Chronic Critical Illness and the Long Term Sequela of Critical Care




(1)
Division of Pulmonary and Critical Care Medicine, Eastern Virginia Medical School, Norfolk, VA, USA

 




Keywords
Chronic critical illnessPolyneuropathyMyopathyCognitive dysfunctionDementia preventionLong term care


Although advances in intensive care have enabled more patients to survive an acute illness they have also created a large and growing population of patients with prolonged dependence on mechanical ventilation and other intensive care therapies. The term “chronically critically ill” was coined for this group of patients by Girard and Rafin in a 1985 article that asked in its title “to save or let die?” [1] They focused on patients who survived an initial episode of critical illness but remained dependent on intensive care, neither dying in the acute period of intensive care unit treatment nor recovering. Chronic critical illness (CCI) usually defined as an icu patient who requires more than 21 days of assisted ventilation. The placement of a tracheostomy for long term ventilation is used by many to identify CCI patients [2]. Although prolonged dependence on mechanical ventilation is a hallmark of CCI, CCI is not simply an extended period of acute critical illness but a discreet syndrome including profound weakness attributed to myopathy, neuropathy, alteration in body composition, anasarca, neuroendocrine changes, brain dysfunction manifesting as coma or delirium, increased vulnerability to infections and skin breakdown leading to decubital ulceration [36].

Depending on the setting, CCI patients account for between 5 and 10 % of adult ICU admissions. It is estimated that there are currently approximately 100,000 CCI in the United States [2, 6]. This increasing number of CCI patients led to an 8.8 % increase in the number of long term acute care (LTAC) hospital beds between 1997 and 2006 [2]. Mechanically ventilated patients with a history of prior pulmonary disease and who require renal replacement therapy are at the greatest risk of CCI [3, 79]. These patients are usually elderly with a slight male predominance. Patients suffering postoperative complications make up a large percentage of CCI patients. These are usually patients with underlying cardio—pulmonary disease who have undergone cardiac or abdominal surgery. Trauma and burn patients as well as those with acute lung injury (ARDS) and patients with chronic respiratory failure (usually COPD) make up the majority of the remaining patients. CCI occurs in the setting of multiple episodes of sepsis with SIRS, multiorgan dysfunction syndrome (MODS) and respiratory failure. The prognosis of patients with CCI is generally poor, surprisingly the hospital survival is about 50 % with a 1 year survival of approximately 25 %. Nearly all patients with chronic critical illness leave the hospital with profound impairments of physical function, cognitive status or both, and most therefore require institutional care. Hospital readmission during the year after hospital discharge exceeds 40 % [6]. Only about 10 % of CCI patients are alive at home and functionally independent at 1 year [2].

In addition to the CCI patients who remain ventilator dependent and are managed in long term acute care facilities (LTAC) is an even larger group of patients who recover from their acute illness but suffer from long term disabilities, most notably neuromuscular dysfunction. These patients are distinguished from CCI in that they are not ventilator dependent. The chronic sequela of critical illness represent an extension of many of the characteristic morbidities of CCI. The number of patients with persistent cognitive dysfunction after CCI may be as high as 65 % [6]. In survivors of ARDS, Herridge and colleagues demonstrated muscle weakness and functional impairment up to 5 years after hospital discharge [10]. In this study only 48 % of survivors had returned to work at 1 year, with only 78 % of these returning to their previous employment.

The pathophysiology of CCI is complex and incompletely understood. The need for chronic respiratory support is due to the complex interplay between critical illness polyneuropathy, critical ill myopathy, recurrent chest infections, delerium and immobility. Chronic elevations in cortisol, catecholamines and cytokines, resulting from recurrent infection and inflammation, act in concert to depress hypothalamic-pituitary growth hormone, gonadal and thyroid axes, as well as modulate renal, bone and energy metabolism. These derangements lead to clinical manifestations, such as altered body composition (increased fat and decreased lean mass), hyperglycemia, osteoporosis and immune dysfunction [4, 5]. In patients with CCI the pulsatile secretion of GH is suppressed with very low mean nocturnal concentration of GH. These findings are suggestive of relative GH deficiency, which is postulated to play a role in the wasting syndrome of CCI. These changes appear to be more severe in men. The acute phase of critical illness is characterized by low levels of T3 with normal levels of TSH and T4. This contrasts with the pattern in CCI, in which the TSH is low (or low-normal), with low T4 and T3 levels. The pulsatility in the TSH secretory pattern is dramatically diminished and like the GH axis, the loss of TSH pulse amplitude, is related to low levels of thyroid hormone.

Metabolic bone disease is prevalent in the CCI patient population. Prolonged immobilization and cytokine-mediated events increase the risk of bone hyper-resorption. Vitamin D deficiency is extremely common resulting from lack of exposure to sun, malnutrition, malabsorption and impaired renal or hepatic function [11]. Nierman and Mechanick demonstrated that 92 % of CCI patients had bone hyper-resorption due to either vitamin D deficiency and/or immobilization [12]. These authors have used the combination of pamidronate and calcitriol [1, 25 (OH)2 vitamin D] to control bone hyper-resorption [13].


Neuromuscular Abnormalities


Neuromuscular problems are an extremely common in CCI patients. These include critical illness polyneuropathy, delirium, metabolic encephalopathy (with coma) and myopathy. The problems further delay weaning from mechanical ventilation and increase the morbidity and mortality of this syndrome. In addition, the persistence of neuromuscular dysfunction is largely responsible for the long term disabilities following acute critical illness.


Critical Illness Polyneuropathy


Critical illness polyneuropathy (CIP) first described by Bolton in 1983, is defined as a predominantly motor, axonal dysfunction of peripheral nerves in the setting of SIRS, MODS and respiratory insufficiency [1416]. Postmortem examination of peripheral nerve specimens from patients with CIP has shown primary degeneration of motor and sensory nerves that supply the limbs and respiratory system. Although this denervation is more widespread and severe in the distal muscle groups, the phrenic nerve, diaphragm, and intercostals muscles are also involved.

Classically CIP is associated with a symmetric predominantly distal paresis, with legs involved worse than arms, along with impaired sensory testing in the feet and hyporeflexia. CIP is difficult to diagnose clinically and is often suspected when critically ill patients are otherwise improving yet continue to have difficulty in weaning from mechanical ventilation. In most patients the initial neurologic symptom of CIP is failure to wean. The definitive diagnosis of CIP is made by EMG and nerve conduction studies. EMG is characterized by:



  • Widespread fibrillations and positive sharp waves


  • Reduced amplitude of compound muscles and sensory nerve action potentials


  • Relatively normal conduction studies

There are no proven treatments that will speed the recovery of peripheral nerve function in patients who have developed CIP. CIP is associated with prolonged weaning difficulties, a long convalescence and a high mortality. Both the time to liberation from mechanical ventilation and the mortality are directly related to the severity of the polyneuropathy.


Critical Illness Myopathy (See also Chap. 32 on Nutrition)


Multiple studies have shown an accelerated loss of muscle mass in patients admitted to the ICU and this play a major role in terms of post-ICU functional disability. This disorder is known as Critical illness myopathy (CIM). CIM is characterized by a diffuse non-necrotizing myopathy accompanied by fiber atrophy, fatty degeneration of muscle fibers and fibrosis. Loss of muscle mass results from an imbalance between muscle proteolysis and protein synthesis, with proteolysis overwhelming an inadequate synthetic response. Proteolysis is achieved by several cellular signaling networks, but the predominant proteolytic pathway activated in animal models of muscle atrophy is the ubiquitin–proteasome system. In the critically ill patient multiple factors are likely to play a role in inducing muscle atrophy including muscle inactivity, inflammation, cellular energy stress and inadequate provision of amino acids (low quality and continuous rather than bolus feeding). Clinically, patients with CIM may demonstrate weakness, failure to wean or paresis. Creatinine phosphokinase (CPK) levels are relatively normal, consistent with a myopathy and not a myositis. CIM remains difficult to distinguish clinically from CIP because they share similar clinical characteristics and may occur in the same patient. Although the presence of normal sensory nerve action potentials with small compound muscle action potentials on electrodiagnostic studies may suggest a component of CIM, muscle biopsy remains the gold standard for diagnosis. However, because there is no effective treatment for CIM, the indications for invasive biopsies are unclear.

Puthucheary and colleagues demonstrated a 17 % reduction in the rectus femoris cross sectional area in critically ill patients after 10 days of mechanical ventilation [17]. Casaer and colleagues demonstrated a 6.9 % loss of femoral muscle volume over 7 days of mechanical ventilation [18]. The loss of muscle mass in these studies occurred despite provision of adequate dietary protein. Indeed, the provision of high concentrations of amino acids parenterally or as continuous enteral feeding may inhibit protein synthesis [17]. CIM may persist for years after discharge from the ICU.

The diaphragm is the principle muscle of respiration. Respiration is essentially an endurance effort, and the structure of the normal human diaphragm reflects its major contribution to sustaining ventilation. In addition to loss of skeletal muscle mass, loss of diaphragmatic mass occurs in mechanically ventilated patients. Grosu and colleagues demonstrated the loss of diaphragm thickness at a rate of 6 % per day of mechanical ventilation [19]. Levine and colleagues obtained biopsy specimens from the diaphragms of 14 brain-dead organ donors who had undergone mechanical ventilation for between 18 and 69 h before organ harvest and compared them with intraoperative biopsy specimens from the diaphragms of control patients [20]. As compared with diaphragm-biopsy specimens from controls, specimens from case subjects showed decreased cross-sectional areas of slow-twitch and fast-twitch fibers of 57 % and 53 %, and a marked upregulation of the mRNA transcripts of those proteins involved in the ubiquitin–proteasome muscle breakdown system. Difficulties in discontinuing ventilatory support are encountered in 20–25 % of mechanically ventilated patients, with a staggering 40 % of time spent in the ICU being devoted to weaning [21]. Because the respiratory muscles play a pivotal role in determining the weaning outcome, diaphragmatic dysfunction plays a major role in patients who fail weaning from mechanical ventilation. Patients with diaphragmatic dysfunction demonstrated frequent early and delayed weaning failures. CIM has profound implications in the elderly. Body composition changes dramatically with aging. There is an increase in body fat and a decrease in lean muscle mass by up to 40 % at age 80 years [22]. Furthermore, the acute loss of muscle mass (CIM) is most severe in the elderly [17]. This suggests that critically ill elderly patients who have been ventilated for over 7–10 days may develop severe diaphragmatic atrophy to the point that they are unable to breathe without mechanical assistance. This progresses into a vicious cycle in which ongoing mechanical ventilation results in further diaphragmatic atrophy which further compromises attempts at weaning. These patient remain ventilator dependent frequently develop multiple complications including pneumonia, delirium, bed-sores and ultimately succumb to multi-organ system failure.


Brain Dysfunction


Cognitive dysfunction is reported to occur in up to 65 % of CCI patients [23]. Unlike the delirium of acutely ill patients which usually lasts about 48 h, the delirium occurring in CCI patients may persist for a prolonged period of time. Followup studies reveal that most of the hospital survivors including those living at home remain profoundly cognitively impaired [23]. Pandharipande and colleagues evaluated the long-term cognitive impairment of 821 patients who were admitted to an ICU with respiratory failure or shock [24]. Delirium developed in 74 % of patients during their hospital stay. At 3 months, 40 % of the patients had global cognition scores that were 1.5 SD below the population means (similar to scores for patients with moderate traumatic brain injury). Deficits occurred in both older and younger patients and persisted, with 34 % and 24 % of all patients with assessments at 12 months that were similar to scores for patients with moderate traumatic brain injury and scores for patients with mild Alzheimer’s disease, respectively. A longer duration of delirium was independently associated with worse global cognition and worse executive function at 12 months.


“Prevention” of CCI


CCI is essentially an iatrogenic disease resulting from the aggressive management of acute critical illness. This may not be a preventable state but reflects advances in acute resuscitation and support of critical illness. However there are important strategies that may decrease the incidence of CCI and reduce the burden of CCI for patients who are affected. Most importantly, only “functional” patients who have a reasonable chance of surviving their ICU stay and returning to their previous level of functioning should be admitted to the ICU. For bed-ridden frail patients and those with advanced end-stage organ failures admission to the ICU is unlikely to be curative and is likely create a population of CCI patients who are destined to die; with advanced life support serving only to prolong death. These patients should not be admitted to the ICU.

All attempts should be made reduce the length of time patients remain on mechanical ventilation, as this is a major factor leading to neuromuscular and cognitive dysfunction. Evidence-based management strategies including lung protective ventilation [25], conservative fluid management [26] and spontaneous breathing trials [27] not only improve survival but result in fewer ventilator days for survivors. Limiting the use of sedatives and avoiding benzodiazepines reduces duration of ventilation and likely reduces the risk of delirium and post ICU cognitive dysfunction [28]. Strategies to prevent ventilator associated pneumonia are likely to reduce the length of mechanical ventilation. Strategies to limit loss of lean body mass (muscle) may expedite liberation from ventilation and limit long term functional disabilities. Early mobility programs, coupled with less sedation and high quality protein may limit the loss of muscle mass [29]. Why protein which is high in leucine and other branch chain amino acids is more effective in stimulating protein synthesis than soy or casein protein [30, 31]. Furthermore, bolus as opposed to continuous tube feeds may be more effective in promoting muscle synthesis [32] (see Chap. 32). Parenteral nutrition does not support muscle synthesis and should be avoided [18]. Interventions such as preservation of the Day-Night cycle, improvement in the quality and duration of sleep, control of noise pollution, music therapy and orientation therapy may limit acute delirium and long term cognitive dysfunction. Medications such as benzodiazepines, H2-antagoists, anticholinergics, tricyclic antidepressants, fluoroquinolone antibiotics, clozapine, thioridazine and clonidine, etc have been linked with delirium particularly in elderly patients and should be avoided [33]. Opiates (especially meperidine) are associated with delirium and the lowest doses should be used to treat pain; avoid if no pain. Dexmedetomidine appears to be a useful sedative agent that may limit delirium [34, 35].

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Oct 12, 2016 | Posted by in CRITICAL CARE | Comments Off on Chronic Critical Illness and the Long Term Sequela of Critical Care

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