differences in criteria used to assign the diagnosis of SAE. Neuropathy and myopathy may also add to the morbidity of critical illness and sepsis in children and can be diagnosed using the clinical examination. Clearly in the ED, encephalopathy in the septic patient should raise concerns for direct CNS infection requiring brain imaging and lumbar puncture. Electroencephalography may be helpful in identifying SAE once other causes of encephalopathy have been ruled out. However, the current lack of consensus on the definition of SAE and sparse pediatric data limit the specific recommendations, which can be made for the assessment and treatment of this disorder in the ED setting.
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