Neurologic Complications of Sepsis

Abstract

Purpose of Review:

This article reviews the current understanding of sepsis, a critical and often fatal illness that results from infection and multiorgan failure and impacts the brain, peripheral nervous system, and muscle.

Recent Findings:

Encephalopathy occurs early in association with sepsis, and its severity correlates with mortality. Neuroimaging in patients with CNS manifestations is typically normal. EEG is nonspecific. EMG is commonly diagnostic, showing a combination of nerve and muscle injury already early in the clinical course. Rapid recognition and correction of reversible causes of encephalopathy and avoidance of risk factors for intensive care unit–acquired weakness may limit sequelae. Major deficiencies in our understanding of the complications of sepsis remain. Studies to improve the recognition and rehabilitation of these patients are imperative in a clinical syndrome affecting countless patients each year.

Summary:

The risk of later cognitive and physical disability may be increased after sepsis; therefore, attention to neurologic complications is urgent.

INTRODUCTION

Sepsis is the clinical syndrome that occurs in response to severe infection. An identical syndrome, known as the systemic inflammatory response syndrome (SIRS) may occur in response to a noninfectious trigger such as a burn. The body’s typical response to infection is to localize and control the invasion of bacteria while simultaneously repairing damaged tissue. Sepsis and SIRS occur when the response to infection or another trigger becomes generalized, involving normal tissue. This is thought to result from dysregulation of the normal inflammatory response, resulting in uncontrolled release of proinflammatory mediators that lead to widespread injury and often to multiple organ dysfunction syndrome (MODS).

SIRS, sepsis, severe sepsis, septic shock, and MODS were defined in 1991 by a consensus panel convened by the American College of Chest Physicians and the Society of Critical Care Medicine,1 and although these definitions were revised in 20012 and again in 2012,3 the basic premise of their pathophysiology has remained largely unchanged (Table 5-1).

Table 5-1.

Definitions of Sepsis and Organ Failure^a

Approximately half of patients admitted to intensive care units (ICUs) at any given time have a nosocomial infection and thus are at high risk for sepsis.4 Other risk factors include bacteremia, advanced age, immunosuppression, and community-acquired pneumonia (Table 5-2).4,5,6,7 Genetic defects have been identified that may increase susceptibility to specific classes of microorganisms.8 Gram-positive bacteria are the most commonly identified microbes in patients with sepsis in the United States, followed by gram-negative bacteria, and then fungi.3,9 While cultures of the presumed source of infection are useful to guide antimicrobial selection, they are negative in up to 50% of patients. The genitourinary tract is a common site of infection from which bacteremia is often initiated by instrumentation. Other common foci include the gastrointestinal and respiratory tracts, wounds, burns, pelvic infections, and contaminated invasive lines and catheters. Mortality in sepsis ranges from 12% to 50%.9,10,11,12,13,14,15 In one study, the mortality rate of SIRS, sepsis, severe sepsis, and septic shock was 7%, 16%, 20%, and 46%, respectively.16 Mortality is declining, possibly because of improved detection in the early phase and compliance with practice guidelines, which stress the use of sepsis bundles. A bundle is a defined set of tasks that when implemented as a protocol more positively affect outcomes than the implementation of any of the individual tasks alone. The sepsis bundle includes a set of tasks that must be completed within 3 hours of presentation, such as the administration of 30 mL/kg of crystalloid, and a separate set of tasks that must be completed within 6 hours, such as the administration of vasopressors to maintain a mean arterial pressure ≥65 mm Hg (Table 5-317).10 Sepsis occurs when proinflammatory mediators released in response to a local infection exceed the capacity of the local environment and lead to a systemic response (Figure 5-1)

Table 5-2.

Risk Factors for Developing Sepsis

Table 5-3.

Surviving Sepsis Campaign Care Bundles^a

Figure 5-1.

Relationship between infection, systemic inflammatory response syndrome (SIRS), and sepsis (see Table 5-1 for definitions of terms). Reprinted with permission from Bone RC, et al, Chest.1 © 1992, American College of Chest Physicians. journal.publications.chestnet.org/article.aspx?articleid=1065037.

All organ systems may sustain the deleterious effects of sepsis. The most commonly affected organs and organ systems include the lungs, kidneys, and liver and the circulatory system and nervous system. This article summarizes the important neurologic complications seen in association with sepsis.

ACUTE BRAIN DYSFUNCTION (SEPSIS-ASSOCIATED ENCEPHALOPATHY)

Clinical Features

Case 5-1 is a typical example of a patient with sepsis-associated encephalopathy.

Case 5-1

A 46-year-old woman with a history of alcohol abuse presented to the hospital with cough and dyspnea. She was confused, febrile, tachycardic, and hypotensive. A chest x-ray showed consolidation of the left lung base. Lactic acid was 6.5 mmol/L. Fluid resuscitation was begun, and she was started on cefepime, vancomycin, and metronidazole. She required norepinephrine and vasopressin to maintain normotension. She was anuric. On repeat examination she was difficult to arouse. She became increasingly tachypneic with increasing oxygen requirements and ultimately required endotracheal intubation and mechanical ventilation. She was difficult to oxygenate because of the development of acute respiratory distress syndrome. She required sedation with propofol and fentanyl infusions to maintain oxygenation. Repeat laboratory evaluation revealed elevated transaminases, blood urea nitrogen of 89 mg/dL, and creatinine of 5.9 mg/dL. Continuous venovenous hemodialysis was initiated, and she was weaned off vasopressor support on hospital day 4. Sedation was discontinued on hospital day 5, and neurology was consulted the following day when she did not awaken. On examination there was no eye opening to voice or nociceptive stimulation. Pupil, corneal, and oculocephalic reflexes were intact. She grimaced to nociceptive stimulation and had weak withdrawal responses in all four extremities. Occasional multifocal myoclonus was noted during examination.

Comment. This case demonstrates the challenges faced by a neurologist asked to determine the cause of diminished responsiveness in a previously septic patient. This patient had severe sepsis due to community-acquired pneumonia resulting in shock and MODS. She can be said to have sepsis-associated encephalopathy, but such an umbrella term (such as the term toxic-metabolic multifactorial encephalopathy) is not particularly meaningful. As is often the case, she had acute kidney and hepatic injury (so-called shock liver), both of which theoretically can individually produce an encephalopathy. Drug administration in the intensive care unit is often an underappreciated cause and major factor. Fentanyl may have markedly reduced clearance in the context of renal failure. Cefepime may produce an encephalopathy with myoclonus and sometimes seizures in patients with reduced renal function. Additionally, she may have experienced hypoxic-ischemic injury due to hypoxia and the profound shock state. Finally, while unlikely given that she has been hospitalized 6 days, the possibility of severe alcohol withdrawal must be considered.

While well over half of septic patients have encephalopathy,18,19 the incidence and severity are difficult to characterize because systematic studies have not been performed, and definitions in published retrospective studies are varied. The clinical features of sepsis-associated encephalopathy are listed in Table 5-4. These features are nonspecific and do not reliably identify a particular etiology. Initially, patients are confused, disoriented, and restless, and that may be just simply a manifestation of any major illness. Tachypnea and hyperventilation are common and may result from early lung injury or from the effects of circulating immunologic mediators on the brainstem. The level of alertness reflects the degree of critical illness. Patients with septic shock and MODS may become comatose. The presence and severity of encephalopathy correlate with mortality.18,19,20

Table 5-4.

Clinical Features of Sepsis-Associated Encephalopathy

On examination of the cranial nerves, pupillary response to light remains intact; however, pupils may be pinpoint because of opioid administration. Ocular motility is preserved, although patients’ eyes may rove and rest in a disconjugate position with the eyes deviated upward and outward bilaterally (Bell phenomenon). Corneal, gag, and cough reflexes are typically preserved. Motor examination may reveal coarse tremor,18 asterixis, or rarely multifocal myoclonus.21 Additionally, patients have varying motor responses that depend largely on the level of consciousness. Paratonia (a form of increased tone with an involuntary variable resistance during passive movement), extensor plantar responses, or even flexor or extensor posturing may be present, but these are findings commonly found in comatose patients.20

Pathophysiology

Sepsis can affect anyone, but in general it is a disease of the elderly. Patients may have varying degrees of preexisting cognitive impairment predisposing them to decompensation upon hospitalization. The term sepsis-associated encephalopathy implies that part of the brain dysfunction directly results from the body’s response to infection, but it also acknowledges that other factors are at play. It may be nothing more than a quiet delirium, a syndrome so commonly seen in critically ill patients. While our current understanding of the pathophysiology of brain dysfunction in sepsis is far from precise, it likely involves two major principles (Figure 5-222). First, the body’s response to sepsis produces a vulnerable brain. This response involves inflammatory mediators, cytokines, a reduction in monamine transmitters, disruption of the blood-brain barrier, and microcirculatory abnormalities.23 The exact pathophysiology of this response is not well delineated. Second, the vulnerable septic brain is exposed to a myriad of toxins, including osmotically active molecules not appropriately metabolized by the liver or kidneys because of organ dysfunction; sedative or analgesic agents; or other drugs or drug combinations that are neurally active, including cefepime, serotonergic agents, and dopaminergic agents. Thus, patients with sepsis may be more vulnerable to uremic or hepatic encephalopathy as well as to the effects of medications. Patients have certainly been described who do not have other clearly delineated causes of encephalopathy (eg, renal or hepatic dysfunction; sedative administration; or toxidrome, a syndrome caused by a dangerous level of toxins in the body) who likely have an encephalopathy resulting directly from the maladaptive response to the septic state. In the opinion of the authors of this article, these represent the minority of patients with sepsis-associated encephalopathy. In the vast majority, patients with a vulnerable brain due to the septic state experience a second injury due to uremia, acute hepatic dysfunction, drug effect, or other insult. An extensive review of the pathophysiology of each of these conditions is beyond the scope of this article.

Figure 5-2.

Pathophysiology of sepsis-associated encephalopathy. ^a Risk is higher if a preexisting cognitive impairment is present. Modified from Sonneville R, et al, Ann Intensive Care.22 © 2013, Sonneville et al. www.annalsofintensivecare.com/content/3/1/15.

Diagnosis and Differential Diagnosis

The differential diagnosis in a patient with SIRS and encephalopathy includes CNS infection, acute alcohol or drug intoxication or withdrawal, and Wernicke encephalopathy. Other conditions that may mimic sepsis include nonconvulsive status epilepticus, serotonin syndrome, neuroleptic maligant syndrome, malignant catatonia, or immune-mediated encephalitis (Table 5-5).

Table 5-5.

Differential Diagnosis of Sepsis and Encephalopathy

A lumbar puncture, often necessary to exclude encephalitis or meningitis, will typically demonstrate a normal or mildly elevated protein level with normal glucose and negative Gram stain and culture. Other diagnostic testing may include neuroimaging and EEG (Table 5-624,25). The EEG typically demonstrates progressive slowing corresponding with the level of consciousness. Subclinical seizures or periodic epileptiform discharges may be present; however, whether identification and treatment of these discharges in the setting of sepsis is beneficial is controversial. The incidence of subclinical seizures in the setting of sepsis is probably low, and routine EEG monitoring is not justified based on current evidence. One prospective study of continuous EEG monitoring in sepsis reported a rate of less than 10% of subclinical seizures and no episodes of status epilepticus.26 Another study of continuous EEG monitoring in sepsis demonstrated seizures or periodic epileptiform discharges in 32% of patients; however, the percentage of these patients who had seizures was not specified.27 Neuroimaging is often normal. Some patients may have multiple ischemic strokes or subcortical lesions in the centrum semiovale.

Table 5-6.

Diagnostic Testing in Sepsis-Associated Encephalopathy^a

Many conditions coassociate with sepsis and may contribute to or solely account for encephalopathy. These include both irreversible and reversible factors. Irreversible factors include multiple intracranial hemorrhages that may occur in combination with embolic strokes resulting from atrial fibrillation, endocarditis, or coagulopathy; and decompensated dementia. Patients with an underlying neurodegenerative disorder such as Parkinson disease, Alzheimer disease, or static encephalopathies due to previous traumatic brain injury or cerebral palsy are more susceptible to the effects of critical illness with its associated drugs, organ dysfunctions, and even the ICU environment itself. Reversible factors include hypercapnia, hypoxemia, hypotension, hyperthermia, hepatic dysfunction, uremia, metabolic disturbances such as hyponatremia or dysglycemia, cefepime neurotoxicity, nonconvulsive seizures (rare), posterior reversible encephalopathy syndrome (PRES), serotonin syndrome, hypoperfusion, cerebral abscesses, and cerebritis. Additionally, patients have often received sedative or analgesic agents that may have accumulated in the context of organ dysfunctions. Patients with sepsis may be more sensitive to the effects of these agents because of dysfunction of the blood-brain barrier.

Management Approach

A systematic approach (Table 5-7) helps to eliminate reversible causes of encephalopathy. Our approach is essentially a process of elimination and observation. It is useful to have a mental checklist in mind when evaluating these patients (Table 5-8). Few patients have no coassociating conditions or have only minor conditions, such as mild acute kidney injury or a modest elevation in the transaminases. In these instances, when significant contributing factors are not identified, the clinician may feel uncertain of the specific diagnosis—this is appropriate, as septic encephalopathy may not even exist as a pure entity. Mild confusion or fluctuations in the level of alertness may be explainable by the septic state alone, but profoundly diminished responsiveness should prompt a search for alternative explanations when clear toxic or metabolic abnormalities are not identified. This search generally begins with neuroimaging, CSF analysis, and EEG, which may reveal one of the more uncommon causes of sepsis-associated encephalopathy, such as infection of the CNS, nonconvulsive status epilepticus, or multiple intracranial hemorrhages or infarctions.

Table 5-7.

Systematic Approach to the Patient With Sepsis and Diminished Responsiveness

Table 5-8.

Consultant’s Checklist for Use in the Evaluation of the Patient With Sepsis and Diminished Responsiveness

A thorough discussion of all sepsis-associated conditions is beyond the scope of this article. We will briefly highlight a few of the conditions that are probably more common than generally appreciated. More importantly, reversal of these syndromes often results in rapid improvement in the encephalopathy.

Serotonin syndrome is a syndrome of excess serotonin. It may be caused by intentional self-poisoning, but, in the context of sepsis, it results from therapeutic drug use or inadvertent interactions between drugs.28 The syndrome is potentially life threatening and should be suspected when antidepressants are continued on hospital admission and other serotonergic agents, most commonly opioids (especially fentanyl) and antiemetics, are prescribed during hospitalization. Patients are encephalopathic, hyperreflexic, and rigid, and often have myoclonus or sustained clonus. Some have a flushed appearance.

Cefepime neurotoxicity typically manifests as encephalopathy with or without myoclonus, seizures, or status epilepticus.29 Renal insufficiency is a well-recognized risk factor for development of cefepime neurotoxicity; however, cases have been reported in patients with normal renal function. It typically develops after several days of exposure to the drug and improves within 24 to 72 hours of drug withdrawal.

Posterior reversible encephalopathy syndrome (PRES) is a clinical syndrome characterized by headache, encephalopathy, seizures, and visual disturbances with or without radiologic findings of focal reversible vasogenic edema. Risk factors for development of PRES include acute hypertension, sepsis, renal disease, exposure to immunosuppressant drugs, preeclampsia or eclampsia, and the setting of autoimmune disease.30 When possible, the trigger should be removed (ie, treatment of infection or removal of immunosuppressant drugs). While in the majority of cases seizures associated with PRES are clinically apparent, patients with decreased level of consciousness should undergo routine EEG to exclude nonconvulsive seizures.

Neuroleptic malignant syndrome, malignant catatonia, and parkinsonism-hyperpyrexia syndrome are three designations for clinical syndromes that have many features alike and may occur with administration of antidopaminergic medications, in acutely ill psychiatric patients, or in patients with Parkinson disease who have an acute discontinuation of dopamine, respectively. The syndromes are characterized by encephalopathy, rigidity, and dysautonomia. The condition is life threatening if unrecognized. Administration of dantrolene may result in rapid stabilization of the dysautonomia, allowing time to identify and correct the trigger (ie, resume carbidopa-levodopa in patients with Parkinson disease).31

Prognosis

Coma or significant decline in cognitive functioning during or after sepsis predicts a poor outcome. Survivors of sepsis have been shown to develop substantial and persistent new cognitive deficits and functional disability.32 The risk of development of persistent cognitive dysfunction likely increases with increasing patient age, but this has not yet been systematically studied.

INTENSIVE CARE UNIT–ACQUIRED WEAKNESS (CRITICAL ILLNESS POLYNEUROPATHY AND MYOPATHY)

Clinical Features

ICU-acquired weakness is a complication of critical illness caused by polyneuropathy, myopathy, or both in combination. Both critical illness polyneuropathy (CIP) and critical illness myopathy (CIM) may affect limb and respiratory muscles and may result in delayed weaning or failure to wean from mechanical ventilation as well as delayed mobilization and rehabilitation. The true prevalence of ICU-acquired weakness is not exactly known, but it may occur in up to 50% of patients with severe sepsis.33,34

Case 5-2

Neurologic consultation was re-requested for the patient with septic shock and MODS described in Case 5-1 2 weeks after the initial neurologic consultation because of difficulty weaning the patient from the ventilator. Initial neurologic recommendations had been to replace cefepime with an appropriate alternative antimicrobial, to avoid sedating agents including opioids, and to observe. Within 3 days of the initial consultation she had markedly improved, such that on examination she consistently opened eyes to voice and fixated and tracked visually but did not follow commands. Multifocal myoclonus disappeared. Motor response was absent. She remained in this state for several days and over the following week gradually improved commensurate with improvement in her renal and hepatic dysfunction. On reevaluation she was consistently alert and followed commands, but had not been liberated from mechanical ventilation. Examination was remarkable for a flaccid quadriparesis with diffusely reduced reflexes and atrophy. When placed on a spontaneous mode of mechanical ventilation, she quickly demonstrated use of accessory muscles and a paradoxical pattern of breathing. Tracheostomy was pursued, and she was transferred to a ventilator weaning unit. Several months later she was liberated from mechanical ventilation and ambulated independently.

Comment. Case 5-2 illustrates many points. First, the encephalopathy was apparent early, was severe, and dramatically improved with treatment of the sepsis. Second, difficulty weaning from mechanical ventilation is an important early manifestation of neuromuscular weakness. Finally, quadriparesis develops later and recovery is gradual (Figure 5-3). This patient typifies the neurologic complications associated with sepsis. The initial improvement in her encephalopathy within 3 days of the initial neurologic consultation was likely due to clearance of cefepime and fentanyl. She then gradually improved as her underlying organ dysfunctions resolved. An index of suspicion for ICU-acquired weakness develops when the patient fails to wean from the ventilator, as quadriparesis is often overlooked in critically ill patients. The paradoxical breathing and accessory muscle use indicate diaphragmatic failure and intercostal weakness. Flaccid quadriparesis with reduced reflexes and muscle atrophy suggest a diffuse polyneuropathy with or without superimposed myopathy.

Figure 5-3.

Time course of neurologic complications of sepsis. Scale changes depending on severity of sepsis. This is a severe form in which the time course was measured in months. Reprinted with permission from Bolton CF, et al, Ann Neurol.18 © 1993, The American Neurological Association. onlinelibrary.wiley.com/doi/10.1002/ana.410330115/abstract.

On neurologic examination patients may have mild facial weakness. Cranial nerve examination is otherwise normal, including extraocular muscle strength, swallowing function, tongue protrusion, and jaw closure strength. Limb weakness is typically symmetric, severe, more pronounced distally, and associated with muscle wasting. Diffuse fasciculations may be present. Deep tendon reflexes are typically reduced or absent. Patients generally do not have associated autonomic dysfunction. Involvement of the phrenic nerve has been proven in some patients who come to autopsy, but whether neuromuscular respiratory weakness in survivors of sepsis exists is unresolved and very difficult to assess clinically in patients who have had a major acute lung injury. Case 5-2 illustrates a typical example of ICU-acquired weakness.

Pathophysiology

Whether or not CIP and CIM are distinct entities or represent varying organ dysfunctions with a common pathogenesis is controversial. The authors of this article suspect they are related entities resulting from the same set of insults. That is, nerve dysfunction leads to effects on the muscles, and, similarly, diseased muscle can influence the nerves in a retrograde fashion. These insults include the systemic inflammatory state and sepsis themselves, and metabolic changes, including multiple organ failures. Risk factors for ICU-acquired weakness that have been identified in prospective studies include severity of illness, duration of organ dysfunction, MODS, duration of vasopressor and catacholamine support, duration of ICU stay, hyperglycemia, female sex, renal failure and renal replacement therapy, parenteral nutrition, low serum albumin, hyperosmolality, SIRS, and sepsis. Aminoglycoside antibiotics, neuromuscular blocking agents, and steroids have been identified as risk factors in some studies but not in others. Immobility and duration of mechanical ventilation have been independently associated with the development of muscle weakness during critical illness.35 The neuropathy of critical illness is a primary axonal degeneration, predominantly of distal motor fibers (Figure 5-436).

Figure 5-4.

Nerve biopsy specimen from a patient with critical illness polyneuropathy showing marked axonal loss and fibers undergoing wallerian degeneration.

Reprinted with permission from Wijdicks EFM, Oxford University Press.36 © 2009, Mayo Foundation for Medical Education and Research.

Diagnosis

ICU-acquired weakness is suspected when patients fail to wean from mechanical ventilation despite the absence of cardiopulmonary causes. When sedation is withdrawn, or as encephalopathy resolves, flaccid weakness of the limbs becomes apparent. If weakness fails to improve over a period of days, electrodiagnostic testing including EMG and nerve conduction studies—and in some cases, muscle biopsy—are indicated. Diagnostic criteria for both CIP and CIM are well established (Table 5-937,38).

Table 5-9.

Diagnostic Criteria for Intensive Care Unit–Acquired Weakness^a

Differential Diagnosis

Depending on the circumstances, alternative causes of acute axonal polyneuropathy such as Guillain-Barré syndrome, acute hypophosphatemia, or thyrotoxicosis-associated weakness may need to be excluded. A less common form of neuromuscular weakness resulting from sepsis is a defect in neuromuscular junction transmission that may be indentified by electrophysiologic testing. Impaired neuromuscular transmission may be caused by severe depletion of potassium or phosphorus or excess of magnesium. Other causes of impaired neuromuscular transmission include chemotherapeutic agents, neuromuscular blocking agents, statins, and antiretroviral agents. The clinician must remain vigilant to the possibility of an acute spinal shock that may mimic the flaccid quadriplegia seen with ICU-acquired weakness. This complication may result from spread of malignancy, epidural abscess, or hematoma.

Management

To date, no specific therapy for ICU-acquired weakness has been established, and supportive care is the only available option. Patients with ICU-acquired weakness should receive passive range of motion, protection from nerve compression at vulnerable sites such as ulnar and peroneal nerves, and splinting or braces during the later phases of rehabilitation when they can support their weight but have persistent distal muscle weakness. In addition to avoidance of risk factors, early active mobilization of critically ill patients may be beneficial. Plasma exchange and corticosteroids have been used in some cases without dramatic improvement. IV immunoglobulin has been used at the authors’ institution in three patients with CIP but did not result in improvement at 2 months.39 However, a post hoc analysis of a prospective series of 62 patients with sepsis-induced MODS suggested a reduced incidence of CIP with early (less than 24 hours from diagnosis) IV administration of immunoglobulin.40 Until further data are made available, IV immunoglobulin cannot be routinely recommended.

Prognosis

ICU-acquired weakness significantly increases the duration of mechanical ventilation in septic patients and prolongs ICU and hospital stays.34 The majority of patients who survive the acute illness recover completely over weeks to months. Even those with severe quadriplegia may achieve complete recovery. Improvement begins in the upper extremities and proximal lower limbs followed by improvement in the respiratory muscles and liberation from mechanical ventilation and ultimately recovery of distal lower limb strength. Approximately 22% of 1-year survivors do not improve, and this is likely related to axonal destruction or comorbid compression neuropathies.41

CONCLUSIONS AND FUTURE DIRECTIONS

Encephalopathy and ICU-acquired weakness are frequent occurrences in septic patients. The encephalopathy appears early and may be severe but largely reverses as control of the septic state is achieved. Neuroimaging and CSF analysis are often normal. The EEG may correlate with the severity of encephalopathy but is not very useful unless seizures are suspected, in which case it may be diagnostic. ICU-acquired weakness due to CIP or CIM develops later, and resolution of weakness is gradual. Difficulty weaning from the ventilator is an early clue. EMG is often diagnostic. Medications including sedatives, analgesics, and neuromuscular blocking agents often confound the evaluation.

Future directions should include prospective cohort studies of patients who survive sepsis during the acute stage of confusion and weakness and structured long-term follow-up in order to better understand prognosis and predictors of good functional outcomes. This would also add to our understanding of incidence and risk factors in the sepsis population. Additionally, studies of early intervention are needed. The use of techniques such as ICU diaries to help patients understand their illness and deal with delusional memories they may have has been shown to aid psychological recovery in critically ill patients, some of whom have experienced sepsis.42 An ongoing prospective study testing the feasibility of a complex intervention incorporating cognitive, physical, and functional rehabilitation beginning at the time of hospital discharge and lasting 12 weeks utilizes in-home visits and teletechnology (ClinicalTrials.gov Identifier: NCT00715494). This and other similar studies should be pursued to identify whether early aggressive multimodal therapies speed improvement of neuropsychological and physical performance.

KEY POINTS

• Sepsis occurs when proinflammatory mediators released in response to a local infection exceed the capacity of the local environment and lead to a systemic response. Why immune responses sometimes spread beyond the local infection is not well understood, but may relate to effects of invading microorganisms, release of massive amounts of proinflammatory mediators, and complement activation. Widespread cellular injury occurs and results in organ dysfunction. Possible mechanisms of cellular injury include tissue ischemia due to increased demand and insufficient delivery, dysregulated apoptosis, and direct cellular injury by proinflammatory mediators resulting in necrosis.

• All organ systems may suffer deleterious effects of sepsis. The most commonly affected organs and organ systems include the lungs, kidneys, and liver and the circulatory system and nervous systems.

• The level of alertness reflects the degree of critical illness. Patients with septic shock and multiple organ dysfunction syndrome may become comatose. The presence and severity of encephalopathy correlate with mortality.

• The term sepsis-associated encephalopathy implies that part of the brain dysfunction directly results from the body’s response to infection, but it also acknowledges that other factors are at play.

• The incidence of subclinical seizures in the setting of sepsis is probably low, and routine EEG monitoring is not justified based on current evidence.

• Patients with an underlying neurodegenerative disorder such as Parkinson disease, Alzheimer disease, or static encephalopathies due to previous traumatic brain injury or cerebral palsy are more susceptible to the effects of critical illness with its associated drugs, organ dysfunctions, and even the intensive care unit environment itself.

• Mild confusion or fluctuations in the level of alertness may be explainable by the septic state alone, but profoundly diminished responsiveness should prompt a search for alternative explanations when clear toxic or metabolic abnormalities are not identified.

• Coma or significant decline in cognitive functioning during or after sepsis predicts a poor outcome. Survivors of sepsis have been shown to develop substantial and persistent new cognitive deficits and functional disability.

• Both critical illness polyneuropathy and critical illness myopathy may affect limb and respiratory muscles and may result in delayed weaning or failure to wean from mechanical ventilation as well as delayed mobilization and rehabilitation.

• The neuropathy of critical illness is a primary axonal degeneration, predominantly of distal motor fibers.

• Intensive care unit–acquired weakness is suspected when patients fail to wean from mechanical ventilation despite the absence of cardiopulmonary causes.

• Patients with ICU-acquired weakness should receive passive range of motion, protection from nerve compression at vulnerable sites such as ulnar and peroneal nerves, and splinting or braces during the later phases of rehabilitation when they can support their weight but have persistent distal muscle weakness.

• ICU-acquired weakness significantly increases the duration of mechanical ventilation in septic patients and prolongs ICU and hospital stays.

• Future directions should include prospective cohort studies of patients who survive sepsis during the acute stage of confusion and weakness and structured long-term follow-up in order to better understand prognosis and predictors of good functional outcomes.