Mannitol Vs Hypertonic Saline

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Mannitol Vs Hypertonic Saline

  1. 1. Downloaded from jnnp.bmj.com on January 28, 2010 - Published by group.bmj.com Effect of mannitol and hypertonic saline on cerebral oxygenation in patients with severe traumatic brain injury and refractory intracranial hypertension M Oddo, J M Levine, S Frangos, et al. J Neurol Neurosurg Psychiatry 2009 80: 916-920 originally published online March 16, 2009 doi: 10.1136/jnnp.2008.156596 Updated information and services can be found at: http://jnnp.bmj.com/content/80/8/916.full.html These include: References This article cites 35 articles, 3 of which can be accessed free at: http://jnnp.bmj.com/content/80/8/916.full.html#ref-list-1 Email alerting Receive free email alerts when new articles cite this article. Sign up in the service box at the top right corner of the online article. Topic collections Articles on similar topics can be found in the following collections Neurological injury (1744 articles) Trauma CNS / PNS (1883 articles) Hypertension (11759 articles) Trauma (12138 articles) Injury (11382 articles) Notes To order reprints of this article go to: http://jnnp.bmj.com/cgi/reprintform To subscribe to Journal of Neurology, Neurosurgery & Psychiatry go to: http://jnnp.bmj.com/subscriptions
  2. 2. Downloaded from jnnp.bmj.com on January 28, 2010 - Published by group.bmj.com Research paper Effect of mannitol and hypertonic saline on cerebral oxygenation in patients with severe traumatic brain injury and refractory intracranial hypertension M Oddo,1 J M Levine,1,2,3 S Frangos,1 E Carrera,4 E Maloney-Wilensky,1 J L Pascual,5 W A Kofke,1,3 S A Mayer,4 P D LeRoux1 1 Department of Neurosurgery, ABSTRACT HTS improves systemic haemodynamics,8 9 cere- University of Pennsylvania Background: The impact of osmotic therapies on brain bral blood flow (CBF)9–11 and may enhance cerebral Medical Center, Philadelphia, oxygen has not been extensively studied in humans. We microcirculation by reducing the adhesion of Pennsylvania, USA; 2 Department of Neurology, examined the effects on brain tissue oxygen tension polymorphonuclear cells12 13 and by stimulating University of Pennsylvania (PbtO2) of mannitol and hypertonic saline (HTS) in patients local release of nitric oxide.14 Medical Center, Philadelphia, with severe traumatic brain injury (TBI) and refractory Although ICP and cerebral perfusion pressure Pennsylvania, USA; intracranial hypertension. (CPP) traditionally are the major targets of TBI 3 Department of Anesthesiology and Critical Care, University of Methods: 12 consecutive patients with severe TBI who treatment, the interstitial partial pressure of Pennsylvania Medical Center, underwent intracranial pressure (ICP) and PbtO2 mon- oxygen in brain tissue (PbtO2) is emerging as an Philadelphia, Pennsylvania, USA; itoring were studied. Patients were treated with mannitol additional complementary therapeutic target. 4 Department of Neurology, (25%, 0.75 g/kg) for episodes of elevated ICP (.20 mm Specialised sensors placed directly into brain Critical Care Division, Columbia University Medical Center, New Hg) or HTS (7.5%, 250 ml) if ICP was not controlled with parenchyma allow for continuous bedside assess- York, New York, USA; mannitol. PbtO2, ICP, mean arterial pressure, cerebral ment of PbtO2 and for the quantification of 5 Department of Surgery, perfusion pressure (CPP), central venous pressure and secondary hypoxic events that occur after the University of Pennsylvania cardiac output were monitored continuously. initial brain insult.15 Observational clinical studies Medical Center, Philadelphia, demonstrate a relationship between reduced PbtO2 Pennsylvania, USA Results: 42 episodes of intracranial hypertension, treated with mannitol (n = 28 boluses) or HTS (n = 14 boluses), and poor outcome16 17 and suggest that PbtO2 Correspondence to: were analysed. HTS treatment was associated with an targeted therapy may improve clinical outcomes.18 P D LeRoux, Department of increase in PbtO2 (from baseline 28.3 (13.8) mm Hg to It is therefore important to understand how Neurosurgery, Clinical Research various treatments options impact on PbtO2. Division, University of 34.9 (18.2) mm Hg at 30 min, 37.0 (17.6) mm Hg at Pennsylvania Medical Center, 60 min and 41.4 (17.7) mm Hg at 120 min; all p,0.01) There has been limited study on the effect of Philadelphia, Pennsylvania, USA; while mannitol did not affect PbtO2 (baseline 30.4 (11.4) different osmotic therapies on PbtO2 in brain Peter.LeRoux@uphs.upenn.edu injured patients and the results vary. For example, vs 28.7 (13.5) vs 28.4 (10.6) vs 27.5 (9.9) mm Hg; all p.0.1). Compared with mannitol, HTS was associated in patients with TBI with elevated ICP, mannitol This work was performed at the Neurointensive Care Unit, with lower ICP and higher CPP and cardiac output. does not consistently improve PbtO2.12 19 In con- University of Pennsylvania Conclusions: In patients with severe TBI and elevated trast, in patients with intracranial hypertension Medical Center, Philadelphia, ICP refractory to previous mannitol treatment, 7.5% after subarachnoid haemorrhage, HTS may Pennsylvania, USA. increase CBF20 21 and PbtO2.22 However, little is hypertonic saline administered as second tier therapy is Received 24 June 2008 associated with a significant increase in brain oxygena- known about the impact of HTS on PbtO2 in Revised 17 February 2009 tion, and improved cerebral and systemic haemody- patients with severe TBI and intracranial hyper- Accepted 26 February 2009 tension, and in particular those with elevated ICP Published Online First namics. refractory to mannitol. In this study, we examined 16 March 2009 how mannitol and HTS, used to treat recurrent Intracranial hypertension is common after severe episodes of elevated ICP, influenced brain oxygen traumatic brain injury (TBI) and may adversely in patients with severe TBI. affect outcome.1 2 Control of intracranial pressure (ICP) is therefore a mainstay of treatment after severe TBI. Osmotherapy is frequently used to CLINICAL MATERIAL AND METHODS control ICP. Although no firm recommendations Patient population exist, mannitol is more frequently used as a first Consecutive patients with severe TBI admitted to tier therapy for elevated ICP while hypertonic the Hospital of the University of Pennsylvania, a saline (HTS) is given as a secondline therapy in level I trauma centre, and who underwent PbtO2 patients unresponsive to mannitol therapy.3 The monitoring in the neurointensive care unit were comparative effects of these two agents on cerebral retrospectively identified from a prospective obser- physiology, rather than ICP alone, after severe TBI vational database (the Brain Oxygen Monitoring are only beginning to be elucidated. While some Outcome study) over a 2 year period (2005–2006). authors report that mannitol and HTS have a Severe TBI was defined by (1) a history of trauma, similar effect, at least when given in equimolar (2) a post-resuscitation admission Glasgow Coma doses,4 others have demonstrated that HTS may be Scale score (8 and (3) clinical and radiographic more effective than mannitol in reducing elevated exclusion of alternate causes of coma. Patients who ICP in patients with severe TBI.5 6 In addition to its received osmotherapy with both mannitol and potent osmotic effect, HTS has beneficial effects HTS to treat refractory intracranial hypertension on vascular tone,7 and in animal models of TBI, (defined as the occurrence of recurrent episodes of 916 J Neurol Neurosurg Psychiatry 2009;80:916–920. doi:10.1136/jnnp.2008.156596
  3. 3. Downloaded from jnnp.bmj.com on January 28, 2010 - Published by group.bmj.com Research paper Table 1 Patient clinical characteristics Foundation TBI guidelines.3 This included early evacuation of space occupying mass lesions in the operating room. Each Characteristic patient was fully resuscitated according to Advanced Trauma n 12 Life Support guidelines from the American College of Surgeons, Age (years) 36 (16) intubated and mechanically ventilated with the head of the bed Sex (women/men) 3/9 initially elevated ,20–30u. FiO2 and minute ventilation were Injury type (n) adjusted to maintain SaO2 .93%, PaO2 between 90 and Diffuse injury 6 100 mm Hg and PaCO2 between 34 and 38 mm Hg. Volume Subdural haematoma 6 resuscitation was achieved with 0.9% normal saline and Admission Glasgow Coma Scale (median (range)) 3 (3–8) albumin for a target central venous pressure (CVP) of 6– Time from admission to initiation of PbtO2 monitoring (hours) 8 (7) 10 cm H2O. After adequate fluid resuscitation, CPP was kept Total duration of PbtO2 monitoring (days) 8 (3) above 60 mmHg, using vasopressors if required. Vasopressors Hospital length of stay (days) 20 (13) Mortality (n (%)) 4/12 (33) (mainly phenylephrine) were only used to ensure adequate CPP, and patients who received vasopressors for cardio-circulatory Data are expressed as mean (SD) unless otherwise indicated. PbtO2, brain tissue oxygen pressure. failure were excluded from the present study. ICP .20 mm Hg for more than 10 min despite initial medical Management of elevated ICP management) were included in the analysis. Patients who had A standard stair step approach was used to treat intracranial bilateral fixed and dilated pupils at admission were excluded from hypertension. Therapeutic targets were adjusted to maintain the study. Our Institutional Review Board approved the study. ICP ,20 mm Hg and CPP .60 mm Hg. Initial management consisted of head of bed elevation, sedation (lorazepam), Intracranial and systemic monitors analgesia (fentanyl), muscle paralysis (vecuronium) and inter- ICP, brain temperature and PbtO2 were continuously monitored mittent cerebrospinal fluid drainage using an external ventri- using commercially available products (Licox, Integra cular drain. Optimised moderate hyperventilation (PaCO2 30– Neuroscience, Plainsboro, New Jersey, USA). Intracranial 35 mm Hg) was used selectively to control ICP provided PbtO2 monitors were inserted at the bedside in the neurointensive did not decrease during this intervention. care unit through a burr hole into the frontal lobe and secured with a triple lumen bolt. The monitors were placed into white matter that appeared normal on head CT and on the side of Osmotherapy maximal pathology. When there was no asymmetry in brain If ICP remained .20 mm Hg for more than 10 min despite the pathology on CT, the probes were placed in the right frontal initial management, osmotherapy was started, provided that region. If the patient had undergone a craniotomy, the probes serum osmolarity was ,320 mosmol and serum sodium were placed on the same side as the injury if the craniotomy flap ,155 mmol/l. In all 12 patients, mannitol (25%, 0.75 g/kg, permitted. Follow-up head CT scans were performed in all 412 mosmol/dose, infused over 20 min) was administered as patients within 24 h of admission to confirm correct placement firstline treatment of intracranial hypertension. HTS (7.5% of the various monitors (eg, not in a contusion or infarct). Probe solution, 250 ml, 641 mosmol/dose, infused over 30 min) was function and stability was confirmed by an appropriate PbtO2 used as a secondline therapy to control ICP. The decision to increase following an oxygen challenge (inspired O2 fraction infuse HTS was made at the discretion of the treating neuro- (FiO2) 1.0 for 5 min). PbtO2 measurements were corrected for intensivist and based on each patient’s overall therapeutic brain temperature fluctuations. To allow for probe equilibra- intensity. However, according to our management protocol, tion, data from the first 6 h after PbtO2 monitor insertion were HTS could only be used if a patient had already received discarded. mannitol for a previous episode of increased ICP or had a MAP Each patient had an indwelling arterial (radial artery) (90 mm Hg. HTS was contraindicated if CVP was . catheter. Heart rate, blood pressure (through the arterial line) 15 mm Hg, or the patient had chronic hyponatraemia, heart and arterial oxygen saturation (SaO2) were recorded continu- failure or diabetes insipidus. ously in all patients. CPP was calculated from the measured parameters (CPP = MAP–ICP (corrected for ICP and arterial catheter position)). Patients had a pulmonary artery catheter, Data collection and analysis and central venous pressure and cardiac output (thermodilu- All physiological variables (ICP, brain temperature, MAP, CPP, tion) were recorded. As part of routine care, FiO2, SaO2, CVP, SaO2 and PbtO2) were recorded continuously using a respiratory rate and ventilator settings (eg, ventilator mode, bedside monitor (Component Monitoring System M1046- tidal volume, minute ventilation and positive end expiratory 9090C; Hewlett Packard, Andover, Massachusetts, USA). pressure) were recorded in the ICU flowsheet every 15 min. These variables and respiratory rate, FiO2, ventilator settings Arterial blood gas analysis was usually performed at 08:00 and (ie, ventilatory mode, tidal volume, minute ventilation and 20:00 each day while the patient was ventilated and if there was positive end expiratory pressure) and cardiac output were any significant cardiopulmonary change or at the discretion of recorded in the intensive care unit flowsheet every 30 min. the neuro-intensivist. Arterial samples were analysed for Cardiac output was measured with the use of a pulmonary haemoglobin, arterial oxygen (PaO2) and carbon dioxide artery catheter. Serum sodium and osmolarity before and after (PaCO2) tension and pH. treatment were also measured. As the duration of ICP reduction usually is maintained for 60–120 min after bolus administration General patient management of both mannitol23 and HTS,7 24 ICP and other physiological All patients were managed in the neurointensive care unit variables were averaged at 30, 60 and 120 min after each bolus according to a local algorithm based on the Brain Trauma administration. Treatment baseline was defined as the average J Neurol Neurosurg Psychiatry 2009;80:916–920. doi:10.1136/jnnp.2008.156596 917
  4. 4. Downloaded from jnnp.bmj.com on January 28, 2010 - Published by group.bmj.com Research paper Table 2 Physiological variables before and after a mannitol or hypertonic saline bolus for elevated intracranial pressure Hypertonic Variable Mannitol saline p Value ICP (mm Hg) Baseline 29 (8) 27 (8) 0.40 30 min 21 (8) 17 (7) 0.15 60 min 23 (12) 15 (6) ,0.001 120 min 24 (9) 15 (5) ,0.001 MAP (mm Hg) Baseline 87 (15) 90 (12) 0.52 30 min 85 (23) 93 (16) 0.18 60 min 84 (25) 89 (14) 0.26 120 min 88 (13) 90 (14) 0.27 CPP (mm Hg) Figure 1 Line graph illustrating mean (SD) brain tissue oxygen pressure Baseline 60 (17) 63 (15) 0.56 (PbtO2) at baseline (time 0) and at 30, 60 and 120 min after hypertonic 30 min 71 (16) 78 (18) 0.32 saline and mannitol bolus administration. *p,0.05, **p,0.01 for 60 min 67 (20) 76 (16) 0.05 comparisons between the two treatments. 120 min 65 (19) 76 (17) 0.02 CVP (cm H2O) Baseline 7 (3) 7 (4) 0.86 of all values obtained during the 120 min before a bolus was 30 min 6 (3) 8 (5) 0.21 administered. At each time point, means for each variable were 60 min 6 (2) 7 (4) 0.33 measured for each bolus of mannitol and HTS. 120 min 6 (3) 7 (4) 0.79 Cardiac output (l/min) Baseline 6.7 (1.5) 6.4 (1.8) 0.76 Statistical analysis 30 min 6.3 (0.9) 7.5 (1.4) 0.003 As patients received a variable number of boluses of mannitol 60 min 6.6 (1.2) 7.8 (1.7) 0.007 and HTS, one grand average of treatment was calculated for 120 min 6.1 (1.0) 7.5 (1.4) 0.002 each individual patient. For each variable, differences between Data are expressed as mean (SD). mannitol and HTS treatments at all time points were then CPP, cerebral perfusion pressure; CVP, central venous pressure; ICP, intracranial analysed with ANOVA for repeated measures. The JMP starter pressure; MAP, mean arterial pressure. software (SAS Institute Inc, Cary, North Carolina, USA) was used for data analysis. For all analyses a p value ,0.05 was Effect of osmotherapy on other cerebral and systemic variables considered to be statistically significant. Mean pretreatment values for ICP, MAP, CPP, CVP and cardiac output were similar for mannitol and HTS treatments. Baseline and post-osmotherapy PaO2/FiO2 ratio, respiratory rate and RESULTS ventilator settings (including FiO2) were similar in the two Patient characteristics treatment groups. Arterial blood gas analysis was not performed Twelve consecutive patients with severe TBI (nine men and during osmotherapy: however, SaO2, FiO2 and ventilator three women, mean age 36 (16) years, median admission GCS settings were stable during all interventions. score 3 (range 3–8)) were studied. Baseline clinical and Mannitol and HTS were both associated with a significant demographic characteristics are shown in table 1. One-third of ICP reduction. However, at 60 and 120 min, HTS treatment patients died. was associated with lower ICP and higher CPP than mannitol (table 2). The decrease in ICP and PbtO2 increase did not Effect of osmotherapy on PbtO2 demonstrate a significant correlation. In addition, HTS bolus A total of 42 episodes of intracranial hypertension treated with administration was associated with an increase in cardiac mannitol (n = 28 boluses) or HTS (n = 14 boluses) were output that was more significant than mannitol at all time analysed. The median number of boluses analysed per patient points analysed. MAP and CVP did not differ significantly was 2 (range 1–4) for mannitol and 1 (1–2) for HTS. The between treatment groups at each time point. median time interval between mannitol and HTS administra- Baseline serum sodium and osmolarity were similar before tion was 8.6 (interquartile range 4.3–16.7) h. Effect of HTS and mannitol or HTS administration. At the end of the study mannitol on brain oxygen is shown in fig 1. After HTS, PbtO2 period, HTS treatment was associated with higher serum increased from a mean pretreatment value of 28.3 sodium (141 (6) before vs 149 (6) mmol/l after; p,0.01). (13.8) mm Hg to 34.9 (18.2) mm Hg at 30 min, 37.0 Osmolarity did not differ significantly between the two (17.6) mm Hg at 60 min and 41.4 (17.7) mm Hg at 120 min treatments. After HTS treatment, hypernatraemia (serum (all p,0.01). In contrast, mannitol was associated with a non- sodium .155 mmol/l) was observed in three patients. No other significant decrease in PbtO2 from the pretreatment value (30.4 complications (eg, pulmonary oedema, renal failure) associated (11.4) mm Hg) at 30 min (28.7 (13.5) mm Hg), 60 min (28.4 with osmotherapy were observed. (10.6) mm Hg) and 120 min (27.5 (9.9) mm Hg). Compared with mannitol, HTS treatment was associated with higher DISCUSSION levels of PbtO2 at all times analysed. In particular, brain tissue We analysed 12 consecutive patients who received osmotherapy oxygen after HTS was significantly greater at 60 and 120 min with both mannitol (28 treatments) and HTS (14 treatments) than after mannitol (see fig 1). for refractory intracranial hypertension after severe TBI. We 918 J Neurol Neurosurg Psychiatry 2009;80:916–920. doi:10.1136/jnnp.2008.156596
  5. 5. Downloaded from jnnp.bmj.com on January 28, 2010 - Published by group.bmj.com Research paper observed that: (1) HTS was associated with a significant mannitol.30 34–36 Therefore, whether HTS may be superior to improvement in PbtO2; (2) HTS treatment was also associated mannitol for control of intracranial hypertension is still a with both an effective reduction of ICP and a significant controversial issue. As we did not compare mannitol and HTS improvement in cardiac output; and (3) compared with in a parallel or randomised fashion, and the treatments were not mannitol, HTS had a more favourable effect on PbtO2, ICP, administered in equimolar doses, our study cannot provide a CPP and cardiac output. definitive answer to this question. Rather, our results suggest that HTS may have a more favourable effect on PbtO2 and cerebral and systemic haemodynamics than mannitol when Hypertonic saline and PbtO2 administered as a second tier therapy for elevated ICP refractory The positive impact of HTS on PbtO2 was observed within to mannitol in patients with severe TBI. Our data are also 30 min and was statistically significant at 60 and 120 min. consistent with previous observations in patients with severe Hypertonic saline solutions may improve PbtO2 by increasing TBI that suggest that mannitol has a limited effect on PbtO212 19 CBF, through multiple complementary mechanisms involving but this warrants further clinical investigation. the cerebral macro- and/or microcirculation. Firstly, CBF may increase as ICP decreases, thereby increasing CPP. Consistent with this, the increase in PbtO2 was significant at 60 and Study limitations 120 min when the beneficial effect of HTS on ICP and CPP Our study has several potential limitations. First, HTS was levels were most notable. In addition, as the PbtO2 probe is in administered after mannitol in all patients. Therefore, our data white matter that appears ‘‘normal’’ on CT it is possible that only suggest that HTS improves PbtO2 and systemic haemo- autoregulation is altered. However, we did not measure CBF or dynamics when administered as a secondline osmotherapy in autoregulation and this will need future study. Another patients with severe TBI and recurrent episodes of intracranial possibility is that HTS improved PbtO2 through a relative hypertension. In this context (ie, after mannitol), HTS had augmentation of cardiac output which, in turn, may have more favourable effects on brain oxygen and ICP than the caused an increase in oxygen delivery and CBF. The effect of previous mannitol treatment. Second, the observed physiologi- HTS on cardiac output has previously been documented in non- cal changes after HTS administration may represent the neurological25 and neurological critically ill patients.26 For cumulative effect of mannitol and HTS rather than HTS alone. reasons that are poorly understood, intracranial hypertension However, pretreatment serum osmolarity and serum sodium is associated with reduced systolic function.27 28 It is therefore were similar in the mannitol and HTS groups, and the time plausible after severe TBI that HTS augments cardiac output interval between each treatment was relatively long (median not only by directly increasing cardiac preload but also 8.6 h), suggesting that a cumulative effect is less likely. Third, indirectly by lowering ICP. This hypothesis warrants further mannitol and hypertonic saline were not given at equimolar study. A final possibility is that HTS improves PbtO2 by doses, and we cannot exclude the fact that the higher improving flow in the cerebral microcirculation, by reducing osmolarity of HTS may, at least in part, explain some of the serum viscosity, by improving endothelial function12 29 and/or observed benefits on brain oxygen. Additional studies are through anti-inflammatory and antiapoptotic properties,30 all of needed to analyse whether mannitol and HTS may have which improve CBF and brain oxygen delivery.11 20 21 31 Our comparable beneficial effects when administered in equimolar findings are consistent with others in patients with acute brain doses.4 Fourth, data were obtained from only 12 patients and injury22 and suggest that hypertonic saline solutions may have therefore the results should be considered preliminary. beneficial effects on brain oxygenation in patients with severe However, a total of 42 episodes of elevated ICP were analysed TBI and intracranial hypertension. and the effects of 28 boluses of mannitol and 14 boluses of HTS were studied. Fifth, the retrospective nature of the analysis may have introduced bias. However, patients were treated in a Hypertonic saline and ICP standardised fashion and the data were collected prospectively. Although the potential beneficial effects of HTS on brain Sixth, patients were examined at different time points after the pathophysiology were first observed in 1919, mannitol is initial injury, and variations in CBF and PbtO2 may therefore frequently administered as firstline osmotherapy for intracranial have occurred over time. Each patient however served as his/her hypertension. However, in recent years, there has been own internal control, and this may have partially reduced the resurgent interest in the use of HTS. Recent small clinical series potential influence of time. Seventh, given that MAP was suggest that HTS is an effective agent to treat cerebral oedema comparable between mannitol and HTS therapy, a possible and elevated ICP.5 6 Our results are consistent with these additional explanation for the observed HTS associated increase findings. in cardiac output may be a decrease in peripheral resistance or, alternatively, a difference in vasopressor dose between mannitol Comparison between HTS and mannitol and HTS. These data were not available in our dataset, and we Few clinical studies have compared HTS with mannitol and are unable to more precisely address these issues. However, we there is currently insufficient data to support the use of one over wish to point out that vasopressors were only used at low dose the other. In experimental intracerebral haemorrhage, Qureshi to maintain adequate CPP and none of the patients included in et al found that none of these treatments had a significant the study had low cardiac output (cardiac output ranged from influence on CBF or cerebral metabolism.23 Recent clinical ,6 to 8 l/min) or circulatory shock requiring vasopressors. studies in TBI patients showed that mannitol and HTS had Finally, we examined the effect of only a single dose of 7.5% similar effects on elevated ICP and brain oxygen, at least when HTS and so could not observe any dose dependent effect to given in parallel and in equimolar doses.4 In contrast with these confirm our findings. clinical observations, other studies found HTS to be superior to Despite these study limitations, our findings suggest that mannitol in reducing ICP in patients with severe TBI.5 6 32 33 hypertonic saline solutions may significantly improve brain Furthermore, in animal models of intracranial hypertension, oxygen and systemic haemodynamics in patients with intra- HTS also appears to provide better neuroprotection than cranial hypertension after severe TBI. Randomised clinical J Neurol Neurosurg Psychiatry 2009;80:916–920. doi:10.1136/jnnp.2008.156596 919
  6. 6. Downloaded from jnnp.bmj.com on January 28, 2010 - Published by group.bmj.com Research paper studies are needed to confirm our findings and to examine 12. Hartl R, Bardt TF, Kiening KL, et al. Mannitol decreases ICP but does not improve brain-tissue pO2 in severely head-injured patients with intracranial hypertension. Acta whether hypertonic saline may be superior to mannitol for the Neurochir Suppl 1997;70:40–2. treatment of elevated ICP when both treatments are given in 13. Chen Y, Hashiguchi N, Yip L, et al. Hypertonic saline enhances neutrophil elastase equimolar doses and weight adapted. release through activation of P2 and A3 receptors. Am J Physiol Cell Physiol 2006;290:C1051–9. 14. Steenbergen JM, Bohlen HG. Sodium hyperosmolarity of intestinal lymph causes CONCLUSIONS arteriolar vasodilation in part mediated by EDRF. Am J Physiol 1993;265:H323–8. Our data suggest that osmotherapy with 7.5% hypertonic 15. Nortje J, Gupta AK. The role of tissue oxygen monitoring in patients with acute brain injury. Br J Anaesth 2006;97:95–106. saline, when given as a second tier therapy for elevated ICP, is 16. Valadka AB, Gopinath SP, Contant CF, et al. Relationship of brain tissue PO2 to associated with a significant improvement in brain oxygen, CPP outcome after severe head injury. Crit Care Med 1998;26:1576–81. and cardiac output in patients with severe TBI and intracranial 17. van den Brink WA, van Santbrink H, Steyerberg EW, et al. Brain oxygen tension in hypertension refractory to previous mannitol administration. In severe head injury. Neurosurgery 2000;46:868–76. 18. Stiefel MF, Spiotta A, Gracias VH, et al. Reduced mortality rate in patients with this context, hypertonic saline also appears to have a more severe traumatic brain injury treated with brain tissue oxygen monitoring. J Neurosurg beneficial effect on cerebral and systemic haemodynamics than 2005;103:805–11. mannitol. 19. Sakowitz OW, Stover JF, Sarrafzadeh AS, et al. Effects of mannitol bolus administration on intracranial pressure, cerebral extracellular metabolites, and tissue oxygenation in severely head-injured patients. J Trauma 2007;62:292–8. Acknowledgements: The authors thank Professor Francois Feihl for the careful ¸ 20. Tseng MY, Al-Rawi PG, Pickard JD, et al. Effect of hypertonic saline on cerebral review of statistical analysis. blood flow in poor-grade patients with subarachnoid hemorrhage. Stroke Funding: Supported by Research Grants from the SICPA Foundation, Switzerland (to 2003;34:1389–96. MO and EC), the Swiss National Science Foundation, Grant PBLAB-119620 (EC), the 21. Tseng MY, Al-Rawi PG, Czosnyka M, et al. Enhancement of cerebral blood flow using Integra Foundation (PDL) and the Mary Elisabeth Groff Surgical and Medical Research systemic hypertonic saline therapy improves outcome in patients with poor-grade Trust (PDL). spontaneous subarachnoid hemorrhage. J Neurosurg 2007;107:274–82. 22. Al-Rawi PG, Zygun D, Tseng MY, et al. Cerebral blood flow augmentation in patients Competing interests: None. with severe subarachnoid haemorrhage. Acta Neurochir Suppl 2005;95:123–7. Ethics approval: The study was approved by the Institutional Review Board, Hospital 23. Qureshi AI, Wilson DA, Traystman RJ. Treatment of elevated intracranial pressure in of the University of Pennsylvania, Philadelphia, USA. experimental intracerebral hemorrhage: comparison between mannitol and hypertonic saline. Neurosurgery 1999;44:1055–63. 24. Tyagi R, Donaldson K, Loftus CM, et al. Hypertonic saline: a clinical review. REFERENCES Neurosurg Rev 2007;30:277–89. 1. Marshall LF, Smith RW, Shapiro HM. The outcome with aggressive treatment in 25. de Felippe J Jr, Timoner J, Velasco IT, et al. Treatment of refractory hypovolaemic severe head injuries. Part I: the significance of intracranial pressure monitoring. shock by 7.5% sodium chloride injections. 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