Critical illness and prolonged ICU stay can affect skeletal muscles (critical illness myopathy [CIM]), peripheral nerves (critical illness polyneuropathy [CIP]), or both (critical illness polyneuromyopathy [CIPNM]) (12). In ICU-associated polyneuropathy, typically, the motor nerves are more affected, relatively sparing the sensory nerves (34). The diagnosis of CIP can be made much earlier by the nerve conduction studies which show abnormal spontaneous electrical activity and reduced nerve conduction amplitudes much earlier than the clinical manifestations of polyneuropathy appear (5).
The important risk factors of CIPNM reported from studies in adults include severity of illness, sepsis, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), multiple organ failure, female sex, long duration of mechanical ventilation (> 7 d), immobility, hyperglycemia, status asthmaticus, steroids, neuromuscular-blocking agents, malnutrition, low levels of serum albumin, use of antibiotics like clindamycin and aminoglycosides, parenteral nutrition, shock requiring vasopressor support, and renal failure (26–10).
Systemic inflammation associated increased vascular permeability and vasodilatation with hypoxic injury to neurons, mitochondrial dysfunction causing inadequate adenosine triphosphate production, and inactivation of sodium channels contribute to a spectrum of cytopathic and ischemic hypoxic changes along with an energy-depleted state that finally results in CIP (11–14). Neuropathy is well documented with the deficiency of vitamin B12, folic acid, and copper, whereas the data for zinc deficiency causing neuropathy are scarce in humans (1516). However, the role of micronutrients in CIP is not established.
CIP has a wide spectrum of manifestations, ranging from mononeuropathy to polyneuropathy and isolated limb weakness to quadriplegia also termed as “ICU-acquired weakness” (ICUAW) (717–19). The most common outcome is failure to wean from mechanical ventilation which results in prolonged ICU as well as hospital stay (920–22).
The incidence of neuromuscular weakness in the ICU depends on many factors including the timing of diagnostic evaluation and the diagnostic criteria used (23). In adult patients with SIRS and sepsis, the incidence is as high as 70%, and if multiple organ failure further complicates the illness, the incidence is up to 100% (6). Although CIP occurs frequently in adults and is well documented and characterized, studies are limited in the pediatric age group even though the risk factors for the same do exist in critically ill children (24).
We, therefore, conducted this study to determine the prevalence and risk factors of CIP in the critically ill, mechanically ventilated children in PICU.
MATERIALS AND METHODS
Setting and Participants
An observational study was conducted from June 2016 to September 2017 in PICU of a tertiary care center in North India. All children between 1 and 15 years old admitted in PICU and mechanically ventilated for 7 days or more were enrolled in study. Children with diagnosed neuromuscular disease (anterior horn cell disease, myopathy, neuropathy), or with diagnosed stroke or spinal pathology, or having conditions interfering with nerve conduction evaluations (high-frequency ventilation or neuromuscular blockade) were excluded from the study. The children fulfilling the eligibility criteria were enrolled after obtaining written informed consent from one of the parents/guardians. The study was approved by the Institute Ethics Committee.
Objectives and Outcome Measures
Primary objective was to determine the prevalence of polyneuropathy in critically ill children 1–15 years old, mechanically ventilated for 7 days or more. The assessment of polyneuropathy was done by nerve conduction study. Polyneuropathy was classified as axonal, demyelinating, or uncharacterized. Axonal neuropathy was defined as reduced (< 80% of lower limit of normal, lower limit of normal being “–2.5 sd”) or absent compound muscle action potential (CMAP)/sensory nerve action potential (SNAP) amplitude with or without low conduction velocity (but not < 75% of lower limit of normal) and prolonged distal latencies (but not > 130% of upper limit of normal) (2526). Demyelinating neuropathy was defined as conduction velocity < 75% of lower limit of normal, distal latencies greater than 130% of upper limit of normal, with or without conduction block (at least 50% drop in CMAP amplitude between proximal and distal stimulation sites), and normal CMAP and SNAP values (can be reduced also but not to the tune of axonal definition) (2526). If the results were not fulfilling the criteria of either axonal or demyelinating neuropathy but were abnormal, the neuropathy was labeled as uncharacterized (2526).
Secondary objectives were to evaluate the risk factors of polyneuropathy in critically ill, mechanically ventilated (for ≥ 7 d) children 1–15 years old. The risk factors assessed were Pediatric Index of Mortality (PIM)-2 score, SIRS, sepsis, MODS, steroid use, vasopressor use, hypoalbuminemia, and the use of neuromuscular blockers. International Pediatric Sepsis Consensus Conference definitions for sepsis, SIRS, and organ dysfunction were used (27). Outcome measures assessed were mortality, length of mechanical ventilation, length of hospital and PICU stay, and weakness measured by medical research council (MRC) sum score. Patients received regular positioning and physiotherapy.
Information of eligible children regarding demographic details, diagnosis, treatment details, anthropometry at admission and enrolment, and PIM-2 score at the time of admission to PICU was collected in a structured case record form. Nerve conduction studies were done on day 8 of mechanical ventilation and repeated after 7 days if the child was still in PICU, and other conditions interfering with nerve conduction evaluations were not present (high-frequency ventilation or neuromuscular blockade). Samples for the levels of micronutrients (copper, zinc, folate, and vitamin B12) were collected at the time of enrolling the child, that is, on day 8 of mechanical ventilation and at the time of discharge. Samples were centrifuged and sera were stored at –80°C and processed at the end of the study. Vitamin B12 and folate estimation was done by Chemiluminescent Enzyme Immunoassay using chemiluminescence-based analyzers (Immulite 1000; Siemens Healthineers, Erlangen, Germany; and Architect 2000; Abbott Diagnostics, Lake Forest, IL, respectively). The levels of copper and zinc were estimated by mass spectrometry using a coupled plasma mass spectrometer. After the completion of tests, the values of the parameters were matched with normal reference values (28–30). MRC scoring was done as soon as the child was able to obey commands/could be evaluated for muscle strength, and repeated 24 hours later (31).
Nerve conduction studies were performed using portable equipment (Neurosoft which is a four-channel portable nerve conduction studies [NCV] and electromyography system manufactured by Neurosoft, Ivanovo, Russia) by trained physiologists and pediatric neurologists. The software used for our study was Neuro-MEPω, Version 18.104.22.168 (Neurosoft). All patients underwent electrophysiology examination of at least one upper and one lower limb. The nerve conduction values were matched with normal reference values (32). Motor nerves evaluated were median, ulnar, tibial, and common peroneal; among sensory nerves, median, ulnar, and sural nerves were evaluated (33). The parameters recorded were amplitude of CMAP of motor nerves, amplitude of SNAP of sensory nerves, conduction velocity, distal latency for motor nerves, and latency for sensory nerves (33).
Structured case record form was used for data collection. Data were entered using Microsoft Excel (Microsoft, Redmond, WA). STATA 11.5 (Stata Corp, College Station, TX) software was used for analysis. Descriptive statistics were used: median with interquartile range (IQR) used for continuous and percentage for categorical data. Wilcoxon rank sum (Mann-Whitney U test) was used for comparing continuous and Fisher exact test for categorical data.
During the study period (June 2016 to September 2017), a total of 343 children were screened in the PICU at tertiary care hospital in North India.
Out of the 343 children, 309 were not eligible for enrolment (124 were < 1 yr old, 165 were either extubated or transferred out of PICU or died before day 7, five were on neuromuscular blockers on the day of enrolment, six were on high-frequency mode of ventilation, and nine children had already diagnosed neuromuscular disease/stroke or spinal pathology). Remaining 34 children were eligible for enrolment, out of which two could not be enrolled due to equipment malfunction; 32 were enrolled after receiving written informed consent from parents. Table 1 shows the characteristics of the enrolled children.
A minimum of seven nerves were evaluated in each child: four motor and three sensory. Nerve conduction study could be done for all 32 enrolled children on day 8 of their mechanical ventilation. A repeat study could be done in six of them.
Twenty nine of the 32 children evaluated on day 8, 90.6% (95% CI, 80.5–100%), had polyneuropathy on NCS. Distribution of phenotypes of polyneuropathy was axonal in 26 (81.2%), mixed in one (3.1%), and uncharacterized in two (6.2%) patients. None of the children had isolated demyelinating polyneuropathy. Among the individual nerves, common peroneal was the most commonly involved (Table 2).
A repeat nerve conduction study after 7 days of the first evaluation could be performed for six children. All the six patients had axonal neuropathy during the first evaluation, and repeat nerve conduction study showed axonal neuropathy in five and uncharacterized neuropathy in one patient.
Because the number of patients without polyneuropathy was small (n = 3), we could not identify risk factors of polyneuropathy. Characteristics of the patients with or without polyneuropathy including baseline characteristics, anthropometric parameters, primary diagnosis, and various risk factors (total parenteral nutrition, steroid use, neuromuscular blocker use, hypoalbuminemia, vasopressors, and micronutrient levels) are shown in supplementary data (Supplemental Digital Content 1, http://links.lww.com/PCC/B4).
The various outcome characteristics studied including mortality, duration of mechanical ventilation, duration of PICU stay, and duration of hospital stay were similar among the patients with or without polyneuropathy (Table 3).
MRC scoring was done in 19 children who survived. Fifteen children (78.9%) were classified to have weakness based on low MRC score. There was no weakness in the three children who had no polyneuropathy and the score was 60 for all of them, whereas children classified as “polyneuropathy” on NCS had significantly lower median (IQR) MRC score (40 [36–41]; p = 0.009).
We observed a high prevalence (91%) of polyneuropathy in critically ill children, mechanically ventilated for 7 days or more. Axonal polyneuropathy was the most common variant. Overall, the most commonly involved nerve was the common peroneal motor nerve, which was involved in nearly 94% children, followed by the tibial motor nerve (87.5%). Median sensory was the most commonly involved sensory nerve (84.3%).
The data about polyneuropathy are scarce in the pediatric age group and are limited to a few case reports and case series except for one prospective, cross-sectional study carried out by Banwell et al (24) in 2003; the incidence of polyneuropathy was quite low in this study (1.7%) (24). They included a total of 830 children admitted for greater than or equal to 24 hours in the PICU. Clinical examination and MRC scoring were performed 2–3 times every week in all the enrolled children. Electrophysiology studies were offered to only those children in whom weakness was identified clinically. This study had the limitation of not offering electrophysiology studies to all the children and relying too much on the clinical evaluation, which is difficult in small ventilated children. In this study, weakness was taken as a screening criterion, whereas it is the outcome of polyneuropathy. Many patients may have subclinical neuropathy and may never develop weakness. They were able to do timely nerve conduction studies in only five children, and all (100%) had polyneuropathy. If they had studied all patients electrophysiologically, the results might have been different. Also, the overall severity of illness was lower than our patients. The children whom we enrolled were mechanically ventilated for 7 days or more; most of them (31, 96.8%) had SIRS, sepsis, and MODS. Steroid use was present in 28 children (87.5%). The high prevalence of polyneuropathy was most likely due to the presence of all the above-mentioned risk factors for CIP (93435).
A recently published study in children with mechanical ventilation for greater than or equal to 7 days, 32.4% had features of CIP/CIM postawakening (36). Nerve conduction studies were conducted in this study once children were awake and able to do MRC score testing for weakness. Although the inclusion criteria in the above-mentioned study were similar to that in our study, we conducted nerve conduction studies much earlier in clinical course than the above-mentioned study (36). We conducted NCS on eighth day of ventilation, and we found very high prevalence of polyneuropathy at that time. Of 19 children who survived in our study, we conducted MRC scoring and found that 15 (79%) had weakness. Our study had higher prevalence of weakness compared with children in the above study which could be due to higher prevalence of risk factors like SIRS, sepsis, MODS, etc in our cohort. Also, it has been proposed that neuropathy is part of MODS, and probably a precursor lesion in ICUAW. Nerve conduction studies early in mechanically ventilated patients is likely to pick up the process of polyneuropathy-ICUAW sequence at an early stage. Probably neuropathy improves gradually once patient stabilizes which could explain the lower prevalence noted by the above-mentioned study compared with our study. Conducting a study with frequent electrophysiology testing starting form early acute phase to recovery phase will provide better insight into pathogenesis of CIPNM.
Among the adult population, where CIPNM is more widely studied, the prevalence varies from 9% to 86% (23). The studies which included patients with established SIRS and multiple organ failure reported higher incidence of polyneuropathy, as seen by Tennilä et al (37) (100%) and Berek et al (82%) (38). Clinical profile and incidence of CIP of our cohort are similar to patients included in these studies. These findings suggest that magnitude of CIP is similar in critically ill children as seen in adults and similar risk factors operate among critically ill children as in adults.
ICUAW is an important outcome of CIP which has been associated with adverse outcomes including mortality. The incidence of ICUAW using clinical examination and MRC score is 40–50% in different studies (3940). In patients where we could assess MRC score, the weakness was present in 78.9%. This higher prevalence than the reported incidence is probably secondary to more severe underlying illness in our cohort. The practical problem with clinical evaluation and MRC score is that the patient should be awake and obeying commands, which is often not feasible in ICU. We could conduct MRC scoring only after patients were extubated and tapered off sedation. MRC score was significantly lower in patients among polyneuropathy group. Because weakness was detected only in children with CIP, it suggests that abnormal NCS represents patients with increased risk of ICUAW. ICUAW weakness was present in all but one of the total 16 children with CIP where it could be tested. Our study suggests that NCS has better feasibility than MRC scoring in critically ill children, and it can serve as an early investigation to screen patients who are likely to develop ICUAW.
CIPNM has been shown to increase mortality and duration of mechanical ventilation in critically ill adults (23). The overall mortality in our study population was 40.6%, all being from the polyneuropathy group. Because our cohort had only three patients in “no polyneuropathy group,” we could not demonstrate significant difference in outcome measures (mortality, duration of mechanical ventilation, and duration of PICU and hospital stay) or risk factors in between the two groups. Similarly, levels of micronutrients (copper, zinc, vitamin B12, and folate) among the two groups were also not significantly different.
Strengths and Limitations
The main strength of our study was the use of electrophysiology parameters for the diagnosis of polyneuropathy. NCS is the most sensitive method to detect polyneuropathy and is an objective method for the evaluation of nerves.
We acknowledge certain limitations in our study as well. The sample size of our study was small because we could include only 32 children. We selected a study population which were likely to have risk factors for polyneuropathy as reported in studies in critically ill adults; resulting in a very few numbers of children in the “no polyneuropathy” group and making the comparison between the two groups difficult. Also, majority of our patients had sepsis and MODS, hence generalization of findings cannot be made to children without sepsis. However, in view of limited pediatric data, we thought that starting with an “at risk” population is a more efficient strategy. There was no control population for our study. We also did not perform the electrophysiology studies at the time of admission.
The prevalence of CIP in children 1–15 years old and mechanically ventilated for 7 days or more in PICU was 90.6% (95% CI, 80.5–100%), almost all of whom had underlying sepsis. Further studies are needed in critically ill children with frequent electrophysiologic studies and clinical testing (such as MRC score) beginning from first week till rehabilitation to throw light on pathogenesis and natural course of CIPNM and identify contributory risk factors.
We are sincerely thankful to Dr. G. S. Toteja and research staff of Micronutrient Laboratory, Indian Council of Medical Research, Delhi, for analyzing serum micronutrient levels. We are thankful to Prof. P. K. Chaturvedi and technical staff of his laboratory for estimation of folate levels. We are sincerely thankful to resident doctors of Pediatric Neurology Division, All India Institute of Medical Sciences Delhi, for helping in interpretation of Nerve Conduction Studies.
1. Latronico N, Bolton CF. Critical illness polyneuropathy
and myopathy: A major cause of muscle weakness and paralysis. Lancet Neurol 2011; 10:931–941
2. Latronico N, Guarneri B. Critical illness myopathy and neuropathy. Minerva Anestesiol 2008; 74:319–323
3. Kress JP, Hall JB. ICU-acquired weakness and recovery from critical illness. N Engl J Med 2014; 371:287–288
4. Stevens RD, Marshall SA, Cornblath DR, et al. A framework for diagnosing and classifying intensive care unit-acquired weakness. Crit Care Med 2009; 37:S299–S308
5. Hermans G, De Jonghe B, Bruyninckx F, et al. Interventions for preventing critical illness polyneuropathy
and critical illness myopathy. Cochrane Database Syst Rev 2014; (1):CD006832
6. Witt NJ, Zochodne DW, Bolton CF, et al. Peripheral nerve function in sepsis
and multiple organ failure. Chest 1991; 99:176–184
7. Fletcher SN, Kennedy DD, Ghosh IR, et al. Persistent neuromuscular and neurophysiologic abnormalities in long-term survivors of prolonged critical illness. Crit Care Med 2003; 31:1012–1016
8. Pandit L, Agrawal A. Neuromuscular disorders in critical illness. Clin Neurol Neurosurg 2006; 108:621–627
9. Garnacho-Montero J, Madrazo-Osuna J, García-Garmendia JL, et al. Critical illness polyneuropathy
: Risk factors and clinical consequences. A cohort study in septic patients. Intensive Care Med 2001; 27:1288–1296
10. Van den Berghe G, Schoonheydt K, Becx P, et al. Insulin therapy protects the central and peripheral nervous system of intensive care patients. Neurology 2005; 64:1348–1353
11. Novak KR, Nardelli P, Cope TC, et al. Inactivation of sodium channels underlies reversible neuropathy during critical illness in rats. J Clin Invest 2009; 119:1150–1158
12. Boczkowski J, Lisdero CL, Lanone S, et al. Peroxynitrite-mediated mitochondrial dysfunction. Biol Signals Recept 2001; 10:66–80
13. Crouser ED, Julian MW, Blaho DV, et al. Endotoxin-induced mitochondrial damage correlates with impaired respiratory activity. Crit Care Med 2002; 30:276–284
14. Schumer W, Erve PR, Obernolte RP. Endotoxemic effect on cardiac and skeletal muscle mitochondria. Surg Gynecol Obstet 1971; 133:433–436
15. Kumar N. Nutritional neuropathies. Neurol Clin 2007; 25:209–255
16. O’Dell BL, Conley-Harrison J, Browning JD, et al. Zinc deficiency and peripheral neuropathy in chicks. Proc Soc Exp Biol Med 1990; 194:1–4
17. Deem S. Intensive-care-unit-acquired muscle weakness. Respir Care 2006; 51:1042–1052
18. Leijten FS, Harinck-de Weerd JE, Poortvliet DC, et al. The role of polyneuropathy in motor convalescence after prolonged mechanical ventilation. JAMA 1995; 274:1221–1225
19. Guarneri B, Bertolini G, Latronico N. Long-term outcome in patients with critical illness myopathy or neuropathy: The Italian multicentre CRIMYNE study. J Neurol Neurosurg Psychiatry 2008; 79:838–841
20. Garnacho-Montero J, Amaya-Villar R, García-Garmendía JL, et al. Effect of critical illness polyneuropathy
on the withdrawal from mechanical ventilation and the length of stay in septic patients. Crit Care Med 2005; 33:349–354
21. De Jonghe B, Bastuji-Garin S, Durand M-C, et al. Respiratory weakness is associated with limb weakness and delayed weaning in critical illness. Crit Care Med 2007; 35:2007–2015
22. Rudis MI, Guslits BJ, Peterson EL, et al. Economic impact of prolonged motor weakness complicating neuromuscular blockade in the intensive care unit. Crit Care Med 1996; 24:1749–1756
23. Stevens RD, Dowdy DW, Michaels RK, et al. Neuromuscular dysfunction acquired in critical illness: A systematic review. Intensive Care Med 2007; 33:1876–1891
24. Banwell BL, Mildner RJ, Hassall AC, et al. Muscle weakness in critically ill children. Neurology 2003; 61:1779–1782
25. Chakrabarty B, Kabra SK, Gulati S, et al. Peripheral neuropathy in cystic fibrosis: A prevalence study. J Cyst Fibros 2013; 12:754–760
26. Fuglsang-Frederiksen A, Pugdahl K. Current status on electrodiagnostic standards and guidelines in neuromuscular disorders. Clin Neurophysiol 2011; 122:440–455
27. Goldstein B, Giroir B, Randolph A; International Consensus Conference on Pediatric Sepsis
: International Pediatric Sepsis
Consensus Conference: Definitions for sepsis
and organ dysfunction in pediatrics. Pediatr Crit Care Med 2005; 6:2–8
28. de Benoist B. Conclusions of a WHO Technical Consultation on folate and vitamin B12 deficiencies. Food Nutr Bull 2008; 29:S238–S244
29. Brown KH, Rivera JA, Bhutta Z, et al.; International Zinc Nutrition Consultative Group (IZiNCG): International Zinc Nutrition Consultative Group (IZiNCG) technical document #1. Assessment of the risk of zinc deficiency in populations and options for its control. Food Nutr Bull 2004; 25:S99–S203
30. Wu AHB. Tietz Clinical Guide to Laboratory Tests. 2006New York, NY, Saunders Elsevier.
31. Schweickert WD, Hall J. ICU-acquired weakness. Chest 2007; 131:1541–1549
32. Darras B, Jones HR, DeVivo D. Neuromuscular Disorders of Infancy, Childhood and Adolescence. A Clinician’s Approach. 2003Oxford, United Kingdom, Butterworth Heinman.
33. England JD, Gronseth GS, Franklin G, et al. Distal symmetric polyneuropathy: A definition for clinical research: Report of the American Academy of Neurology, the American Association of Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology 2005; 64:199–207
34. Visser LH. Critical illness polyneuropathy
and myopathy: Clinical features, risk factors and prognosis. Eur J Neurol 2006; 13:1203–1212
35. de Letter MA, Schmitz PI, Visser LH, et al. Risk factors for the development of polyneuropathy and myopathy in critically ill patients. Crit Care Med 2001; 29:2281–2286
36. Thabet Mahmoud A, Tawfik MAM, Abd El Naby SA, et al. Neurophysiological study of critical illness polyneuropathy
and myopathy in mechanically ventilated children; additional aspects in paediatric critical illness comorbidities. Eur J Neurol 2018; 25:991–e76
37. Tennilä A, Salmi T, Pettilä V, et al. Early signs of critical illness polyneuropathy
in ICU patients with systemic inflammatory response syndrome or sepsis
. Intensive Care Med 2000; 26:1360–1363
38. Berek K, Margreiter J, Willeit J, et al. Polyneuropathies in critically ill patients: A prospective evaluation. Intensive Care Med 1996; 22:849–855
39. Wieske L, Dettling-Ihnenfeldt DS, Verhamme C, et al. Impact of ICU-acquired weakness on post-ICU physical functioning: A follow-up study. Crit Care Lond Engl 2015; 19:196
40. Parry SM, Berney S, Granger CL, et al. A new two-tier strength assessment approach to the diagnosis of weakness in intensive care: An observational study. Crit Care Lond Engl 2015; 19:52