Acute Physiology and Chronic Health Evaluation II score of ≥15: A risk factor for sepsis-induced critical illness polyneuropathy
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.185356
Source of Support: None, Conflict of Interest: None
Background: Critical illness polyneuropathy (CIP) is a common complication of severe sepsis and systemic inflammatory response syndrome (SIRS). The risk factors for sepsis-induced CIP have not been well established.
Keywords: Acute Physiology and Chronic Health Evaluation II; critical illness polyneuropathy; risk factor
A patient admitted with sepsis to the Intensive Care Unit (ICU) can develop weakness of all four limbs, which may be due to either critical illness polyneuropathy (CIP) or critical illness myopathy (CIM). Several patients have a combination of the two syndromes. Therefore, due to the frequent association of both, the terms “CIP” and/or myopathy (CIM) were introduced in 2000. The clinical features of CIP and CIM are similar and include muscle weakness and atrophy, primarily of the lower limbs and respiratory muscles, delayed weaning from the respirator and prolonged immobilization. Neurological examination reveals decreased or absent tendon reflexes, muscular wasting, and symmetrical flaccid quadriparesis. However, their absence does not reliably exclude a neuromuscular disorder in a critically ill patient. The gold standard needed to diagnose CIP and CIM are electrophysiology and muscle biopsy. Electrophysiological studies demonstrate an axonal polyneuropathy on nerve conduction studies (NCSs) and widespread features of denervation such as fibrillation potentials and positive sharp waves on electromyography (EMG). Muscle biopsy would be a more definite way to establish CIM and to distinguish it from CIP.,
CIP appears to be a common complication of severe sepsis and is said to be a manifestation of systemic inflammatory response syndrome (SIRS). In prospective studies, about 60–80% of patients with multiple organ failure with or without sepsis or SIRS developed neuromuscular disorders.,, It is believed that injury to the microcirculation of distal nerves causes ischemia and axonal degeneration contributing to the development of sepsis-induced CIP. Early in the course of sepsis, electrical inexcitability due to poorly functioning sodium channels in otherwise intact nerves may be present. At present, there is no definite treatment for sepsis-induced CIP. The development of this condition delays weaning from the ventilator as well as recovery, and increases complications and mortality. A reasonable approach would be to control the risk factors so as to reduce the possibility of developing CIP. The risk factors for sepsis -induced CIP have not been clearly defined in previous studies. The duration of mechanical ventilation, hyperosmolality, parenteral nutrition, use of nondepolarizing neuromuscular blocking agents (NMBAs), low Glasgow coma scale (GCS), high glucose, low albumin, and severity of organ dysfunction have been shown in some studies to be influencing the development of CIP.,, However, the findings are not consistent among the few available studies.
It is likely that CIP is a part of organ dysfunction in a septic patient with SIRS. CIP is more likely to develop in a patient with severe illness. The relationship of sepsis-induced CIP with the severity of illness has not been established. We conducted this study with a view to determine the risk factors (specifically the severity of illness at admission) associated with the development of sepsis-induced CIP in patients admitted in ICU.
This study was a prospective cohort study done in the ICU of a tertiary care hospital between May 2011 and November 2013. Consecutive patients admitted with a diagnosis of sepsis or developing it within 24 h of admission were screened. A patient was said to be having sepsis if he or she had features of SIRS of suspected or proven microbial etiology. SIRS was defined as the presence of two or more of the following: (a) Fever (oral temperature >38°C) or hypothermia (<36°C), (b) tachypnea (>24 breaths/min), (c) tachycardia (heart rate >90 beats/min), and (d) leukocytosis (>12,000/µL), leukopenia (<4000/µL), or 10% immature band forms. A patient was included in the study if the criteria for sepsis were met at admission or within the first 24 h of admission. The following patients were excluded from the study: Age <18 years; any history of neuromuscular involvement before admission; a family history suggestive of hereditary neuropathy; a history of malignancy or having received chemotherapeutic agents, or of suffering from human immunodeficiency virus (HIV) infection, connective tissue disorder, diabetes; existence of any chronic conditions where neuropathy could coexist such as a chronic kidney disease, liver disease, or alcoholism; or, the development of features of sepsis 24 h after admission. A total of 100 consecutive patients with sepsis and meeting the above criteria were included in the study. All patients included in the study were subjected to NCSs. The first NCS was done within the first 14 days of admission. Those who had a normal initial NCS underwent a second study between day 21 and day 28 of admission. The patients were shifted to the neuro-electrophysiology laboratory for NCS. NCSs were performed using Cadwell system model Sierra Wave 4 Channel machine (manufactured by Cadwell Inc, Kennewick, WA, USA)., using surface electrodes for both stimulation and recording. The NCS protocol for all patients included right sided motor and sensory studies of median and ulnar nerves, motor studies of common peroneal and posterior tibial nerves, and sensory study of the sural nerve. Efforts were taken to maintain the normal temperature of the limb. Based on the screening, two groups were formed. 'Cases' were those patients who had features of neuropathy in the first or second study; 'controls' included patients who had no evidence of neuropathy even after the second screening NCS had been performed. Informed written consent was taken from either the patient or the accompanying person. Ethical clearance was obtained from the Institutional Ethical Committee.
The following risk factors were evaluated for the development of sepsis-related CIP: Duration of symptoms before admission, duration of stay in the ICU, use and duration of mechanical ventilation, use of neuromuscular blocking agents (NMBAs), steroids, insulin infusion, and inotropes. Laboratory parameters considered for evaluation were those that were recorded in the first 24 h of admission. If there were multiple values, the most abnormal value in the first 24 h was taken. The following laboratory parameters were included: Hemoglobin (Hb), total leukocyte count, serum urea, serum creatinine, plasma glucose, HbA1C, serum aminotransaminases (aspartate aminotransferase and alanine aminotransferase), serum total protein, serum albumin, serum potassium, serum creatinine kinase, and Acute Physiology and Chronic Health Evaluation II (APACHE II) score at 24 h after admission. APACHE II score is one of the most widely used ICU mortality prediction scores. APACHE II score can be readily calculated by an application in smartphones and takes into account several acute physiological parameters including the temperature, mean arterial pressure, heart rate, respiratory rate, arterial pH, and arterial partial pressure of oxygen, serum sodium, potassium, creatinine, hematocrit, white blood cell count, Glasgow Coma Scale (GCS), age, and certain specific chronic health conditions. The APACHE II score was calculated at admission to help determine the patient's mortality risk at the time of admission. The worst values recorded during the initial 24 h in the ICU were used. It gave an indication of mortality at a certain score.
The sample size of hundred was derived assuming α error to be 5% and power of study (1 − β) to be 80%, with the approximate relative risk (RR) from the previous studies being reported as 3.5. Appropriate statistical tests were performed where indicated. Univariate analysis was carried out with Mann–Whitney U-test and Kruskal–Wallis test or Chi-square test. Multivariate analysis was carried out using linear regression. All statistical analyses were performed using IBM (IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY, IBM Corp). P< 0.05 was considered statistically significant.
A total of 152 patients meeting the inclusion criteria for sepsis at admission or within 24 h of admission were screened for the study. Twenty-one were excluded from the study as eight of them had a preexisting neuromuscular disorder and 13 met the other exclusion criteria. Eighteen of the patients or their relatives were unwilling for the study. Thirteen patients expired before NCS could be done. Finally, 100 patients were included in the study. The study population was divided into two groups of patients after 28 days: Group A included 63 patients with normal NCS whereas Group B had 37 patients with features of neuropathy on NCS. Of the 37 patients with neuropathy, 30 patients (81%) showed an abnormal NCS in the first 14 days (mean: 10.3 days, range: 6–14 days) while the remaining seven were detected later (between 21 and 28 days) to be having NCS abnormalities. All patients had features of axonal neuropathy on NCS. Clinical data related to neuropathy were not recorded. The mean age in the study population was 50.6 years. There were overall 72 males and 28 females in the study. The presumed source of sepsis is shown in [Table 1].
Univariate analysis was performed for multiple clinical and laboratory risk factors, as shown in [Table 2]. The risk factors associated with the development of sepsis-induced CIP and found to be significant on univariate analysis included the duration of stay in the ICU, the number of patients requiring a ventilator, longer mean number of days on ventilator, a higher mean APACHE II score, more number of patients with APACHE II score of ≥15, and more number of patients requiring inotropes, steroids, and NMBAs. The laboratory parameters at 48 h of admission found to be associated with the development of sepsis-induced CIP included serum urea, creatinine, potassium, albumin, and creatine phosphokinase levels.
The variables that were found to be significant on univariate analysis were further studied by multivariate analysis using linear regression. This showed APACHE II score and use of NMBAs to be the significant factors. The relationship between APACHE II score and presence of CIP on NCS is shown in [Figure 1]. An APACHE II score of ≥15 was associated with a significant risk of developing CIP (RR: 11.6, 95% confidence interval [95% CI]: 4.9–27.2, P < 0.0001).
We have demonstrated that in a cohort of patients with sepsis, an APACHE II score of ≥15 within 24 h of admission (which is predictive of 25% or higher subsequent mortality) is a significant risk factor for the development of sepsis-induced CIP (RR: 11.6, 95% CI: 4.9–27.2, P < 0.0001). This helps to support our hypothesis that the severity of illness in the initial 24 h of admission is an indicator of the development of sepsis-related CIP. The severity of illness is best represented by a popular, easy to use, validated ICU mortality score, the APACHE II score. This uses multiple parameters to calculate a score.
We found that 37% of our patients admitted to a medical ICU with sepsis developed CIP as documented by a NCS. About 60–80% of patients in the previously published series had developed sepsis-induced CIP.,,, The lower figure in our study was probably due to three reasons. First, even mild cases with sepsis meeting the SIRS criteria but not necessarily having organ dysfunction admitted to ICU were included in our study. The second reason was that we had excluded all patients who, during the ICU stay, expired, as NCS could not be done in them. They obviously had a more severe illness and may have had CIP. Third, most but not all other series have included CIP and CIM while our series had only CIP patients., The majority of our patients (30/37, 81%) developed the neuropathy in the first 2 weeks of the illness. This is consistent with the results of other studies.,
There are two studies which have correlated the severity of illness in septic patients with the development of CIP. Bednarík et al., in 2005 found that the presence and duration of SIRS and severity of multiple organ failure were associated with an increased risk of development of CIPM. They demonstrated that the independent predictors of CIP or CIM obtainable within the 1st week of critical illness were the admission sequential organ failure assessment score (odds ratio [OR]: 1.15, 95% CI: 1.02–1.36), the 1st week total sequential organ failure assessment scores (OR: 1.14, 95% CI: 1.06–1.46), and the 1st week duration of SIRS (OR: 1.05, 95% CI: 1.01–1.15). Our findings are similar in which we have demonstrated that in a cohort of patients with sepsis, it is the severity of the illness and organ dysfunction as represented by APACHE II score of ≥15, which is associated with a significant risk of development of CIP (RR: 11.6, 95% CI: 4.9–27.2, P < 0.0001). Our finding differs from that of Garnacho-Montero et al., who found that the APACHE II scores of patients with or without CIP were similar on admission and the day of the first episode, which was day 10. Sixty-eight percent of their patients (50/73) with sepsis were found to have CIP. They found that hyperosmolality, parenteral nutrition, nondepolarizing neuromuscular blockers, and neurologic failure (low GCS) favored the development of CIP. Other than the use of NMBAs (the use of which was significantly associated with the development of sepsis-induced CIP in our study), we did not examine the role of other risk factors.
Risk factor evaluation other than the severity of illness has been carried out by some researchers. A paper by Garnacho-Montero in 2005 concluded that in critically ill septic patients, CIP significantly increased the duration of mechanical ventilation and prolonged the lengths of ICU and hospital stays. Similar findings were reported by Bednarík et al., in the same year. Our study too showed a trend toward similar findings, although we could not establish it on multivariate analysis. The longer duration of stay in ICU and prolonged mechanical ventilation in critically ill septic patients occur as a consequence of CIP. They should not be viewed as risk factors. The use of nondepolarizing NMBAs has been implicated as a risk factor of sepsis-induced CIP. We, too, found a similar association. NMBAs are used in some critically ill septic patients requiring prolonged mechanical ventilation and hence the association. It may not, on its own merit, be a risk factor. In one of the earlier studies, Witt et al., found a significant correlation with elevations in blood glucose and reductions in serum albumin. Our study did not show a similar association.
CIP and myopathy in a critically ill septic patient should be viewed as an organ dysfunction. Pathogenetic mechanisms cited include microvascular changes in peripheral nerves (with increased endothelial expression of E-selectin), the possible role for an altered lipid serum profile in promoting organ dysfunction (including nerve dysfunction), the damage or inhibition of complex I of the respiratory chain as a cause of muscle adenosine triphosphate depletion and bioenergetic failure, and the activation of specific intracellular proteolytic systems causing myofilament loss and apoptosis in CIM., All are believed to cause axonal nerve degeneration and acquired sodium channelopathy causing reduced nerve excitability.
Some of the shortcomings of our study include lack of clinical, EMG, and muscle biopsy data. We included a large number of mild cases (possibly a reflection of our ICU admission policy) and excluded those patients with severe illness who expired, as we could not get the NCS done. Laboratory parameters at admission or within 24 h only were taken for correlation with the development of sepsis-induced CIP. Finally, we used only one ICU mortality score (APACHE II score) as a measure of the severity of the illness.
In spite of these limitations, we conclude that patients with sepsis and APACHE II score at admission or within 24 h of ≥15 are at a significant risk of development of critical illness neuropathy. This data will help to increase awareness among clinicians to try and detect this complication early since it will influence the course of the illness and outcome. It will help researchers to plan studies associating CIP with the severity of illness and as a part of organ failure. It will also prompt research on the therapeutic options available.
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[Table 1], [Table 2]