Multiple organ failure

The occurrence of the sepsis and multiple organ failure syndrome (critical illness) in patients being managed in critical care units has been recognized with increasing frequency in the last 15 years. [1-3] Sepsis may be defined as the systemic response to invading and dividing organisms of all types, including fungi and viruses, [4] and multiple organ failure as significant dysfunction of at least two major organ systems of the body. [5,6]

The nervous system is especially affected by this syndrome. Septic encephalopathy, at times severe, is an invariable manifestation. [7-9] Muscle wasting, observed since the time of Osler, [10] has more recently been attributed to a catabolic myopathy, possibly due to activation of lysosomal proteases. [11,12] In the last 12 years, we have documented a polyneurapathy, termed critical illness polyneuropathy, characterized both electrophysiologically and morphologically by a primary axonal degeneration of motor and sensory fibers. [6,13-15] Full recovery is possible, provided the patient survives the critical illness, as occurs in at least 40 percent of the cases. [2,16] This complication has been largely unrecognized, perhaps due to difficulties in performing a clinical exam or electrophysiologic studies in the setting of a critical care unit. Nonetheless, patients have been reported from other centers who, in our opinion, likely suffered from critical illness polyneuropathy. In some reports, the polyneuropathies were attributed to other causes: gentamycin; [16] the muscle relaxant, pancuronium bromide; [17] Guillain-Barre syndrome; [18] and pancreatic disease, [19] but in others, the polyneuropathy was linked to critical illness. [20-24]

In comprehensive retrospective studies, [6,14] there was no evidence that the polyneuropathy was due to commonly recognized conditions such as Guillain-barre syndrome, or to certain toxins, drugs, or specific nutritional deficiency. We suspected that the sepsis-multiple organ failure syndrome was itself the cause of the polyneuropathy. Thus, in the present study, we prospectively investigated patients who had the syndrome. A peripheral nerve function index was determined from electrophysiologic measurements. This allowed a grading of peripheral nerve function. The incidence and severity of the polyneuropathy could then be determined and correlated with variables related to the syndrome. The nerve function index was also correlated with the diaphragm compound muscle action potential, since difficulty in weaning from the ventilator has been a prominent sign in these patients.

METHODS

Definition of Patients and Entry Into the Study

Our retrospective studies [6,13-15] were completed in 1983. This prospective study was approved by the Ethics Committee of the University of Western Ontario. During 14 months, 1,167 patients were admitted to the Victoria Hospital critical care unit. Three hundred and twenty-four were in the unit for longer than five days, a group which we believe to be at risk of developing sepsis and multiple organ failure. From this group, patients were entered who met the following criteria; (1) had evidence of sepsis (defined below); (2) had multiple organ failure (defined below); (3) were over the age of 16 years; and (4) were without previous evidence of peripheral neuropathy, as determined by history and examination of admission to the unit. some were not entered because of limitation of technical time for the electrophysiologic examinations, or failure to obtain a consent from relatives. Moreover, after being entered, 15 were eliminated because, in retrospect, they failed to meet these criteria. Thus, among the 324 patients, 43 patients satisfactorily met the criteria and were studied. They had a variety of primary conditions on admission to the critical care unit (Table 1).

Sepsis was defined as septicemia (positive blood culture) or a focus of infection with systemic effects. [4] The systemic effects included fever, elevated peripheral white blood cell count, episodes of hypotension, and multiple organ failure.

The precise definition of multiple organ failure is still debated. Our criteria for each major organ system were similar to those of Borzotta and Polk [5]: lung--respiratory failure requiring mechanical ventilation for more than five days; kidney--evidence of oliguric renal failure, creatinine greater than 200 [mu]mol/L; liver--serum bilirubin level greater than 35 [mu]mol/L, serum glutamic oxaloacetic transaminase value greater than 40, and lactic dehydrogenase

Table 1--Categories and Primary Conditions on Admission to the Critical Care Unit

Table 2--Incidence of Organ System Dysfunction

transaminase value greater than 225 U/L; cardiovascular system--hypotension requiring inotropic support; brain--clinical signs of mental confusion and a depressed level of consciousness, or abnormal electroencephalogram, neither due to medication; hematologic system--lymphocyte count less than 1.1 X 10[.sup.9]/L, platelet count less than 40 X 10[.sup.9]/L or signs of disseminated intravascular coagulation; gastrintestinal system--fresh blood from nasogastric tube and/or melena or fresh blood in feces. Involvement of two or more major organ systems constituted multiple organ failure. The pattern of involvement in the 43 patients is shown in Table 2.

The details of routine management of this group of patients have been published. [6,14] All were intubated, maintained on mechanical ventilation, given total parenteral or enteral nutrition and a variety of other supportive measures. Muscle relaxant drugs were rarely used. Inotropic drugs to support blood pressure were required in 31 of the patients. The following drugs (number of patients) were prescribed before the first electromyogram: ampicillin (38), cephalosporin (35) tobramycin (33), dopamine (29), other inotropes (17), gentamycin (16), vancomycin (13), metronidazole (12), amphotericin (6), erythromycin (6), co-trimoxazole (5), clindamycin (3), and cephalothin sodium (1).

Clinical and Electrophysiologic Assessment

The initial neurologic and electromyographic examination occurred at the time the patients were identified as meet the criteria for study - at mean 20 ([+ / -] 20 SD, range 5 to 89) days after admission to the critical care unit. Follow-up was obtained, if they survived, at one, three, and six months after the initial examination. Patients were lost to follow-up after one or three months because of death in 20, and because of transfer to another hospital in 13.

The electophysiologic studies [15,25] were performed in the critical care unit using a portable electromyographic machine. Conventional orthodromic motor and antidromic sensory nerve conduction studies and F wave determinations were performed on the median, ulnar, sural, common peroneal and tibial nerves using surface electrodes for stimulting and recording. [26-28] the ulnar nerve was stimulated above and below the elbow, and the peroneal nerve, above and below the fibula. If there was evidence of nerve compression at these sites, noted infrequently in this study, results for these and needle electromyography of first dorsal interosseus and extensor digitorum brevis muscles were eliminated from the calculation of the nerve function index. The phrenic nerve was stimulated, and the diaphragmatic compound muscle action potential was recorded with surface electrodes according to Markand et al. [29] Near nerve needle electrode recordings were obtained of the sural nerve. [30] Neuromuscular transmission studies were performed by supramaximally stimulating the ulnar nerve at the wrist, six times at 3 and 20 per second, and recording from hypothenar muscles. Skin temperature was recorded at the palm and dorsum of the foot. Needle electromyographic examinations included deltoid, first dorsal interosseus, quadriceps muscles and extensor digitorum brevis muscles in all patients. Where abnormalities were found, other muscles were often included. An electroencephalogram was performed in 16 of the 43 patients and classified according to Young et al. [8]

Analysis of data

The first step was to determine a nerve function index which would identify those patients without neuropathy, and the degree of impairment of nerve function in those who had it.

electrophysiologic data on the 43 patients at the time of the first examination were compared to control data from our electromyography laboratory, which consisted of 95 subjects, men and women, representing the third to the eighth decades. Since previous electrophysiologic studies of patients with critical illness polyneuropathy have shown that the speed of impulse conduction - conduction velocity, distal and F response latencies - are near normal, [6,15] only the amplitude of compound muscle and sensory nerve action potentials were utilized in the analysis of nerve conduction measurements. The amplitude measurements for each patient were normalized (calculated as a percentage of the mean control value) and corrected for age and sex. While skin temperatures were significantly higher in patients than control subjects, as expected in sepsis, there was no significant relationship between skin temperature and the nerve function index (Table 3). Therefore, correction factors for temperature were not applied. [31] The other main electrophysiologic abnormality was abnormal spontaneous activity, fibrillation potentials and positive sharp waves in muscle. The degree of abnormality was graded as 0 to 4. This grading of needle EMG abnormalities was changed to a percentage, with 4 = 0.3 = 25 percent, 2 = 50 percent, 1 = 75 percent, and 0 = 100 percent, to conform to the grading system of the nerve conduction studies. $TThe nerve function index was calculated as follows: The compound action potential amplitude percentages and electromyographic needle percentages for individual nerves and muscles were each totalled and averaged to give a percentage value for each person. The amplitude percentages and electromyographic needle percentages were halved to give an equal, 50 percent weighting to each of these electrophysiologic measurements for each patient and control subject. The total provided a nerve function index, with decreasing percentages representing decreasing levels of peripheral function. One hundred percent was the mean normal value, and 95 percent confidence limits gave a normal range for the nerve function index of 81 to 119 percent, taking into account age and sex.

The nerve function index was then utilized to determine the incidence and range of degrees of dysfunction of peripheral nerve and to see if there was any correlation with a number of variables that were related to the sepsis and multiple organ failure syndrome (Table 3). The analysis was performed only after all data had been finally tabulated for the 43 patients. The only exception was the results of phrenic nerve conductions which were analyzed separtely. Since 19 patients could not be studied due to surgical wonds, dressing, etc, of the neck or chest, a further five patients were included who had been studied later, but who met entry criteria and had electrophysiologic studies to determine the nerve function index. The statistical methods included analysis of variance, simple and partial correlation, and linear and multiple regression analyses. Bonferroni corrections were used to adjust for the effects of the multiple statistical tests that were performed. A p value of less than 0.01 was chosen as the level of statistical significance.

[TABLE DATA OMITTED]

RESULTS

The 43 patients comprised 22 men and 21 women of mean age 64 (21 to 78) years. They presented with a variety of primary conditions (Table 1). At a mean of 28 (5 to 89) days, sepsis and multiple organ failure (Table 2) were first identified. The nerve function index was determined at this time and was abnormal in 30 patients, an incidence of 70 percent. The spread of abnormalities was relatively uniform, from the most severe neuropathy at 35 percent of normal function, to the least severe at 79 percent (Fig 1). Among therese 30 patients, 15 had clinical signs of polyneuropathy. There was difficulty in weaning from the ventilator, defined as hypercarbia with reduction in intermittent mandatory ventilation frequency, and a predominantly distal muscle weakness with reduced or absent deep tendon reflexes. These signs were mild in 18 and moderately severe in 7. Three had a polyneuropathy that was severe -- absence of any voluntary or reflex-induced movement in all four limbs.

Follow-up observations during a mean of 72 (range 10 to 190) days from the time of admission to the critical care unit, indicated the polyneuropathy worsened in 12, remained the same in 2, and improved in 13 patients. Virtually complete recovery occurred only in mild and moderately severe neuropathies failed to improve and ultimately died.

All patients had evidence of septic encephalopathy. [7-9] The severity of the encephalopathy was difficult to determine on a clinical basis, and was not graded, but it varied from drowsiness and inability to perform complex commands to deep coma. Seizures and focal signs were uncommon. Sixteen patients had an electrocephalogram ...ch was graded according to Young et al; [8] abnormalities were severe in five, moderate in eight, and mild in three patients.

A large number of variables were correlated with the nerve function index for all 43 patients (Table 3). Signficant (p<0.01) correlations were as follow: the number of days in the critical care unit prior to the first clinical and electrophysiologic examination (Fig 1); the number of invasive procedures performed on each patient, and the level of serum glucose (Fig 2), all of which gave a negative correlation with the nerve function index; and the sreum albumin value which gave a positive correlation (Fig. 3).

These four variables were then subjected to partial correlation analysis. he relationship of the number of] invasive procedures then became insignificant ([r.sup.2] = -0.1199). The remaining three variables were then subjected to multiple regression analysis. They bore a highly significant relationship to the nerve function index, together accounting for 47 percent ([r.sup.2] = 0.4678) of all potential variables related to the nerve function index (Table 4).

[TABLE DATA OMITTED]

There was no statistically significant relationship between the nerve function index and the other variables, notably the various categories of primary condition (Table 1), the total number of failed organs per patient, the total number of antibiotics administered to each patient, aminoglycoside antibiotic blood levels, nutritional factors, water and electrolyte disturbances, indices of kidney failure, indices of liver failure, and muscle enzymes (creatinine phosphokinase) (Table 3). However, mean values of srum albumin and creatinine clearance were depressed below, and blood urea nitrogen, serum glutamic oxaloacetic transaminase, serum lactic dehydrogenase, serum alkaline phosphatase, serum bilirubin and blood glucose levels were elevated above, the normal range (Table 3).

These variables were determined on three occasions: at the time of admission and then one month ] and wo months folllwing admission to the critical care unit. Correlations with the nerve function index are shown only for values at one month. This was the mean time when patients had their first examination and when the nerve function index was determined. Correlation and regression analyses for values on admission and at three months bore no significant relationship to the nerve function index. The only exception was the sreum phosphate value on admission, which showed a negative correlation (p=0.007). The only variables which showed a significant change during the three-month period of observation were the creatine phosphokinase value which fell from (mean [+/-] SD) 487 [+/-] 684 to 27 [+/-] 16 U/L, the serum glutamic oxaloacetic transaminase value which fell from 103 [+/-] 168 to 41 [+/-] 30 U/L, and the alkaline phosphatase level which rose from 98 [+/-] 78 to 248 [+/-] 175 U/L.

Phrenic nerve conduction studies indicated a mean [+/-] SD diaphragmatic muscle compound action potential (average of stimulation on each side) of 355 [+/-] 281 (normal 790 [+/-] [190.sup.29]) uV. There was a positive correlation of this action potential amplitude with the nerve function index (p=0.009) (Fig 4).

DISCUSSION

During the 14-month period of this prospective study, 43 patients were identified in our critical care unit who had sepsis and multiple organ failure and met entry criteria. This identification occurred at 28 (5 to 89) days after admission to the unit. The incidence of the polyneuropathy was 70 percent. However, due to the attendant endotracheal tube and the lingering effects of septic encephalopathy, the clinical examination to detect polyneuropathy was often unreliable. Thus, only half (15) of the 30 patients with electrophysiologic evidence of polyneuropathy had "apparent" or "detectable" clinical signs: difficiculty in weaning from the ventilator, distal weakness of limb muscles and reduced deep tendon reflexes. Electrophysiologic studies revealed near normal conduction velocities and distal latencies, but reduced compound muscle and sensory nerve action potential amplitudes and abnormal spontaneous activity in muscle, consistent with a pure, primary axonal degeneration of both motor and sensory fibers.

In the 23 (53 percent) patients who survived, recovery from the polyneuropathy was complete when it was mild or moderately severe. However, three patients with severe polyneuropathy who had total paralysis of respiration and of all four limbs failed to improve and ultimately died.

Phrenic nerve conduction and needle electromyographic studies of intercoastal muscles have shown abnormalities in earlier studies. {6,14,15] Moreover, autopsy studies have shown axonal degeneration of the phrenic nerve and denervation atrophy of diaphragm and intercostal muscles in such patients. [6] The present study showed a positive correlation between the nerve function index and the diaphragm compound muscle action potential. (The nerve function index expresses electrophysiologic measurements in each patient as a single value, a percentage of normal nerve function). Thus, we believe the difficulty in weaning from the ventilator is clearly due to neuropathy. It appears to be an invariable cause of intractable difficulty in weaning from the ventilator. [32]

The contribution of a myopathy, possibly on a catabolic [6,33] or other basis, to the neuromuscular problem in these patients, is unsettled. Such a myopathy could not only contribute to the clinical signs, including difficulty in weaning from the ventilator, but could also lower the compound muscle action potential amplitude and produce positive sharp waves and fibrillation potentials on needle electromyography. However, in this study, creatinine phosphokinase levels were only mildly elevated initially and then fell to normal levels, and morphology of muscles has shown mainly denervation atrophy with only the occasional evidence of necrosis. [6] Nonetheless, further studies are clearly needed to address this problem.

A chief concern was still whether antibiotics might be causing the polyneuropathy. In previous studies, [6,15] and in the present study, we ruled out a defect in neuromuscular transmission, a well-documented complication of antibiotics. [34] We have failed to implicate any particular antibiotic. No single aminoglycoside antibiotic was given to all patients. Moreover, the total number of different antibiotics given to each patient, and peak and trough levels of tobramycin and gentamycin, could not be significantly correlated with the nerve function index. Metronidazole in toxic doses frequently causes a polyneuropathy, [35,36] but it was prescribed in only 12 of our patients and it causes a predominantly sensory, at times painful, polyneuropathy, that is unchracteristic of critical illness polyneuropathy.

The present study emphasizes the strong link between the sepsis and multiple organ failure syndrome and critical illness polyneuropathy. The polyneuropathy tended to be more severe the longer each patient was in the critical care unit (Fig 1). It is recognized that sepsis and multiple organ failure also tend to increase in frequency and severity under simlar circumstances. [4,37] Increasing blood glucose and decreasing serum albumin also correlated with decreasing peripheral nerve function. These two variables, and days in the critical care unit, accounted for 47 percent of potential variables affecting the nerve function index (Table 4). While other variables (Table 3) did not show statistically significant correlations, in the main, were all consistent with the sepsis and multiple organ failure syndrome. [38,39]

Critical illness polyneuropathy may be due to the same fundamental defect that affects all organ systems, but the precise mechanism is not known. the changes in glucose and albumin may simply be nonspecific markes of the septic syndrome, but viewed in the light of current knowledge of peripheral nerve function and the systemic effects of sepsis, these changes invite speculation on a more specific mechanism.. The deteriorating peripheral nerve function was associated with a rising level of blood glucose, a well-documented event in sepsis that is associated with insulin resistance, [12,40,41] studies of the nerve microenvironment in experimental animals, [42] it was shown that hyperglycemia increases endovascular resistance, with reduced nerve blood flow and resulting endoneurial hypoxia. It is now theorized that hypoxia by this or other mechanisms may induce not only diabetic but other types of neuropathy. [43] Such hypoxia could affect mitochondria and impair axonal transport of structural proteins, a highly energy-dependent system. [44] The distal type of primary axonal degeneration of peripheral nerves that is characteristic of critical illness polyneuropathy would thereby be induced. [6] Deteriorating peripheral nerve function was also associated with a progressive fall in serum albumin. This may reflect increased microvascular permeability and a shift of albumin out of the intravascular compartment. [45,46] Such a shift could be occurring at the peripheral blood-nerve barrier which is particularly susceptible to the histamine-like substances that are secreted in sepsis. [6,47,48] This process would theoretically further increase endoneurial edema, and hence, hypoxia.

A third mechanism may be particularly relevant. Recent studies have indicated a disturbance of the microcirculation of various organs in the sepsis and multiple organ failure syndrome. [49,50] Shunting of blood from peripheral tissues to more central tissues such as the brain, heart, liver and kidneys may be one mechanism of this disturbance. Since blood vessels supplying peripheral nerve lack autoregulation, [51] such nerves would be particularly susceptible to peripheral microcirculation disturbances. Only further investigations will determine if this or other mechanisms are operative.

Thus, polyneuropathy, whose severity can be quantitated by electrophysiologic measurements, should now be regarded as an integral part of the sepsis and multiple organ failure syndrome (Table 2). It is a significant cause of difficulty in weaning from the ventilator in critically ill patients [33] (although lack of central drive due to encephalopathy, a primary "septic myopathy," and "muscle fatigue" may be contributing factors). It enduces a limb weakness which may be severe enough to cause quadriplegia. In less severe cases, the polyneuropathy can only be detected with certainty by performing nerve conduction and needle electromyographic studies. Sepsis is the underlying cause of polyneuropathy, as it is a cause of dysfunction of other organs, although the primary mechanism is not known. However, all means to bring the sepsis to a halt should be utilized, including appropriate antibiotics and surgical treatment, if necessary. When this is achieved, full recovery from the polyneuropathy is possible, within weeks in mild cases, and months in moderately severe cases. However, in very severe cases, recovery may not occur.

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