See the corresponding editorial in this issue, pp 1226–1227.
J Neurosurg 119:1228–1232, 2013 ©AANS, 2013
Decreased risk of acute kidney injury with intracranial pressure monitoring in patients with moderate or severe brain injury Clinical article Jingsong Zeng, M.D.,1 Wusong Tong, Ph.D.,1 and Ping Zheng, M.D. 2 Department of Neurosurgery, Pudong New Area People’s Hospital, Shanghai, China; and 2Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Victoria, Australia
Object. The authors undertook this study to evaluate the effects of continuous intracranial pressure (ICP) monitoring–directed mannitol treatment on kidney function in patients with moderate or severe traumatic brain injury (TBI). Methods. One hundred sixty-eight patients with TBI were prospectively assigned to an ICP monitoring group or a conventional treatment control group based on the Brain Trauma Foundation guidelines. Clinical data included the dynamic changes of patients’ blood concentrations of cystatin C, creatinine (Cr), and blood urea nitrogen (BUN); mannitol use; and 6-month Glasgow Outcome Scale (GOS) scores. Results. There were no statistically significant differences with respect to hospitalized injury, age, or sex distribution between the 2 groups. The incidence of acute kidney injury (AKI) was higher in the control group than in the ICP monitoring group (p < 0.05). The mean mannitol dosage in the ICP monitoring group (443 ± 133 g) was significantly lower than in the control group (820 ± 412 g) (p < 0.01), and the period of mannitol use in the ICP monitoring group (3 ± 3.8 days) was significantly shorter than in the control group (7 ± 2.3 days) (p < 0.01). The 6-month GOS scores in the ICP monitoring group were significantly better than in the control group (p < 0.05). On the 7th, 14th, and 21st days after injury, the plasma cystatin C and Cr concentrations in the ICP-monitoring group were significantly higher than the control group (p < 0.05). Conclusions. In patients with moderate and severe TBI, ICP-directed mannitol treatment demonstrated a beneficial effect on reducing the incidence of AKI compared with treatment directed by neurological signs and physiological indicators. (http://thejns.org/doi/abs/10.3171/2013.7.JNS122131)
Key Words • intracranial pressure • traumatic brain injury • acute kidney injury • mannitol • cystatin C • creatinine
brain injury is the primary cause of death and disability in individuals younger than 45 years of age in industrialized countries.19 It may result in a reduction of the intracranial volume reserve followed by a rise in ICP,4 which is considered to be a key factor in secondary injuries, a series of complications, and worse outcomes.23 Acute kidney injury is one of the most common and serious complications after TBI, especially during the acute stage of brain injury. The incidence rate of AKI following TBI is reported to vary from 1.5% to 18.1%.2,25 Traditionally, mannitol infusion is the most widely used pharmacological agent in the treatment of raumatic
Abbreviations used in this paper: AKI = acute kidney injury; BUN = blood urea nitrogen; Cr = creatinine; GCS = Glasgow Coma Scale; GOS = Glasgow Outcome Scale; ICP = intracranial pressure; TBI = traumatic brain injury.
patients receiving neurocritical care for TBI.5 Most of these patients are treated with high-dose mannitol therapy for an extended period without the support of evidencebased medicine.12 Therefore, it is difficult to optimize the total dose and period of mannitol treatment according to the neurological signs. The excessive use of mannitol is reported to be an independent risk factor for AKI after cerebral trauma,12 and further induce serious electrolyte disorders in patients with TBI.8 Other related risk factors are age and lower GCS score.22 ICP monitoring allows early detection of pressure changes and can guide treatment of elevated ICP. It has become an integral part in the management of patients with severe TBI in most trauma centers.16 However, the efficacy of ICP monitoring has never been verified with respect to preservation of kidney function through guiding the mannitol dosage. Therefore, in this study we investiJ Neurosurg / Volume 119 / November 2013
ICP monitoring in patients with TBI gated the potential effects of continuous ICP monitoring in adjusting the total dose and period of mannitol use, and further on the incidence rate of AKI following moderate or severe TBI.
markers included cystatin C and BUN. Six-month neurological outcome was assessed with the GOS, (1 [dead] to 5 [good recovery]). The GOS score was determined through an outpatient follow-up or a structured telephone interview. Protocol Approval and Patient Consent
This prospective controlled study involved TBI patients admitted to the neurosurgical department of the Shanghai Pudong New Area People’s Hospital between January 2010 and January 2012.
The study protocol was approved by the local ethics committee of the Shanghai Pudong New Area People’s Hospital. For follow-up by telephone interview, verbal informed consent was obtained, and for outcome assessment through outpatient, we gained written informed consent.
The inclusion criteria for this study were a GCS score of less than 13, age 15–70 years, and normal kidney function at admission. Patients with accompanying kidney injury, abdominal injury, or lung contusion, as determined by physical signs and imaging studies, were excluded.
The decision to use ICP monitoring or treat patients on the basis of neurological signs and other physiological indicators was based on the widely accepted Brain Trauma Foundation guidelines (no randomization). ICP should be monitored in patients with severe TBI and an abnormal CT scan or a normal CT scan and the presence of 2 or more of the following features at admission: age over 40 years, motor posturing, or systolic blood pressure lower than 90 mm Hg.6 Some of the patients in the control group met these criteria but did not undergo ICP monitoring due to other factors. Some patients in the control group were in a continuous coma or demonstrated irritability and had normal results on initial CT scans but were found to have diffuse axonal injury on the basis of a subsequent MRI study. Both groups received standard medical treatment based on vital signs and consciousness level. Procedures
Patients in the ICP-monitoring group underwent implantation of the ICP monitoring sensor under general anesthesia (Codman). The sensor was put into the anterior horn of the lateral ventricle, allowing for drainage of CSF. When the ICP was greater than 25 mm Hg, mannitol or a diuretic was immediately administered. If the ICP was higher than 30 mm Hg for 15 minutes or longer, the patient was required to undergo CT scanning to assess the progression of brain injury. In the control group, the dosage of mannitol and the duration of mannitol use were based on neurological signs and physiological measurements. The routine dosage was 1–2 g/kg/day for the 1st week postinjury; the dose was then reduced by one-half for the following week. The time interval between mannitol doses was 4, 6, 8, or 12 hours, based on the clinical situation, maintenance of urinary volume at 50–80 ml per hour, and maintenance of osmotic pressure at less than 320 osmol/L.
Acute kidney injury was determined using the criteria from clinical practice guidelines.20 Other important bio-
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All statistical analyses were performed using IBM SPSS Statistics 20.0. A p value < 0.05 was considered statistically significant. Patients were grouped as guideline compliant (ICP-monitoring group) or noncompliant (control group). Characteristics of the ICP-monitoring group and control group were compared using a chi-square test or Mann-Whitney U-test in case of ordinal variables. The biomarkers of kidney function were compared using an independent-samples t-test and the GOS scores were compared between the 2 groups by means of the Wilcoxon rank-sum test.
Results Patient Demographics and Early Injury Characteristics
A total of 168 patients with moderate or severe TBI were enrolled in our study, including 77 patients in the ICP-monitoring group and 91 patients in the control group. A summary of the demographic characteristics is presented in Table 1. The general characteristics, such as age, sex, and admission GCS score, did not differ significantly between the 2 groups (p > 0.05).
Incidence Rate of AKI Following TBI
Most cases of AKI were identified 3–10 days postinjury. The incidence of AKI in the ICP-monitoring group (6.49%) was significantly lower than in the control group (13.19%) (c2 = 5.2176, p = 0.022). The odds ratio was 2.1375, and the 95% confidence interval was 1.108–4.124. Thus it appears that the patients without ICP monitoring after TBI had approximately twice the risk of AKI compared with patients with ICP monitoring (Table 2). Furthermore, the kidney function parameters in the TABLE 1: Patient characteristics and injury severity parameters Variable mean age in yrs (range) sex male female GCS score at admission 3–8 9–12
ICP-Monitoring Group (n = 77)
Control Group (n = 91)
p Value 0.12 0.09
J. Zeng, W. Tong, and P. Zheng TABLE 2: Incidence of AKI in the ICP-monitoring and control groups No. of Cases Group
control ICP monitoring total
12 5 17
79 72 151
91 77 168
ICP-monitoring group were much better than the control group. Among them, the mean cystatin C value was significantly lower in the ICP-monitoring group than in the control group on the 14th and 21st days postinjury (p = 0.004 and p = 0.003, respectively). The Cr level was also significantly lower in the ICP-monitoring group than in the control group on the 14th and 21st days postinjury (p = 0.039 and p = 0.019, respectively). The BUN level was significantly lower in the ICP-monitoring group than in the control group only on the 14th day postinjury (p = 0.048) (Table 3). Mannitol Use in Each Group
The average dose of mannitol used in the ICP-monitoring group (443 ± 133 g) was significantly less than that used in the control group (820 ± 412 g). Also, the average duration of mannitol use was shorter in the ICPmonitoring group (3 ± 3.8 days) than the control group (7 ± 2.3 days) (p < 0.01) (Table 3).
A statistical analysis showed significantly more unfavorable outcome (GOS Score 2–3) and more mortality (GOS Score 1) in the control group, while much more favorable outcome (GOS Score 4–5) was found in the ICPmonitoring group (Z = 3.177, p < 0.01) (Table 3).
In this prospective study, compared with patients who did not undergo ICP monitoring, the ICP-monitoring group had a lower incidence of AKI and better neurological outcome at 6 months postinjury. Further, kidney function parameters were much better in the ICP-monitoring group than in the control group. An increased incidence of renal dysfunction has been described in patients with TBI.9 The reason might be that TBI may damage renal function through ischemia and hypoxia induced by hypovolemia, mediators of inflammation, nephrotoxic drugs, and large dose of mannitol, which may lead to decreased effective blood volume and renal plasma flow, then tubular ischemic injury, decreased glomerular filtration rate, and finally AKI.12,25 These findings can be explained by the fact that the kidney, in contrast to other organs, responds with vasoconstriction to an ischemia state and especially a shock state following severe TBI and, therefore, decreases its own blood supply.14 Mannitol is metabolically inert and is mostly excreted by the kidney, with only about 7% reabsorption in the renal
TABLE 3: Comparison of measures of kidney function, mannitol treatment, and outcome in the ICP-monitoring and control groups Variable mean cystatin C level (mg/L) Day 7 Day 14 Day 21 mean Cr level (mmol/L) Day 7 Day 14 Day 21 mean BUN level (mmol/L) Day 7 Day 14 Day 21 mannitol treatment mean dosage (g) mean duration (days) 6-mo GOS score* 5 4 3 2 1
ICP-Monitoring Group (n = 77)
Controls (n = 91)
0.54 ± 0.18 0.58 ± 0.22 0.56 ± 0.22
0.52 ± 0.22 0.73 ± 0.40 0.68 ± 0.32
−0.55 2.92 3.05
0.586 0.004 0.003
49.38 ± 9.96 48.59 ± 9.21 49.90 ± 14.40
46.45 ± 12.10 52.27 ± 12.97 58.20 ± 27.65
−1.69 2.08 2.38
0.923 0.039 0.019
5.25 ± 1.89 5.31 ± 1.77 5.32 ± 1.75
4.79 ± 1.96 5.99 ± 2.53 6.12 ± 2.05
−1.52 2.08 2.38
0.129 0.048 0.062
443 ± 133 3 ± 3.8
820 ± 412 7 ± 2.3
38 25 9 3 2
22 21 27 11 10
* Z score 3.177.
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ICP monitoring in patients with TBI tubule.27 As an extracellular solute with an osmotic effect, mannitol is clinically widely used in decreasing ICP and cerebral edema to prevent brain herniation.27 The nephrotoxicity of mannitol, however, is often ignored; few studies have focused on the effects of mannitol on the pathogenesis of AKI following cerebral trauma, and there is no largescale clinical trial to verify the relationships between ICP monitoring, mannitol use, and AKI following TBI.12 The major pathogenic mechanisms of mannitol-induced AKI involve injury to the tubule, including swelling of proximal tubular cells, tubuloglomerular feedback, vasoconstriction, and vacuolization, the so-called osmotic nephrosis.24 Mannitol can also induce the accumulation of exogenous substances in proximal tubule and reduce the glomerular filtration rate, thus leading to AKI.15 Traditionally, the decision to treat a patient with osmotherapy was based on clinical observations, such as neurological signs, GCS score, ventilation parameters, and arterial blood gas concentrations, as well as head CT findings. The patient received 20% mannitol solution at an initial dose of 1 g/kg. The dose was adjusted to maintain the urine volume at 50–80 ml/hour and within a serum osmolarity of 320 mosm/L. Normally, the more severe the injury, the higher the ICP was, and the more doses of mannitol were used. Therefore, ICP monitoring was used to eliminate bias due to casual observation and provide the exact evidence to guide the dose and period of mannitol and other osmotic agents. In our study, ICP monitoring was found to be associated with decreased dose and frequency of mannitol use, and the 6-month GOS score of patients in the ICP-monitoring group was much better than that of patients in the control group, which was consistent with the findings of a large retrospective study concluding that ICP monitoring was associated with significantly decreased mortality.18 In contrast, other studies have not demonstrated benefits from ICP monitoring.11,21 Furthermore, a few studies have shown that ICP monitoring was associated with worsening survival.10,26 Nevertheless, there is evidence to support the use of ICP monitoring in severe TBI patients at risk for intracranial hypertension.13,16 The latest randomized controlled trial of ICP monitoring in TBI showed that for patients with severe TBI, care focused on maintaining monitored ICP at 20 mm Hg or less was not shown to be superior to care based on imaging and clinical examination.7 In that study, intraparenchymal monitoring was chosen for its accuracy, whereas in our study we used intraventricular monitoring, which allowed us to drain the CSF and further decrease the ICP in a safe way. The authors of the recent randomized trial also recognized ICP as a treatment variable rather than merely an indication of disease severity.7 Therefore, the essential function of ICP monitoring is to demonstrate the dynamic change of ICP and to provide objective evidence for adjusting the dosing of osmotic agents. With regard to dynamic kidney function parameters, our results indicate that the incidence of AKI was approximately twice as high in patients without ICP monitoring compared with patients with ICP monitoring. Accordingly, the concentrations of cystatin C, Cr, and BUN in the ICP monitoring group were much lower than the control J Neurosurg / Volume 119 / November 2013
group, which indicated ICP monitoring in TBI patients could effectively decrease the mannitol dose and significantly reduce the incidence of mannitol-induced AKI. Finally, some limitations of our study have to be mentioned. First, the study was not randomized. We cannot easily draw the conclusion that ICP monitoring can improve the neurological outcome in TBI patients because of the small statistical power, insufficient data, and nonrandom nature. Nonetheless, according to the generally accepted guidelines, it seems difficult to carry out a completely randomized trial of ICP monitoring. In addition, some studies have suggested that ICP monitoring is associated with an increased chance of developing iatrogenic complications, such as intracranial infections and hemorrhage,1,3 but these variables were not assessed in our study. Further studies are required to evaluate the risk factors involved in AKI following TBI excluding the ICP monitoring factor. Hyperosmolar saline is starting to be used in clinical settings, and it is reported that hypertonic saline may be safe and effective in patients with renal failure.17 A recent research done by Yunos et al. found that restriction of intravenous chloride intake might reduce the incidence of AKI in critically ill patients.28 Therefore, this should also be validated in a future prospective and randomized study.
There are many studies supporting the effect of ICP monitoring in TBI patients, but few that have reliably evaluated the relationship between continuous ICP monitoring and the kidney function. In this prospective study, we found multiple differences between TBI patients with and without ICP monitoring with respect to kidney function and total dose of mannitol. Some of the between-groups differences with respect to kidney function and mannitol dose in this study may be accounted for by differences in case composition in the 2 cohorts in this study; however, we believe that our findings emphasize the importance of optimizing mannitol use in clinical practice as well as the need for ongoing study. Disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. Author contributions to the study and manuscript preparation include the following. Conception and design: Zeng. Acquisition of data: Zeng, Tong. Analysis and interpretation of data: Zeng. Drafting the article: Zheng. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Zheng. Statistical analysis: Zheng, Zeng. Administrative/technical/material support: Zeng. Study supervision: Tong. Acknowledgments The authors thank Dr. Yijun Guo, Dr. Hui Yu, Dr. Yongsheng Li, Dr. Bing He, Dr. Wenjin Yang, Dr. Gaoyi Li, and Dr. Wei Chen from the Department of Neurosurgery, Shanghai Pudong New Area People’s Hospital, who performed the operations and follow-up for these patients.
J. Zeng, W. Tong, and P. Zheng References 1. Anderson RC, Kan P, Klimo P, Brockmeyer DL, Walker ML, Kestle JR: Complications of intracranial pressure monitoring in children with head trauma. J Neurosurg 101 (1 Suppl): 53–58, 2004 2. Bagshaw SM, George C, Gibney RT, Bellomo R: A multicenter evaluation of early acute kidney injury in critically ill trauma patients. Ren Fail 30:581–589, 2008 3. Bekar A, Doğan S, Abaş F, Caner B, Korfali G, Kocaeli H, et al: Risk factors and complications of intracranial pressure monitoring with a fiberoptic device. J Clin Neurosci 16:236– 240, 2009 4. Biersteker HA, Andriessen TM, Horn J, Franschman G, van der Naalt J, Hoedemaekers CW, et al: Factors influencing intracranial pressure monitoring guideline compliance and outcome after severe traumatic brain injury. Crit Care Med 40: 1914–1922, 2012 5. Bilotta F, Giovannini F, Aghilone F, Stazi E, Titi L, Zeppa IO, et al: Potassium sparing diuretics as adjunct to mannitol therapy in neurocritical care patients with cerebral edema: effects on potassium homeostasis and cardiac arrhythmias. Neurocrit Care 16:280–285, 2012 6. Bratton SL, Chestnut RM, Ghajar J, McConnell Hammond FF, Harris OA, Hartl R, et al: Guidelines for the management of severe traumatic brain injury. VI. Indications for intracranial pressure monitoring. J Neurotrauma 24 (Suppl 1):S37– S44, 2007 (Erratum in J Neurotrauma 25:276–278, 2008) 7. Chesnut RM, Temkin N, Carney N, Dikmen S, Rondina C, Videtta W, et al: A trial of intracranial-pressure monitoring in traumatic brain injury. N Engl J Med 367:2471–2481, 2012 8. Concezione T, Valentina P: Volume and electrolyte management. Best Pract Res Clin Anaesthesiol 21:497–516, 2007 9. Corral L, Javierre CF, Ventura JL, Marcos P, Herrero JI, Mañez R: Impact of non-neurological complications in severe traumatic brain injury outcome. Crit Care 16:R44, 2012 10. Cremer OL: Does ICP monitoring make a difference in neurocritical care? Eur J Anaesthesiol Suppl 42:87–93, 2008 11. Cremer OL, van Dijk GW, van Wensen E, Brekelmans GJF, Moons KGM, Leenen LPH, et al: Effect of intracranial pressure monitoring and targeted intensive care on functional outcome after severe head injury. Crit Care Med 33:2207–2213, 2005 12. Fang L, You H, Chen B, Xu Z, Gao L, Liu J, et al: Mannitol is an independent risk factor of acute kidney injury after cerebral trauma: a case-control study. Ren Fail 32:673–679, 2010 13. Forsyth RJ, Wolny S, Rodrigues B: Routine intracranial pressure monitoring in acute coma. Cochrane Database Syst Rev (2):CD002043, 2010 14. Froelich MM, Ni QQ, Wess CC, Ougorets II, Härtl RR: Continuous hypertonic saline therapy and the occurrence of complications in neurocritically ill patients. Crit Care Med 37: 1433–1441, 2009
15. Gadallah MF, Lynn M, Work J: Case report: mannitol nephrotoxicity syndrome: role of hemodialysis and postulate of mechanisms. Am J Med Sci 309:219–222, 1995 16. Haddad SH, Arabi YM: Critical care management of severe traumatic brain injury in adults. Scand J Trauma Resusc Emerg Med 20:12, 2012 17. Hirsch KG, Spock T, Koenig MA, Geocadin RG: Treatment of elevated intracranial pressure with hyperosmolar therapy in patients with renal failure. Neurocrit Care 17:388–394, 2012 18. Lane PL, Skoretz TG, Doig G, Girotti MJ: Intracranial pressure monitoring and outcomes after traumatic brain injury. Can J Surg 43:442–448, 2000 19. Langlois JA, Rutland-Brown W, Wald MM: The epidemiology and impact of traumatic brain injury: a brief overview. J Head Trauma Rehabil 21:375–378, 2006 20. Marklund N, Hillered L: Animal modelling of traumatic brain injury in preclinical drug development: where do we go from here? Br J Pharmacol 164:1207–1229, 2011 21. Mauritz W, Steltzer H, Bauer P, Dolanski-Aghamanoukjan L, Metnitz P: Monitoring of intracranial pressure in patients with severe traumatic brain injury: an Austrian prospective multicenter study. Intensive Care Med 34:1208–1215, 2008 22. Moore EM, Bellomo R, Nichol A, Harley N, Macisaac C, Cooper DJ: The incidence of acute kidney injury in patients with traumatic brain injury. Ren Fail 32:1060–1065, 2010 23. Padayachy LC, Figaji AA, Bullock MR: Intracranial pressure monitoring for traumatic brain injury in the modern era. Childs Nerv Syst 26:441–452, 2010 24. Pérez-Pérez AJ, Pazos B, Sobrado J, Gonzalez L, Gándara A: Acute renal failure following massive mannitol infusion. Am J Nephrol 22:573–575, 2002 25. Schirmer-Mikalsen K, Vik A, Gisvold SE, Skandsen T, Hynne H, Klepstad P: Severe head injury: control of physiological variables, organ failure and complications in the intensive care unit. Acta Anaesthesiol Scand 51:1194–1201, 2007 26. Shafi S, Diaz-Arrastia R, Madden C, Gentilello L: Intracranial pressure monitoring in brain-injured patients is associated with worsening of survival. J Trauma 64:335–340, 2008 27. Tsai SF, Shu KH: Mannitol-induced acute renal failure. Clin Nephrol 74:70–73, 2010 28. Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M: Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA 308:1566–1572, 2012 Manuscript submitted November 14, 2012. Accepted July 1, 2013. Please include this information when citing this paper: published online August 2, 2013; DOI: 10.3171/2013.7.JNS122131. Address correspondence to: Ping Zheng, M.D., Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Victoria 3050, Australia. email: [email protected]
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