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 [14–16]. 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:

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.

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.

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.