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Early complications of high-dose methylprednisolone in acute spinal cord injury patients
Injury, Int. J. Care Injured (2008) 39, 748—752
www.elsevier.com/locate/injury
Early complications of high-dose methylprednisolone in acute spinal cord injury patients ´lez-Castro a, Javier Llorca b, Borja Suberviola a, Alejandro Gonza ˜ambres a,* ´n a, Eduardo Min Fernando Ortiz-Melo a
´s de Valdecilla, Santander, Spain Service of Intensive Care, Hospital Universitario Marque Division of Epidemiology and Computational Biology, University of Cantabria, School of Medicine, Santander, Spain
b
Accepted 3 December 2007
KEYWORDS Spinal cord injury; Methylprednisolone; Neurological function; Outcome
Summary Background: To evaluate the early complications and effect on neurological outcome of methylprednisolone (MP) treatment in spinal cord injury (SCI) patients during the acute phase. Methods: We retrospectively reviewed the whole cohort of patients admitted to our ICU between January 1994 and December 2005 due to acute SCI. Patients were grouped according to the medical treatment received (MP group versus no-MP group). Patient data as age, gender, Glasgow coma score (GCS), APACHE II, injury severity score (ISS) and ICU stay were recorded. Outcome at ICU discharge and neurological function based on Frankel grade was recorded at ICU admission and at ICU discharge. Early complications were also noted. Results: There were no differences between both groups in ICU mortality (OR = 0.48; 95% CI: 0.08—3.64) nor neurological function at ICU discharge. (OR = 1.09; 95% CI: 0.35—3.66). MP group presented an increase in respiratory tract infections (OR = 8.19; 95% CI: 1.10—358.6) and in total infections (OR = 4.90; 95% CI: 1.46—18.83) compared to no-MP group during the ICU stay. There was a significant increase in the incidence of hyperglycaemia in the MP group (OR = 17.0; 95% CI: 4.52—66.3). Conclusions: : The use of MP in patients with acute SCI is not associated with an improvement in outcome or neurological function at ICU discharge. Moreover, the use of MP is associated with an increased risk of infectious and metabolic complications during ICU stay. # 2007 Elsevier Ltd. All rights reserved.
* Corresponding author at: Servicio de Medicina Intensiva, Hospital Universitario Marque ´s de Valdecilla, Av. Valdecilla s/n, 39008 Santander, Spain. Tel.: +34 942 203304; fax: +34 942 203543. E-mail address: [email protected] (E. Min ˜ambres). 0020–1383/$ — see front matter # 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.injury.2007.12.005
Early complications of high-dose methylprednisolone
Introduction Few conditions are as devastating as traumatic spinal cord injury (SCI). This type of injury is a major cause of morbidity in young individuals and as a result has a major impact on society as a whole.11 During most of the last century, the management of acute SCI has traditionally concentrated on preventive measures as well as conservative care. In 1990, Bracken et al.1 first reported the effectiveness of methylprednisolone (MP) treatment in recovery from SCI. After this study the use of intravenous high-dose MP in acute SCI became a standard aspect of care in these patients. A number of published critiques of the NASCIS II data and their presentation in support of the use of MP in the management of patients with acute SCI have been offered. Over the past 10 years, a lively debate has ensued in the literature over whether or not steroids should be used at all in SCI. Many authors have tried to further distil and objectify the results of the NASCIS studies, most with unfavourable conclusions.12,20 Moreover, some authors have suggested that the use of high-dose MP in acute SCI is associated with an increase in complications.14,19 Finally, the American Association of Neurological Surgeons Joint Section of Disorders of the Spine and Peripheral Nerves recommended the use of MP only as an option, not as a guideline or standard.17 Despite these considerations, many physicians continue to prescribe methylprednisolone for acute SCI even today.2,13 We aimed to review the outcome of patients admitted to our intensive care unit (ICU) with SCI from 1994 to 2005, according to the use or not of MP (NASCIS II protocol).
Patients and methods We retrospectively reviewed the whole cohort of patients admitted to our ICU between January 1994 and December 2005 due to SCI. Eligible patients were those who were older than 14 years and ICU hospitalisation within 8 h of vertebral trauma with spinal cord involvement. Patients were grouped according to the medical treatment received. Those patients who received MP according to NASCIS II protocol were considered as MP group, and patients who did not receive MP were considered as no-MP group. MP was administered in a 15-min bolus, followed by a pause for 45 m and then a 23-h maintenance infusion. The rate of infusion of the MP bolus was 30 mg/kg, and the maintenance infusion was 5.4 mg/kg per hour. Those patients who received MP at different doses to NASCIS II or
749 received MP later than 8 h after ICU admission were excluded. Clinical data were recorded at ICU admission and at ICU discharge collected retrospectively by review of clinical records. Patient data for age, gender, level of SCI, Glasgow coma score (GCS), APACHE II, injury severity score (ISS) and ICU stay were recorded. Outcome at ICU discharge and neurological function based on Frankel grade5 was recorded at ICU admission and at ICU discharge by ICU physicians and surgeons. Complications such as hyperglycaemia and infectious complications were also noted. We defined respiratory tract infection as tracheobronchitis, ICU-acquired pneumonia and, ventilator-associated pneumonia. Septicaemia was defined as blood infection documented by positive blood culture. All patients had a urethral catheterisation. Urinary tract infection was defined as presence of bacteriuria with more than 100.000 CFU/ml in urine culture. Wound infection was defined when it occurred within 30 days of the operative procedure and involved only the skin or subcutaneous tissue of the incision and at least one of the following: (1) purulent drainage from the superficial incision; (2) organism isolated from an aseptically obtained culture of fluid or tissue from the superficial incision; (3) at least one of the following signs or symptoms of infection (pain or tenderness, localised swelling); (4) diagnosis of superficial incisional wound infection by the surgeon or attending physician. Blood glucose levels were measured on admission and subsequently every 6 h in all patients. More frequent blood glucose measurements were performed whenever there had been a steep rise or fall in the blood glucose level on the previous reading. Odds ratios (OR) with exact 95% confidence intervals were estimated using no-MP group as reference, so OR values higher than 1 suggest higher risk in MP group. p-values were estimated via Chi-square test or Fisher’s exact method.
Results There were 59 patients in the MP group and 23 patients in the No-MP group. There was no significant difference in sex ratio or age between the groups (Table 1). All patients had a neurological deficit of varying degrees according to Frankel scale at ICU admission, and there was no difference between the groups (Table 2). There were no differences between both groups in ICU mortality. Four patients died in MP group (6.7%) and 3 patients in No-MP group (13%) (OR = 0.48; 95% CI: 0.08—3.64). There were no significant differences
750
B. Suberviola et al.
Table 1 Principal epidemiological characteristics Age Males (%) ICU stay (days) Lession associated (%) GCS ISS APACHE II Cervical level (%) Frankel A at ICU admission (%)
MP group (n = 59)
No-MP group (n = 23)
p
40.8 20.1 51 (86%) 11.5 13.9 39 (66%) 13.1 3.9 21.9 11.3 8.9 6.3 30 (51%) 32 (55%)
46.7 17.3 18 (78%) 20.2 20.8 17 (74%) 11.2 5.5 30.7 16 11.2 7.2 14 (60%) 10 (43%)
0.219 0.362 0.031 0.495 0.071 0.006 0.160 0.414 0.381
ICU: Intensive care unit; GCS: Glasgow coma score; ISS: injury severity score. The values are expressed as mean S.D. or number and percentage.
Table 2 Neurological status of patients at ICU admission Frankel Frankel Frankel Frankel
grade grade grade grade
A B C D
MP group (n = 59)
No-MP group (n = 23)
Total
32 4 13 10
12 1 6 4
44 5 19 14
among the groups in terms of Frankel grade at ICU discharge. Nineteen patients improved their neurological situation (at least 1 grade in Frankel scale) at ICU discharge in MP group (32.2%) and 7 in no-MP group (30.4%). (OR = 1.09; 95% CI: 0.35—3.66). There were significant differences in respiratory tract infections but not in septicaemia, urinary tract infection or wound infection. We also observed significant differences between both groups in total infections grouped (see Table 3). Hyperglycaemia occurred in 52 out of 59 patients treated with MP (88%) compared to 7 out of 23 patients who did not receive MP (30%) (OR = 17.0; 95% CI: 4.52—66.3). Most cases of hyperglycaemia that appeared early required intravenous insulin, but did not last longer than 4 days. The maximum level of glycaemia in the first 24 h was higher in MP group than in no-MP group (203 55 versus 171 39 mg/dl; p < 0.01). Fifteen patients in the MP group (25%) and 2 patients in the No-MP group (8%) underwent early surgery (<24 h). The surgical procedures were performed to decompress the spinal cord and stabilise
the spine in order to limit the extensiveness of the cord lesions. There was no difference in the neurological recovery of the patients who underwent surgery and those who did not (data not shown).
Discussion The hope that administration of a drug delivered after acute SCI might improve neurological function has long been held. Although other substances, as naloxone and GM-1 ganglioside, have been tested in laboratory and in clinical investigations, corticosteroids, particularly methylprednisolone, have been the most extensively studied drugs in animal and human studies.10,17 The precise mechanism of action is not completely known, but corticosteroids have the potential to stabilise membrane structures, maintain the blood—spinal cord barrier, reducing vasogenic oedema, inhibit endorphin release and limit the inflammatory response after SCI.3,9 The results of NASCIS II showed a significant neurological improvement in patients with acute SCI,
Table 3 Infectious complications observed during ICU stay MP group (n = 59)
No-MP group (n = 23)
p
Respiratory tract infection Septicaemia Urinary tract infection Wound infection
16 8 7 3
1 2 1 1
0.02 0.55 0.30 0.89
Total infections
34
5
0.004
Early complications of high-dose methylprednisolone when MP was administered within 8 h of the injury. However, the findings of NASCIS II were not uniformly accepted as the main conclusions of the trial were based on an analysis of a subset of the original cohort, which has been argued to represent a post hoc analysis.12,17 Only two other Class I clinical trials have been performed in a prospective randomised manner, but neither of them with the power of the NASCIS studies. In both, the primary outcome measures should no differences between treatment and control groups.16,18 However, harmful side effects associated with the administration of methylprednisolone at NASCIS II doses continue to be reported including myopathy.19 Our results are similar to the findings of other studies which did not shown any benefit in terms of mortality or neurological recovery with the use of MP therapy.18,7 So, in our patients not only was there no significant difference in mortality, but also there was no significant difference in the improvement of neurological function between those patients who received steroids and those who did not. Although the role and timing of early decompression in SCI is still debated,4 we did not find differences in surgical procedures between both groups. There was a limitation in our study due to the different ISS score between both groups. Nevertheless, the MP-treated patients were the less severely injured patients which confirms the absence of benefit of MP because there was equivalent outcome (mortality and neurological function) in steroid and no-steroid groups, despite the no-MP group being more severely injured. George et al. did not find any difference in mortality or neurological outcome with the use of MP despite younger age and less severe injury in MPtreated patients.6 Another limitation of our study was the short followup (ICU discharge instead of long-term followup). Moreover, the use of high-dose MP therapy may be associated with an increase in complications after SCI. In 2001, Matsumoto et al. reported their results of a prospective, randomised double-blind clinical trial comparing MP with placebo in the treatment of patients with acute cervical SCI. Patients treated with MP had a higher incidence of complications compared with placebo-treated patients at 2-month follow-up.14 Respiratory complications and gastrointestinal complications were the most significant difference between the two treatment populations. The authors concluded that patients with acute SCI treated with methylprednisolone (particularly older patients) were at increased risk of pulmonary and gastrointestinal complications and deserve special care. Pointillart et al., in a prospective and randomised trial with 106 patients with SCI confirmed the absence of benefit of methylprednisolone; also
751 there was a trend towards an increase in septic complications in the methylprednisolone group versus control group.18 Other retrospective studies have concluded that the use of MP in SCI does not increase neurological function and is associated with a higher incidence of infectious diseases.8 In our study, the percentage of infectious complications is lower than the reported studies. The reason could be that most of these studies included only patients with cervical spinal cord injuries who are the patients in more need of mechanical ventilation (with the increase risk of ventilator-associated pneumonia). In our study, nearly the half of patients did not have a cervical lesion. However, our results confirm the deleterious effect of corticoids in these patients. We also observed an increase in metabolic complications in the MP group. These patients developed a significant transient hyperglycaemia. The absence of this complication in previous studies is surprising (NASCIS II), although other prospective studies observed it.18 Nevertheless, there is increasing evidence that maintaining normoglycaemia and treatment with insulin-based regimens is beneficial in limiting organ damage and significantly reduces both morbidity and mortality in critically ill patients who require intensive care therapy.21,22 In the present study, we observed a higher incidence of hyperglycaemia than in previous studies.18 The reason could be the greater severity of our patients compared with those studies. Critical illness is clearly associated with hyperglycaemia.22 The severity and frequency of hyperglycaemia during critical illness is determined in part by acute stimuli, including corticosteroids, exogenous catecholamines, and carbohydrates. Therapy was generally initiated if the plasma glucose level was >150 mg/dl. Moreover, the use of methylprednisolone has been related to higher acute care charges and longer hospital stays.15 In our study, the longer ICU stay in no-MP group could be attributed to the more severe injuries in this group (according to ISS score). Finally, the present study has several limitations. First, most of the patients had injuries at other levels. In fact, the MP group was less severely injured than the No-MP group, although this difference confirms the absence of benefit of MP in SCI patients. The other limitations are its small size and retrospective nature. Finally, patients’ outcome was analysed at ICU discharge instead of 1-year follow up. In summary, according to the guidelines and the latest studies the results of the present study indicates that the use of MP in patients with acute SCI is not associated with an improvement in outcome or neurological function at ICU discharge. Moreover, the use of MP is associated with an increased risk of
752 infectious and metabolic complications during ICU stay. Further prospective randomised controlled studies are needed to conclude this issue definitively.
Conflict of interest None.
References 1. Bracken MB, Shepard MJ, Collins WF, et al. A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. N Engl J Med 1990;322:1405—11. 2. Eck JC, Nachtigall D, Humphreys SC, Hodges SD. Questionnaire survey of spine surgeons on the use of methylprednisolone for acute spinal cord injury. Spine 2006;31:E250—3. 3. Fehlings MG, Baptiste DC. Current status of clinical trials for acute spinal cord injury. Injury 2005;36(Suppl. 2):113—22. 4. Fehlings MG, Perrin RG. The role and timing of early decompression for cervical spinal cord injury: update with a review of recent clinical evidence. Injury 2005;36(Suppl. 2):13—26. 5. Frankel HL, Hancock DO, Hyslop G, et al. The value of postural reduction in the initial management of closed injuries of the spine with paraplegia and tetraplegia. Paraplegia 1969;7:179—92. 6. George ER, Scholten DJ, Buechler CM, et al. Failure of methylprednisolone to improve the outcome of spinal cord injuries. Am Surg 1995;61:659—64. 7. Gerhart KA, Johnson RL, Menconi J, et al. Utilization and effectiveness of methylprednisolone in a population-based sample of spinal cord injured persons. Paraplegia 1995;33: 316—21. 8. Gerndt SJ, Rodriguez JL, Pawlik JW, et al. Consequences of high-dose steroid therapy for acute spinal cord injury. J Trauma 1997;42:279—84.
B. Suberviola et al. 9. Hall ED, Springer JE. Neuroprotection and acute spinal cord injury: a reappraisal. NeuroRx 2004;1:80—100. 10. Hausmann ON. Post-traumatic inflammation following spinal cord injury. Spinal Cord 2003;41:369—78. 11. Holtslag HR, Post MW, Lindeman E, Van der Werken C. Longterm functional health status of severely injured patients. Injury 2007;38:280—9. 12. Hurlbert RJ. Methylprednisolone for acute spinal cord injury: an inappropiate standard of care. J Neurosurg (Spine 1) 2000;93:1—7. 13. Hurlbert RJ. Strategies of medical intervention in the management of acute spinal cord injury. Spine 2006;31(Suppl. 11): S16—21. 14. Matsumoto T, Tamaki T, Kawakami M, et al. Early complications of high-dose methylprednisolone sodium succinate treatment in the follow-up of acute-cervical spinal cord injury. Spine 2001;26:426—30. 15. McCutcheon EP, Selassie AW, Gu JK, Pickelsimer EE. Acute traumatic spinal cord injury, 1993—2000. A population-based assessment of methylprednisolone administration and hospitalisation. J Trauma 2004;56:1076—83. 16. Otani K, Abe H, Kadoya S, et al. Beneficial effect of methylprednisolone sodium succinate in the treatment of acute spinal cord injury. Sekitsu Sekizui 1994;7:633—7. 17. Pharmacological therapy after acute cervical spinal cord injury. Neurosurgery 2002; 50 (suppl.): 63—72. 18. Pointillart V, Petitjean ME, Wiart L, et al. Pharmacological therapy of spinal cord injury during the acute phase. Spinal Cord 2000;38:71—6. 19. Qian T, Guo X, Levi AD, et al. High-dose methylprednisolone may cause myopathy in acute spinal cord injury patients. Spinal Cord 2005;43:199—203. 20. Short DJ, El Masry WS, Jones PW. High dose methylprednisolone in the management of acute spinal cord injury: a systematic review from a clinical perspective. Spinal Cord 2000;38:273—86. 21. Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006;354:449—61. 22. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001;345:1359—67.
www.elsevier.com/locate/injury
Early complications of high-dose methylprednisolone in acute spinal cord injury patients ´lez-Castro a, Javier Llorca b, Borja Suberviola a, Alejandro Gonza ˜ambres a,* ´n a, Eduardo Min Fernando Ortiz-Melo a
´s de Valdecilla, Santander, Spain Service of Intensive Care, Hospital Universitario Marque Division of Epidemiology and Computational Biology, University of Cantabria, School of Medicine, Santander, Spain
b
Accepted 3 December 2007
KEYWORDS Spinal cord injury; Methylprednisolone; Neurological function; Outcome
Summary Background: To evaluate the early complications and effect on neurological outcome of methylprednisolone (MP) treatment in spinal cord injury (SCI) patients during the acute phase. Methods: We retrospectively reviewed the whole cohort of patients admitted to our ICU between January 1994 and December 2005 due to acute SCI. Patients were grouped according to the medical treatment received (MP group versus no-MP group). Patient data as age, gender, Glasgow coma score (GCS), APACHE II, injury severity score (ISS) and ICU stay were recorded. Outcome at ICU discharge and neurological function based on Frankel grade was recorded at ICU admission and at ICU discharge. Early complications were also noted. Results: There were no differences between both groups in ICU mortality (OR = 0.48; 95% CI: 0.08—3.64) nor neurological function at ICU discharge. (OR = 1.09; 95% CI: 0.35—3.66). MP group presented an increase in respiratory tract infections (OR = 8.19; 95% CI: 1.10—358.6) and in total infections (OR = 4.90; 95% CI: 1.46—18.83) compared to no-MP group during the ICU stay. There was a significant increase in the incidence of hyperglycaemia in the MP group (OR = 17.0; 95% CI: 4.52—66.3). Conclusions: : The use of MP in patients with acute SCI is not associated with an improvement in outcome or neurological function at ICU discharge. Moreover, the use of MP is associated with an increased risk of infectious and metabolic complications during ICU stay. # 2007 Elsevier Ltd. All rights reserved.
* Corresponding author at: Servicio de Medicina Intensiva, Hospital Universitario Marque ´s de Valdecilla, Av. Valdecilla s/n, 39008 Santander, Spain. Tel.: +34 942 203304; fax: +34 942 203543. E-mail address: [email protected] (E. Min ˜ambres). 0020–1383/$ — see front matter # 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.injury.2007.12.005
Early complications of high-dose methylprednisolone
Introduction Few conditions are as devastating as traumatic spinal cord injury (SCI). This type of injury is a major cause of morbidity in young individuals and as a result has a major impact on society as a whole.11 During most of the last century, the management of acute SCI has traditionally concentrated on preventive measures as well as conservative care. In 1990, Bracken et al.1 first reported the effectiveness of methylprednisolone (MP) treatment in recovery from SCI. After this study the use of intravenous high-dose MP in acute SCI became a standard aspect of care in these patients. A number of published critiques of the NASCIS II data and their presentation in support of the use of MP in the management of patients with acute SCI have been offered. Over the past 10 years, a lively debate has ensued in the literature over whether or not steroids should be used at all in SCI. Many authors have tried to further distil and objectify the results of the NASCIS studies, most with unfavourable conclusions.12,20 Moreover, some authors have suggested that the use of high-dose MP in acute SCI is associated with an increase in complications.14,19 Finally, the American Association of Neurological Surgeons Joint Section of Disorders of the Spine and Peripheral Nerves recommended the use of MP only as an option, not as a guideline or standard.17 Despite these considerations, many physicians continue to prescribe methylprednisolone for acute SCI even today.2,13 We aimed to review the outcome of patients admitted to our intensive care unit (ICU) with SCI from 1994 to 2005, according to the use or not of MP (NASCIS II protocol).
Patients and methods We retrospectively reviewed the whole cohort of patients admitted to our ICU between January 1994 and December 2005 due to SCI. Eligible patients were those who were older than 14 years and ICU hospitalisation within 8 h of vertebral trauma with spinal cord involvement. Patients were grouped according to the medical treatment received. Those patients who received MP according to NASCIS II protocol were considered as MP group, and patients who did not receive MP were considered as no-MP group. MP was administered in a 15-min bolus, followed by a pause for 45 m and then a 23-h maintenance infusion. The rate of infusion of the MP bolus was 30 mg/kg, and the maintenance infusion was 5.4 mg/kg per hour. Those patients who received MP at different doses to NASCIS II or
749 received MP later than 8 h after ICU admission were excluded. Clinical data were recorded at ICU admission and at ICU discharge collected retrospectively by review of clinical records. Patient data for age, gender, level of SCI, Glasgow coma score (GCS), APACHE II, injury severity score (ISS) and ICU stay were recorded. Outcome at ICU discharge and neurological function based on Frankel grade5 was recorded at ICU admission and at ICU discharge by ICU physicians and surgeons. Complications such as hyperglycaemia and infectious complications were also noted. We defined respiratory tract infection as tracheobronchitis, ICU-acquired pneumonia and, ventilator-associated pneumonia. Septicaemia was defined as blood infection documented by positive blood culture. All patients had a urethral catheterisation. Urinary tract infection was defined as presence of bacteriuria with more than 100.000 CFU/ml in urine culture. Wound infection was defined when it occurred within 30 days of the operative procedure and involved only the skin or subcutaneous tissue of the incision and at least one of the following: (1) purulent drainage from the superficial incision; (2) organism isolated from an aseptically obtained culture of fluid or tissue from the superficial incision; (3) at least one of the following signs or symptoms of infection (pain or tenderness, localised swelling); (4) diagnosis of superficial incisional wound infection by the surgeon or attending physician. Blood glucose levels were measured on admission and subsequently every 6 h in all patients. More frequent blood glucose measurements were performed whenever there had been a steep rise or fall in the blood glucose level on the previous reading. Odds ratios (OR) with exact 95% confidence intervals were estimated using no-MP group as reference, so OR values higher than 1 suggest higher risk in MP group. p-values were estimated via Chi-square test or Fisher’s exact method.
Results There were 59 patients in the MP group and 23 patients in the No-MP group. There was no significant difference in sex ratio or age between the groups (Table 1). All patients had a neurological deficit of varying degrees according to Frankel scale at ICU admission, and there was no difference between the groups (Table 2). There were no differences between both groups in ICU mortality. Four patients died in MP group (6.7%) and 3 patients in No-MP group (13%) (OR = 0.48; 95% CI: 0.08—3.64). There were no significant differences
750
B. Suberviola et al.
Table 1 Principal epidemiological characteristics Age Males (%) ICU stay (days) Lession associated (%) GCS ISS APACHE II Cervical level (%) Frankel A at ICU admission (%)
MP group (n = 59)
No-MP group (n = 23)
p
40.8 20.1 51 (86%) 11.5 13.9 39 (66%) 13.1 3.9 21.9 11.3 8.9 6.3 30 (51%) 32 (55%)
46.7 17.3 18 (78%) 20.2 20.8 17 (74%) 11.2 5.5 30.7 16 11.2 7.2 14 (60%) 10 (43%)
0.219 0.362 0.031 0.495 0.071 0.006 0.160 0.414 0.381
ICU: Intensive care unit; GCS: Glasgow coma score; ISS: injury severity score. The values are expressed as mean S.D. or number and percentage.
Table 2 Neurological status of patients at ICU admission Frankel Frankel Frankel Frankel
grade grade grade grade
A B C D
MP group (n = 59)
No-MP group (n = 23)
Total
32 4 13 10
12 1 6 4
44 5 19 14
among the groups in terms of Frankel grade at ICU discharge. Nineteen patients improved their neurological situation (at least 1 grade in Frankel scale) at ICU discharge in MP group (32.2%) and 7 in no-MP group (30.4%). (OR = 1.09; 95% CI: 0.35—3.66). There were significant differences in respiratory tract infections but not in septicaemia, urinary tract infection or wound infection. We also observed significant differences between both groups in total infections grouped (see Table 3). Hyperglycaemia occurred in 52 out of 59 patients treated with MP (88%) compared to 7 out of 23 patients who did not receive MP (30%) (OR = 17.0; 95% CI: 4.52—66.3). Most cases of hyperglycaemia that appeared early required intravenous insulin, but did not last longer than 4 days. The maximum level of glycaemia in the first 24 h was higher in MP group than in no-MP group (203 55 versus 171 39 mg/dl; p < 0.01). Fifteen patients in the MP group (25%) and 2 patients in the No-MP group (8%) underwent early surgery (<24 h). The surgical procedures were performed to decompress the spinal cord and stabilise
the spine in order to limit the extensiveness of the cord lesions. There was no difference in the neurological recovery of the patients who underwent surgery and those who did not (data not shown).
Discussion The hope that administration of a drug delivered after acute SCI might improve neurological function has long been held. Although other substances, as naloxone and GM-1 ganglioside, have been tested in laboratory and in clinical investigations, corticosteroids, particularly methylprednisolone, have been the most extensively studied drugs in animal and human studies.10,17 The precise mechanism of action is not completely known, but corticosteroids have the potential to stabilise membrane structures, maintain the blood—spinal cord barrier, reducing vasogenic oedema, inhibit endorphin release and limit the inflammatory response after SCI.3,9 The results of NASCIS II showed a significant neurological improvement in patients with acute SCI,
Table 3 Infectious complications observed during ICU stay MP group (n = 59)
No-MP group (n = 23)
p
Respiratory tract infection Septicaemia Urinary tract infection Wound infection
16 8 7 3
1 2 1 1
0.02 0.55 0.30 0.89
Total infections
34
5
0.004
Early complications of high-dose methylprednisolone when MP was administered within 8 h of the injury. However, the findings of NASCIS II were not uniformly accepted as the main conclusions of the trial were based on an analysis of a subset of the original cohort, which has been argued to represent a post hoc analysis.12,17 Only two other Class I clinical trials have been performed in a prospective randomised manner, but neither of them with the power of the NASCIS studies. In both, the primary outcome measures should no differences between treatment and control groups.16,18 However, harmful side effects associated with the administration of methylprednisolone at NASCIS II doses continue to be reported including myopathy.19 Our results are similar to the findings of other studies which did not shown any benefit in terms of mortality or neurological recovery with the use of MP therapy.18,7 So, in our patients not only was there no significant difference in mortality, but also there was no significant difference in the improvement of neurological function between those patients who received steroids and those who did not. Although the role and timing of early decompression in SCI is still debated,4 we did not find differences in surgical procedures between both groups. There was a limitation in our study due to the different ISS score between both groups. Nevertheless, the MP-treated patients were the less severely injured patients which confirms the absence of benefit of MP because there was equivalent outcome (mortality and neurological function) in steroid and no-steroid groups, despite the no-MP group being more severely injured. George et al. did not find any difference in mortality or neurological outcome with the use of MP despite younger age and less severe injury in MPtreated patients.6 Another limitation of our study was the short followup (ICU discharge instead of long-term followup). Moreover, the use of high-dose MP therapy may be associated with an increase in complications after SCI. In 2001, Matsumoto et al. reported their results of a prospective, randomised double-blind clinical trial comparing MP with placebo in the treatment of patients with acute cervical SCI. Patients treated with MP had a higher incidence of complications compared with placebo-treated patients at 2-month follow-up.14 Respiratory complications and gastrointestinal complications were the most significant difference between the two treatment populations. The authors concluded that patients with acute SCI treated with methylprednisolone (particularly older patients) were at increased risk of pulmonary and gastrointestinal complications and deserve special care. Pointillart et al., in a prospective and randomised trial with 106 patients with SCI confirmed the absence of benefit of methylprednisolone; also
751 there was a trend towards an increase in septic complications in the methylprednisolone group versus control group.18 Other retrospective studies have concluded that the use of MP in SCI does not increase neurological function and is associated with a higher incidence of infectious diseases.8 In our study, the percentage of infectious complications is lower than the reported studies. The reason could be that most of these studies included only patients with cervical spinal cord injuries who are the patients in more need of mechanical ventilation (with the increase risk of ventilator-associated pneumonia). In our study, nearly the half of patients did not have a cervical lesion. However, our results confirm the deleterious effect of corticoids in these patients. We also observed an increase in metabolic complications in the MP group. These patients developed a significant transient hyperglycaemia. The absence of this complication in previous studies is surprising (NASCIS II), although other prospective studies observed it.18 Nevertheless, there is increasing evidence that maintaining normoglycaemia and treatment with insulin-based regimens is beneficial in limiting organ damage and significantly reduces both morbidity and mortality in critically ill patients who require intensive care therapy.21,22 In the present study, we observed a higher incidence of hyperglycaemia than in previous studies.18 The reason could be the greater severity of our patients compared with those studies. Critical illness is clearly associated with hyperglycaemia.22 The severity and frequency of hyperglycaemia during critical illness is determined in part by acute stimuli, including corticosteroids, exogenous catecholamines, and carbohydrates. Therapy was generally initiated if the plasma glucose level was >150 mg/dl. Moreover, the use of methylprednisolone has been related to higher acute care charges and longer hospital stays.15 In our study, the longer ICU stay in no-MP group could be attributed to the more severe injuries in this group (according to ISS score). Finally, the present study has several limitations. First, most of the patients had injuries at other levels. In fact, the MP group was less severely injured than the No-MP group, although this difference confirms the absence of benefit of MP in SCI patients. The other limitations are its small size and retrospective nature. Finally, patients’ outcome was analysed at ICU discharge instead of 1-year follow up. In summary, according to the guidelines and the latest studies the results of the present study indicates that the use of MP in patients with acute SCI is not associated with an improvement in outcome or neurological function at ICU discharge. Moreover, the use of MP is associated with an increased risk of
752 infectious and metabolic complications during ICU stay. Further prospective randomised controlled studies are needed to conclude this issue definitively.
Conflict of interest None.
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