Hypertonic saline in critical care: a review of the literature and guidelines for use in hypotensive states and raised intracranial pressure*

Transcription

1 doi: /j x REVIEW ARTICLE Hypertonic saline in critical care: a review of the literature and guidelines for use in hypotensive states and raised intracranial pressure* G. F. Strandvik Specialist Registrar in Anaesthesia and Intensive Care Medicine, South Eastern School of Anaesthesia, London, UK Summary Hypertonic saline has been in clinical use for many decades. Its osmotic and volumeexpanding properties make it theoretically useful for a number of indications in critical care. This literature review evaluates the use of hypertonic saline in critical care. The putative mechanism of action is presented, followed by a narrative review of its clinical usefulness in critical care. The review was conducted using the Scottish Intercollegiate Guidelines Network method for the review of cohort studies, randomised-controlled trials and meta-analyses. The review focuses specifically on blood pressure restoration and outcome benefit in both haemorrhagic and non-haemorrhagic shock, and the management of raised intracranial pressure. Issues of clinical improvement and outcome benefit are addressed. Hypertonic saline solutions are effective for blood pressure restoration in haemorrhagic, but not other, types of shock. There is no survival benefit with the use of hypertonic saline solutions in shock. Hypertonic saline solutions are effective at reducing intracranial pressure in conditions causing acute intracranial hypertension. There is no survival or outcome benefit with the use of hypertonic saline solutions for raised intracranial pressure. Recommendations for clinical use and future directions of clinical research are presented.... Correspondence to: Dr Gustav Strandvik gstrandvik@doctors.net.uk *Prepared in part as a dissertation for the British Diploma of Intensive Care Medicine, June 2008 Accepted: 1 April 2009 Hypertonic saline solutions have been in experimental and clinical use since the early 1900s [1]. Weed and McKibben published work on brain volume reduction with hypertonic saline as early as 1919 [2]. Experimental work on compartmental fluid shifts in animals [3] confirmed hypertonic saline produced haemodynamic changes and its use in many different clinical settings has followed. In 1980, de Fillipe reported almost miraculous recovery from near-fatal haemorrhagic shock in 11 patients [4]. This was thought to be due to osmotic fluid shifts, and led to a resurgence of interest in the clinical use of hypertonic saline. Subsequent studies have demonstrated that the mechanism of action of hypertonic solutions is due to more than just changes in serum osmolality [5, 6]. Despite further trials, clinical use of hypertonic saline solutions remains inconsistent and few clinical guidelines exist. Various concentrations of hypertonic saline and combinations with colloids have been used in clinical studies. Concerns persist about the safety of hypertonic solutions in critically ill patients as acute hyperosmolar states have been reported to cause harm. Currently the primary clinical areas of use are the management of intracranial hypertension and shock. The purpose of this review is to focus on clinically relevant aspects of the use of intravenous hypertonic saline. Specifically, three areas will be addressed: 1 Does intravenous hypertonic saline increase blood pressure and survival in hypotensive states? 2 Does intravenous hypertonic saline reduce intracranial pressure and improve outcome for patients with intracranial hypertension? 990 Journal compilation Ó 2009 The Association of Anaesthetists of Great Britain and Ireland

2 G. F. Strandvik Æ Hypertonic saline in critical care 3 What is the evidence for adverse effects of hypertonic saline? Methods Medline searches were performed using the terms (hypertonic) AND (saline OR sodium) AND (head injury OR brain injury OR intracranial pressure) AND (sepsis OR shock OR hypotension). Searches were limited to meta-analyses, randomised control trials or clinical trials in humans. Articles related to non-intravenous use (such as in cystic fibrosis) were not considered. All articles were assessed, but only those with a full English-language translation were included in the review. Adult and paediatric studies were included, based on the premise that a positive effect in a paediatric study (in terms of efficacy or lack of harm) would translate to an adult population. Articles appropriate to the questions under consideration were assessed using methodology made available by the Scottish Intercollegiate Guidelines Network (SIGN) [7]. The SIGN methodology includes checklists for use in assessing the methodological quality of a particular paper. Evidence was then assigned a level according to quality. The SIGN levels of evidence for randomised controlled trials range from 1++ for the strongest randomised control trial with the least bias, through to level 4 for evidence based on expert opinion. Levels of evidence were then used to assign strength to a recommendation or guideline, again based on SIGN methodology. The SIGN grades of recommendation range from A through D, with A being the strongest level of recommendation possible (see Table 1). Readers are referred to the SIGN website for further information [8]. Meta-analyses were assessed even if they included original papers reviewed elswewhere in this article. The methodological quality of both original articles and meta-analyses were used to synthesise summary recommendations. Background and mechanisms of potential therapeutic effects Hypertonic saline is used in various concentrations and with varying osmolar loads [9, 10]. The varying concentrations reflect concerns about safety, in particular, that concentrations above 10% may open tight junctions in the blood brain barrier [11]. Furthermore, concerns about the short duration of effect mean that, despite ongoing concerns about the safe use of colloids, hypertonic saline is often used in solution in combination with colloids such as dextran [12]. The sodium and chloride concentration of normal saline is not isosmotic, but slightly hyperosmolar. The development of this balanced salt solution reflects the anticipated physiological requirement in terms of concentration gradient and charge, to maintain iso-osmolarity. The term hypertonic saline is reserved for solutions containing higher molar concentrations of sodium and chloride. The range of concentrations used clinically varies over 10-fold from 1.8% to 30% saline. As mentioned above, dextran may extend intravascular activity. In theory, the combination of hypersomolar and hyperoncotic solutions will also result in a synergistic, increased effect on intravascular fluid shift. Although in vitro experiments confirm this effect, the in vivo effects are not clinically appreciable. Table 2 summarises the osmolarity and sodium concentrations of the different hypertonic saline solutions used in clinical trials. Table 1 Scottish Intercollegiate Guidelines Network grades of evidence [8]. Grade A Grade B Grade C Grade D At least one meta-analysis, systematic review, or RCT rated as 1++, and directly applicable to the target population; or a systematic review of RCTs or a body of evidence consisting principally of studies rated as 1+, directly applicable to the target population, and demonstrating overall consistency of results A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 1++ or 1+ A body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 2++ Evidence level 3 or 4; or extrapolated evidence from studies rated as 2+ Table 2 Physico-chemical properties of various hypertonic solutions used in clinical practice. Solution Osmolarity (mosmol.l )1 ) 0.9% normal saline Ringer s lactate % saline % saline % saline 6% Haes ( ) % saline % saline 6% dextran % saline % saline % saline Sodium concentration (mmol.l )1 ) Journal compilation Ó 2009 The Association of Anaesthetists of Great Britain and Ireland 991

3 G. F. Strandvik Æ Hypertonic saline in critical care Anaesthesia, 2009, 64, pages Osmotic effect The mechanism of action of hypertonic saline is predominantly through the marked osmotic shift of fluid from the intracellular to the interstitial and intravascular space [13]. The reflection co-efficient of the cell membrane for sodium is 1 (as opposed to 0.9 for mannitol) [14]. This is probably maintained by the persistent action of sodium potassium ATPase [15]. The reflection coefficient of the endothelial membrane is only 0.1, however, which means that most of the fluid mobilisation following administration of hypertonic saline is from the intracellular, and not the interstitial, space. This effect is immediate and it has been shown that an infusion of 7.5% hypertonic saline dextran can increase the intravascular volume by as much as four times the infused volume within minutes of infusion [12]. Osmotic equilibrium is reached within about 4 h of a bolus dose, and the net effect (for 7.5% saline dextran) is to increase the plasma volume by 750 ml for every litre administered [16]. This is a substantial improvement upon the 300 ml of plasma volume expansion achieved with 1 l of crystalloid administration. Although the addition of the polysaccharide colloid dextran increases the oncotic pressure, the volume effect is small. The main benefit appears to be an increase in duration of effect [14, 17]. The clinical effect may be prolonged by 2 4 h. A disrupted blood brain barrier creates the potential for leakage of osmotic substances into the brain parenchyma in brain injury, creating a reverse osmotic effect. This may lead to brain tissue oedema, and it has been shown that reduction in intracranial pressure with hypertonic saline occurs mostly in the uninjured portions [18]. Microcirculatory and vascular effects Shock and ischaemic states result in endothelial cell membrane ion exchange dysfunction and ATP loss. Endothelial cell volume increases as a result of water accumulation [13]. An important effect of hypertonic saline induced osmotic fluid shift is the normalisation of endothelial cell volume. This increases capillary diameter and reduces resistance to flow. Furthermore, plasma viscosity is reduced as a result of the increased plasma water content [17, 19]. Hypertonicity has a direct relaxant effect on vascular smooth muscle with resultant arteriolar vasodilatation. The precise mechanism of this effect is unclear [14]. In concert, these physiological effects result in increased capillary blood flow. An improvement in regional blood flow with hypertonic saline has been demonstrated in virtually all areas of the microcirculation [14, 20, 21]. This improved regional blood flow could, potentially, be very useful for patients following subarachnoid haemorrhage, as it may serve to counteract the common problem of cerebral vasospasm [22]. The hyperosmolar state produced by hypertonic solutions may have an independent effect on the barorecepter-controlled sympathetic outflow [23]. A further postulated mechanism of action in the brain involves the concept of reflex cerebral vessel vasoconstriction [24]. The hypertonic saline induced increase in intravascular volume is thought to lead to an autoregulatory reduction in intracerebral blood volume (assuming autoregulation remains intact). Cardiac effects Administration of hypertonic saline results in increased cardiac output. The volume-expanding effect causes increased preload, and the vascular effects described above decrease afterload (reductions in pulmonary and systemic vascular resistance). The latter effect may transiently induce hypotension following bolus doses of hypertonic saline [17, 25]. Myocardial performance may be directly improved through a reduction in myocyte oedema, or by increased myocardial uptake of calcium with restoration of transmembrane potential [5, 17]. Immune-modulator effects Animal studies have demonstrated a survival benefit beyond the transient osmotic effects of hypertonic saline. Basic science studies have confirmed that hypertonic saline has marked effects on the immune system [14]. Neutrophil activation and migration is a key element of the inflammatory response to sepsis or ischaemia [17]. A recent study in human haemorrhagic shock confirmed that hypertonic saline blunted neutrophil activation and altered the cytokine production profile [6]. TNF alpha production was reduced, while anti-inflammatory IL-ra and IL-10 were increased, thus altering the balance between proinflammatory and anti-inflammatory cytokines [5]. Furthermore, there is evidence from early animal and clinical studies, that the neutrophil blunting effect may reduce the incidence of acute lung injury following major haemorrhage [26]. Interestingly, this effect may be specific to lung polymorphonuclear activation, keeping the immune response at other sites intact [27]. Recent animal work suggests that hypertonic saline may reduce the rate of intestinal apoptosis in cases of haemorrhagic shock [28]. This has significant implications for the prevention of ischaemia-induced bowel perforation and sepsis and haemorrhage. It remains to be seen whether these effects will translate into survival benefit in patients with marked inflammatory responses. 992 Journal compilation Ó 2009 The Association of Anaesthetists of Great Britain and Ireland

4 G. F. Strandvik Æ Hypertonic saline in critical care Other effects Recent evidence suggests that particular fluids may be more prone to cause leaky vascular endothelium by virtue of their physico-chemical interaction with the glycolcalyx. It has been shown that albumin does not disrupt the endothelial glyocalyx in human cardiac tissue due to a direct interaction between albumin and gycocalyx [29]. A study in severely burnt patients showed that hypertonic saline reduced the incidence of abdominal compartment syndrome [30]. Although there was less total fluid infused, it is postulated that a reduction in capillary leak may have been partly responsible for the reduced bowel wall and intra-abdominal fluid accumulation. Lastly, in terms of intracranial pressure control, rapid restoration of normal membrane potential in the injured brain with hypertonic saline, may positively affect ICP [31]. In summary, hypertonic saline has osmotic, direct vasodilator and cardiac actions accounting for its clinical effects. Furthermore, there is strong evidence for an immune-modulating effect, as well as a possible direct effect on the endothelial glycocalyx. Hypertonic saline for blood pressure restoration and outcome improvement in shock states There has been interest in hypertonic saline as resuscitative fluid in hypotension since the First World War [32]. Interest resurged in the 1980s with work illustrating that haemorrhaging dogs, and later a series of humans, could be successfully resuscitated with 7.5% hypertonic saline [4]. Clinical work has subsequently focused mainly on the concept of small volume resuscitation for traumatic haemorrhagic shock, but there has also been work in other forms of shock [33]. Table 3 summarises the clinical trials in humans directed at the question of haemodynamic improvement or survival benefit with hypertonic saline in shock states. Unless otherwise specified the bolus doses employed in most studies was 250 ml. Blood pressure restoration in shock Trauma Rapid restoration of circulating volume in shock states has been shown to improve survival [34]. Promptly improving oxygen delivery may prevent deterioration into multi-organ dysfunction syndrome. Current best evidence does not support the use of one particular fluid regimen over another in terms of survival benefit [35]. However, these studies have not addressed the question of hypertonic saline in any depth. Furthermore, there may be some scenarios where small volume resuscitation is beneficial. Specifically, haemodilution of a bleeding patient s circulation with excess amounts of isotonic fluids may exacerbate the problem. The bloody vicious cycle of hypothermia, acidosis and coagulopathy may result in an irredeemable situation [33]. Bickell published a seminal article in 1994 that supported the concept of limited resuscitation for bleeding victims of penetrating trauma [36]. Despite reports of initial hypotension with the rapid infusion of hypertonic saline solutions, the evidence shows that, overall, they may be of benefit in shock states [37]. Of the eleven trials focussing on trauma, single boluses of hypertonic saline were shown to increase blood pressure in six of these [38 43]. However, the methodological quality was considered poor in three of those studies [38, 40, 43]. Furthermore, the blood pressure response was only sustained beyond the first hour of resuscitation in one of the studies [43]. None of the trauma studies considered the effects of continuous hypertonic saline infusion. The majority of trauma studies have evaluated bolus doses of 7.5% hypertonic saline in conjunction with dextran compared with standard isotonic solutions. One early study by McNamara considered 3% hypertonic saline, but this was a cohort study with high degree of bias [38]. Three studies compared 7.5% hypertonic saline with 7.5% hypertonic saline dextran [41, 42, 44]. Meta-analyses of these studies inevitably replicate the shortcomings of the original papers reviewed here. Of the four meta-analyses of hypertonic saline administration in shock, only one comments on blood pressure management [45]. This confirmed that a bolus dose of 7.5% hypertonic saline dextran has a beneficial effect on the initial low blood pressure in bleeding patients. The differences in ranges reported, non-standardisation of adjunctive colloid, and lack of knowledge about techniques used to measure blood pressure, make it impossible to make any further analysis of the blood pressure effect of hypertonic saline in trauma victims. Gastro-intestinal haemorrhage The only study to report a sustained blood pressure effect with 7.5% hypertonic saline dextran in patients with gastro-intestinal bleeding was a cohort study with a very high risk of bias [46]. A second study focusing mainly on patients with haemorrhagic shock from gastro-intestinal bleeding, did not show a benefit with hypertonic saline [47]. Burn victims Two papers reported the use of 2% hypertonic saline infusion in burn victims [48, 49]. There was no discernible blood pressure difference, but the amount of resuscitation fluid required in one study was markedly reduced. Journal compilation Ó 2009 The Association of Anaesthetists of Great Britain and Ireland 993

5 G. F. Strandvik Æ Hypertonic saline in critical care Anaesthesia, 2009, 64, pages Table 3 Clinical trials of hypertonic saline in shock states. RCT, randomised controlled trial; HS, hypertonic saline; HSD, hypertonic saline dextran, NS, normal saline; RL, Ringer s lactate; HES, hydroxyethyl starch, NaHCO 3, sodium bicarbonate. Study Type and quality Clinical scenario (patient numbers in parentheses) Interventions Outcome measures McNamara [38] Cohort (2)) Trauma (60) 3% HS vs 50% glucose vs Blood pressure** mannitol vs NS Holcroft [96] RCT (1++) Trauma (32) 7.5% HSD vs RL Mortality, fluid balance, blood pressure Maningas [93] Cohort (2)) Trauma (pre-hospital) (48) 7.5% HSD vs Plasmalyte B Blood pressure pilot study Mattox [63] RCT (1+) Trauma (pre-hospital) (422) 7.5% HSD vs NS Mortality, fluid balance, blood pressure Vassar [39] RCT(1++) Trauma (pre-hospital) (166) 7.5% HSD vs RL Mortality, fluid balance, blood pressure** Younes [40] RCT (1)) Trauma (105) 7.5% HS vs HSD vs NS Mortality, fluid balance, blood pressure** Vassar [41] RCT (1+) Trauma (258) 7.5% HS vs 7.5% HSD vs NS Mortality, fluid balance, blood pressure Vassar [44] RCT (1+) Trauma (pre-hospital) (194) 7.5% HS vs 7.5% HSD vs Mortality, blood pressure** 7.5% HSD (12%) vs RL Younes [42] RCT (1+) Trauma (212) 7.5% HSD vs NS Mortality, fluid balance, blood pressure** Alpar [43] RCT (1)) Trauma (180) 7.5% HSD vs RL Mortality, fluid balance, blood pressure** Bulger [65] RCT(1)) Trauma (209) 7.5% HSD vs RL Mortality, ARDS-free survival Wade [60] Meta-analysis Trauma (604) 7.5% HSD vs RL Mortality Perel [62] Meta-analysis Trauma (1283) 7.5% HSD vs NS Mortality Wade [45] Meta-analysis Trauma (penetrating) (230) 7.5% HSD vs NS Mortality, blood pressure** Bunn [61] Meta-analysis Trauma, burns and general HS vs NS or RL Mortality, neurological outcome surgery (including head injury) (956) Ghafari [47] RCT (1)) Gastro-intestinal bleed HS vs RL Blood pressure, PaO 2 and trauma (60) Chavez- Cohort (2)) Gastro-intestinal bleed (49) 7.5% HSD vs RL Mortality, fluid balance, blood pressure** Negrete [46] Gunn [49] Cohort (2)) Burn shock (102) 1.8% HS* Fluid balance, blood pressure Bortolani [48] RCT (1)) Burn shock (40) 2% HS* vs RL Mortality, fluid balance Oliveira [53] RCT (1)) Cardiac surgery (20) 7.5% HSD vs RL Fluid balance, blood pressure, cardiac output Rocha-E-Silva [54] Cohort (2)) Cardiac surgery 7.5% HSD vs NS Fluid balance (children) (25) Schroth [52] RCT Cardiac surgery (children) (50) 7.2% HS with 6% HES vs NS Fluid balance, blood pressure**, cardiac output Veroli [57] Cohort (2)) Neurogenic shock (30) 5% HS vs RL Fluid balance, bood pressure Wang [55] RCT (1)) Neurogenic shock (60) 3% HS vs RL Blood pressure** Jarvela [56] RCT (1)) Neurogenic shock (40) 7.5% HS vs NS Fluid balance, blood pressure Gong [50] RCT (1)) Haemodialysis (10) 23% HS vs 7.5% HS vs 7.5% Blood pressure** crossover HSD Van der RCT (1)) Haemodialysis (9) 3% HS vs HES vs albumin Blood pressure Sande [51] crossover Oliveira [58] RCT (1)) Sepsis (29) 7.5% HSD vs NS Mortality, fluid balance, blood pressure, cardiac output** Fang [59] RCT (1+) Sepsis (94) 3.5% HS vs 3.5% NS vs 3.5% NaHCO 3 Mortality, blood pressure, cardiac output *Infusion of hypertonic saline, less intravenous fluid required, sustained improvement, **statistically significant change, apparent mortality benefit. Dialysis patients Two crossover studies were performed in dialysis patients, with divergent results on blood pressure effects [50, 51]. One paper reported a greater increase in blood pressure with 7.5% hypertonic saline compared with hypertonic saline dextran, but this may have been a sampling error [50]. Cardiogenic shock (non-obstructive) Three studies evaluated the use of hypertonic saline in cardiac surgery (two in children) [52 54]. These studies confirmed the beneficial effects of hypertonic saline on haemodynamics, but did not consider outcome variables. Predictably, the cardiac output and blood pressure increased, and systemic vascular resistance reduced. However, the issue of whether cardiac output improved due to a preload effect or direct inotropy could not be answered. Of note, the patients were relatively healthy (for example, they were undergoing ASD or VSD repairs and did not have heart failure or dysrhythmias) and they did not have impaired right ventricular function. It remains to be shown if the volume-expanding effect of 994 Journal compilation Ó 2009 The Association of Anaesthetists of Great Britain and Ireland

6 G. F. Strandvik Æ Hypertonic saline in critical care hypertonic saline is safe in patients with impaired ventricular function. Neurogenic shock Three studies evaluated various hypertonic saline bolus regimes in iatrogenic (spinal anaesthesia) neurogenic shock. All had a high potential for bias, and only one reported an improvement in blood pressure [55]. However, vasopressor use and fluid requirements were both significantly reduced [56, 57]. Septic shock The study by Oliveira et al. showed a definite but shortlived improvement in haemodynamic status in stable patients with sepsis [58]. In contrast, a well-conducted study by Fang et al. failed to find any haemodynamic benefit with hypertonic saline in well-established septic shock [59]. Low power and a heterogeneous patient population weaken this study. Survival benefit in shock To date, four meta-analyses of hypertonic saline (either alone or in conjunction with dextran) have been performed in which the primary outcome was survival. These include most of the original papers reviewed thus far. The first of these was performed by Wade et al., and found that the odds ratio for survival in trauma was 1.5 if a bolus of 7.5% hypertonic saline dextran or 7.5% hypertonic saline was used, as opposed to isotonic fluid bolus [60]. The odds ratio (2.0) was greater for penetrating trauma. The quality of this meta-analysis is marred by failure of the authors to disclose group allocations numbers in their analysis. Furthermore, the intentionto-treat principle is violated, and the pool of patients comes from trials with which the authors are affiliated. In addition, the studies are heterogeneous. Lastly, the use of odds ratio for survival may not be as accurate as relative risk of death, due to the high risk of occurrence of death (the main outcome measure). If relative risk calculations are performed, the value approximates a relative risk of death of 0.8. The meta-analysis by Bunn et al. published in the Cochrane database showed no improvement in relative risk of death [61]. It included some trials not reviewed in this article (the management of semi-elective surgical patients). The outcome measures were not consistently associated with haemodynamic variables, and death was seldom the primary outcome of the studies included (thus they were not powered to find a survival benefit). Some information on survival was obtained post-hoc by personal communication with the authors. They rightly concluded that the confidence intervals for relative risk were wide, and thus no conclusions could be made about mortality. They did not comment on the varying concentrations of hypertonic saline included in their review. The much-publicised Cochrane review of colloids vs crystalloids was performed in 1999, and has recently been updated by Perel [62]. A subsection of the meta-analysis looked at the same question addressed by Wade: does hypertonic saline in combination with dextran provide a survival benefit in trauma? The conclusion was no, with a relative risk of death of 0.88 (95% CI ). In 2003, Wade performed a meta-analysis of individual patient data based on the USA Multicentre Trial published nearly a decade earlier [45, 63]. The purpose of this work was to address Bickells concerns about volume resuscitation with hypertonic saline in bleeding patients [36]. To this end, the paper focuses specifically on the victims of penetrating trauma. Wade and colleagues found no difference in mortality (benefit or harm) when compared with the expected chance of death as assessed by the Modified Trauma Outcome Score [64]. Only 230 patients were assessed, however, and the study focuses only on one trial. Four randomised controlled trials meeting the search criteria have been published since the meta-analysis by Wade in 1997 [42, 43, 59, 65]. The study by Younes et al. shows a small but non-significant survival benefit with an early bolus dose of 7.5% hypertonic saline dextran in trauma. However, the relative risk of death is calculated at 0.74 in favour of hypertonic saline dextran. The study by Bulger and colleagues could not demonstrate an ARDS-free survival or mortality benefit. Fang and colleagues failed to demonstrate a survival benefit with the use of hypertonic saline in septic shock. Summary and recommendation Evaluation of the existing data is difficult due to heterogeneity between studies and solutions used. However, evidence for benefit with hypertonic saline boluses to increase blood pressure in haemorrhagic shock is robust. In other forms of shock, though, there is no high quality data from clinical trials demonstrating that use of hypertonic saline results in a consistent increase in blood pressure. Therefore, the use of bolus dose intravenous hypertonic saline is recommended for use in victims of traumatic hypotension, but not for other shock states. There is insufficient data in the literature to make recommendations about the ideal concentration of hypertonic saline, the addition of colloid, or the use of continuous infusions of hypertonic saline in shock states. There is inconsistent data in the literature regarding survival benefit with bolus doses of hypertonic saline in hypotensive patients. The majority of studies focus on Journal compilation Ó 2009 The Association of Anaesthetists of Great Britain and Ireland 995

7 G. F. Strandvik Æ Hypertonic saline in critical care Anaesthesia, 2009, 64, pages trauma victims and almost exclusively use 7.5% hypertonic saline (usually in combination with dextran). Although meta-analyses exist, their conclusions are either flawed, ambiguous or based on non-heterogeneous samples. There is no information in the literature supporting survival benefit with infusions of hypertonic saline in shock states. Current evidence confirms that hypertonic saline is effective in raising blood pressure in hypovolaemic shock (Grade A), and is probably of benefit in non-obstructive cardiogenic shock (Grade C). The evidence for blood pressure restoration in neurogenic and spinal shock is uncertain. Hypertonic saline administration in current formulations does not improve mortality in shock states (Grade A). Intravenous hypertonic saline for the reduction of intracranial pressure and improvement in outcome for patients with intracranial hypertension Raised intracranial pressure (ICP) is an independent prognostic factor in patients with brain injury from a variety of causes [66]. Reducing intracranial pressure is a cornerstone of management for the brain-injured patient. Cerebral blood flow (CBF) increases with ICP reduction. Various interventions are used to reduce ICP, including hyperosmolar therapy [67]. Table 4 summarises the clinical trials that were assessed to answer the questions of whether hypertonic saline: reduces intracranial pressure; improves neurological outcome; or increases survival. Most studies involved bolus doses of 250 ml of fluid, unless otherwise stated. The meta-analyses reviewed include most of the original papers reviewed here. Intracranial pressure reduction Fifteen studies met the search criteria for patients with traumatic brain injury (TBI). Three of these studies included patients with raised intracranial pressure from subarachnoid haemorrhage [68 70], and one of the 15 studies looked at patients with raised intracranial pressure from all causes including trauma [31]. Hypertonic saline was used in concentrations ranging from 1.7% to 30% saline, most often as bolus doses of 250 ml. Five case-control studies with TBI patients confirmed that hypertonic saline either alone or in combination with a colloid solution could significantly reduce ICP [68, 70 73]. However, the risk of bias towards a treatment effect is inherently greater with this type of study. Of the nine randomised-controlled trials in TBI patients, four used mannitol as the comparator, and three showed significant benefit with the use of hypertonic saline [24, 31, 69]. The most recent study by Francony failed to show a benefit with hypertonic saline compared with mannitol [74]. A further four papers compared a bolus of 0.9% saline or Ringer s lactate with hypertonic saline [75 78]. Two of these papers showed a significant reduction in ICP with hypertonic saline, but two did not. It is worth noting that the paper by Cooper was the RCT with the lowest risk of bias in all the studies, and showed no reduction in ICP with pre-hospital use of hypertonic saline. It was suggested that this reflected the evolving nature of raised intracranial pressure, and should not necessarily be interpreted as a negative study. A recent study by Ichai compared hypertonic sodium lactate with mannitol [79]. The fifteenth study of TBI patients was a retrospective chart review of the management of a cohort of children with traumatic brain injury [80]. A major problem with the papers is that some compare equiosmolar solutions whereas others use similar volumes. Furthermore, outcome measures for ICP are variously measured as either the duration of effect or the regularity of ICP episodes, making meta-analysis very difficult. Seven studies included patients with subarachnoid haemorrhage, and all revealed a significant reduction in intracranial pressure with hypertonic saline. Five were case-control studies [22, 68, 70, 81, 82]. One RCT used mannitol as the comparator [69], and one used normal saline [83]. This study by Bentson showed a good result in ICP reduction as compared with normal saline, but should be interpreted with caution, as the patient population was one with stable intracranial pressure. It may be difficult to extrapolate these results to patients with malignant intracranial hypertension. Two papers in stroke patients found hypertonic saline significantly decreased ICP (case control vs mannitol [84], and after mannitol failure [85]). These papers are small and with poor methodological quality. It is difficult to comment about hypertonic saline rescue therapy in the setting of recent mannitol use. De Vivo and colleagues performed a randomised controlled trial in patients undergoing surgery for cerebral tumours [86]. The comparator was mannitol 18%, either in conjunction with hypertonic saline or alone. They concluded that hypertonic was a safe and effective alternative to mannitol for reducing intracranial pressure. As described earlier, the majority of studies used a bolus of hypertonic saline rather than continuous infusions. One study looked at the prevention of intracranial hypertension in acute liver failure patients with an infusion of 30% hypertonic saline, as compared with normal standard of care. This confirmed an ICP reducing effect in this subgroup of patients [15]. Three of the studies of traumatic brain injury in children utilised infusions of hypertonic saline, targeted at an elevated sodium level or osmolality [71, 78, 80]. These showed a 996 Journal compilation Ó 2009 The Association of Anaesthetists of Great Britain and Ireland

8 G. F. Strandvik Æ Hypertonic saline in critical care Table 4 Clinical trials of hypertonic saline in intracranial hypertension. RCT, randomized controlled trial; HS, hypertonic saline; HSD, hypertonic saline dextran; NS, normal saline; RL, Ringer s lactate; HES, hydroxyethyl starch; NaHCO 3, sodium bicarbonate; ICP, intracranial pressure; CPP, cerebral perfusion pressure; CBF, cerebral blood flow; TBI, traumatic brain injury; SAH, subarachnoid haemorrhage. Study Type and quality Clinical scenario (Patient numbers in parentheses) Interventions Outcome measures Francony [74] RCT (1++) TBI and stroke (20) 7.5% HS vs mannitol 20% ICP, CPP Ichai [79] RCT (1+) TBI (34) 3% hypertonic sodium lactate vs ICP**, CPP, outcome mannitol (1.5 ml.kg )1 ) Perel [62] Meta-analysis Critically ill and injured All fluids and HSD Mortality patients (1283) Tseng [82] Case control (2)) SAH (35) 23.5% HS Mortality, ICP**, CBF CPP Bentsen [83] RCT (1+) SAH (22) 7.2% HS with 6% HES vs NS ICP**, CPP Al-Rawi [22] Case control (2)) SAH (14) 23.5% HS ICP**, CPP CBF Harutjunyan [31] RCT (1+) All causes of raised 7.2% HS with 6% HES vs mannitol 15% Mortality, ICP**, CPP ICP (32) Battison [69] RCT (1)), crossover SAH, TBI (9) 7.5% HSD vs equimolar mannitol 20% ICP**, CPP pilot Cooper [75] RCT (1++) TBI (229) 7.5% HS vs RL Mortality, ICP, CPP Bentson [81] Case control (2)) SAH (7) 7.2% HS with 6% HES ICP**, CPP Bunn [61] Meta-analysis Trauma (including HS vs NS Mortality TBI) (956) Murphy [15] RCT (1+) Acute liver failure (30) 30% HS* ICP** Vialet [24] RCT (1)) TBI (20) 7.5% HS vs mannitol 20% ICP** Schwarz [85] Case-control (2)) Stroke (8) 10% HS ICP**, CPP De Vivo [86] RCT (1)) Tumour surgery (30) 3% HS vs mannitol 18% with 3% HS ICP vs mannitol 18% Petersen [80] Retrospective TBI (children) (68) 3% HS* ICP** chart review (3) Khanna [71] Case control (2)) TBI (children) (10) 3% HS* ICP**, CPP Munar [73] Case-control (2)) TBI (14) 7.2% HS ICP** Horn [68] Case-control (2)) TBI and SAH (10) 7.5% HS ICP**, CPP Schatzmann [70] Case-control (2)) TBI and SAH (6) 10% HS ICP** Schwarz [84] RCT (1)), crossover Stroke (9) 7.5% HS with 6% HES vs mannitol 20% ICP**, CPP Simma [78] RCT (1+) TBI (children) (32) 1.7% HS* vs RL Mortality, ICP**, CPP** Shackford [77] RCT (1)) TBI (34) 1.8% HS vs RL ICP Hartl [72] Case-control (2)) TBI (6) 7.5% HS with 6% HES ICP** Fischer [76] RCT (1)), crossover TBI (children) (18) 3% HS ICP** Vassar [39] RCT (1+) Trauma (and TBI) (166) 7.5% HSD Mortality *Infusion of hypertonic saline, sustained improvement, **reduction, increase, apparent mortality benefit. predictable sustained effect of ICP reduction during the course of the infusions. Survival and neurological outcomes Few studies have considered long-term neurological disability as an outcome measure, although a number of studies and meta-analyses have considered the question of survival benefit with hypertonic saline. Although a recent internet-based database survey from Austria revealed a positive correlation between hypertonic saline use and survival, a review of the evidence does not support this conclusion [87]. Tseng and colleagues recently published their results with the use of 23.5% hypertonic saline in subarachnoid haemorrhage [82]. If cerebral blood flow was enhanced, then outcome appeared to improve significantly. It is unclear from the paper why CBF was not enhanced in those with poor outcome despite all patients receiving the same bolus of hypertonic saline. A study from Australia of pre-hospital use of hypertonic saline in traumatic brain injury failed to show any improvement in survival or neurological outcome at 6 months [75]. This was a well-performed trial with a low risk of bias. However, the lack of effect may reflect timing of treatment with respect to evolution of pathology in traumatic brain injury. A paper by Ichai and colleagues [79] reported an improved neurological outcome with lactated hypertonic saline; the study was not powered adequately for outcome to allow a meaningful interpretation of this result. Interestingly, the study by Vassar et al. more than a decade earlier revealed a trend towards survival in severely headinjured patients who received hypertonic saline with Journal compilation Ó 2009 The Association of Anaesthetists of Great Britain and Ireland 997

9 G. F. Strandvik Æ Hypertonic saline in critical care Anaesthesia, 2009, 64, pages dextran in the pre-hospital setting [39]. The odds ratio for survival in patients with severe head injury was two. However, the sample size was small and there was no actuarial survival benefit. The Cochrane review of hypertonic fluid resuscitation included 956 patients [61]. Specifically, they examined outcome in traumatic brain injury patients, and found no difference in mortality or neurological outcome (relative risk for poor outcome was 1.0, 95% CI ). The Cochrane meta-analysis of colloid vs crystalloid resuscitation in critically ill and injured patients was recently updated [62]. In total 1283 patients were included but no difference in outcome was found with any of the fluids (relative risk of death with hypertonic solutions 0.88, 95% CI ). Summary and recommendations Although most studies are case-controlled or randomised, controlled trials with a high risk of bias, there appears to be enough evidence to suggest that hypertonic saline (alone or in combination with a colloid), either as infusion or bolus dose, is effective at reducing intracranial pressure in traumatic brain injury and subarachnoid haemorrhage. The majority of studies have used 7.5% hypertonic saline boluses. Continuous infusions usually utilise 3% hypertonic saline and this may be effective at reducing ICP in stroke patients, those with acute liver failure and children with traumatic brain injury. There is currently no evidence to suggest a better neurological outcome or survival benefit with the use of hypertonic saline in patients with raised intracranial pressure. However, the available studies are generally small, heterogeneous and show a high degree of bias. It is, therefore, recommended that intravenous hypertonic saline be used in the treatment algorithm for raised intracranial pressure. It should be used instead of and not in conjunction with mannitol for this indication. Survival benefit or improvement in neurological outcomes has not been demonstrated. Current evidence confirms that hypertonic saline as currently used in clinical practice, is effective in reducing raised intracranial pressure (Grade A), but does not improve neurological outcomes (Grade B), nor survival in states of raised intracranial pressure (Grade A). Major adverse effects with the use of hypertonic saline Very few studies have considered the adverse effects of hypertonic saline as a primary outcome measure. However, all the studies considered in this review have included reporting of adverse events. Safety concerns with the use of hypertonic saline centre mostly on the consequences of an acute hyperosmolar state. The most feared complication is central pontine myelinolysis, also known as ODS (osmotic demyelination syndrome) [10]. This condition has been reported in malnourished individuals and those with hyponatremic states when sodium levels have been corrected rapidly [88]. Other consequences of hyperosmolarity include acute heart failure and pulmonary oedema from rapid blood volume expansion [11]. In bleeding patients, this rapid volume expansion may theoretically increase the rate of blood loss [36, 89]. A disrupted blood brain barrier may result in a reverse osmosis phenomenon, with worsening cerebral oedema and raised intracranial pressure [88]. In severely dehydrated patients, there is the theoretical risk of worsening cellular dehydration. This has not, however, been borne out in animal studies [12]. There is a hypothetical risk that acute cerebral dehydration may cause mechanical shearing of bridging vessels, with consequent subarachnoid haemorrhage [9]. Extravasation injuries may cause marked local tissue injury. Acute hypotension has been reported with the administration of hypertonic saline in animal and a number of human studies [12]. Bolus dose hypertonic saline should thus be administered as a slow intravenous dose over 5 min. Further potential side-effects include hyperchloraemic acidosis and hyperosmolar renal failure [90]. This latter effect has been reported with mannitol; isolated reports with hypertonic saline in burns resuscitation in humans found renal failure as an association a causal relationship was not clear [88, 91]. Hypokalemia may occur because of urinary potassium losses [92]. Dilutional coagulopathy with increased bleeding risk is a further potential problem, although this has not been found to be clinically relevant [88]. As noted earlier, very few studies have looked directly at safety as the primary outcome measure with the use of hypertonic saline. A few pilot studies such as the one by Maningas et al. have declared safety as an outcome measure, but none of these studies have the power to ascertain the risk of individual side-effects [93]. Vassar and colleagues evaluated the potential side effects of rapidly infusing 7.5% hypertonic saline with and without dextran [94]. Eight patients out of 166 had significant hyperchloraemic acidosis. However it was felt that their moribund condition accounted for their acidosis rather than the chloride load. There were no significant major sideeffects. The vast majority of trials with bolus dose infusions of hypertonic saline have reported on adverse effects; no significant side-effects have been declared. A number of studies have included autopsies performed on 998 Journal compilation Ó 2009 The Association of Anaesthetists of Great Britain and Ireland

10 G. F. Strandvik Æ Hypertonic saline in critical care non-survivors, and have not found any evidence of osmotic demyelination syndrome [39]. Other studies have included MRI of the brain following administration of hypertonic saline. These include a series of 68 patients who received bolus doses of 23.4% hypertonic saline to treat transtentorial herniation. Post-herniation MRI studies failed to detect any evidence of osmotic demyelination in any of the patients [95]. In the bolus-dose studies, the highest recorded sodium level in a survivor was 169 mmol.l )1. This was thought to be related, in part, to high blood alcohol levels affecting analyser function. All levels returned to normal by 24 h after the hypertonic saline, and most by 4 h [96]. The majority of patients had peak levels < 155 mmol.l )1. There are far fewer studies utilising continuous infusions of hypertonic saline. In the paediatric head injury series by Khanna et al., the mean duration of treatment was 7.6 days [71]. The mean highest serum sodium concentration and osmolarity were mmol.l )1 and mosm.l )1, respectively, but there were no adverse effects thought to be related to hypertonic saline infusion. The maximum serum osmolarity in an individual patient was 431 mosm.l )1. Similarly, a retrospective chart review of 68 children with raised intracranial pressure receiving 3% hypertonic saline infusions, failed to show any adverse effects [80]. This included MRI and autopsy evidence in those with high serum sodium levels; no evidence of ODS was seen. Qureshi and colleagues used 3% hypertonic saline infusions in head injury, and targeted a sodium concentration of mmol.l )1. No adverse effects were reported [97]. Summary and recommendations Although the question of safety is a genuine clinical concern, there is no clear evidence for any adverse effects with the use of bolus doses of intravenous hypertonic saline [61]. However, this is mostly extrapolated evidence from other studies, and the grade of recommendation is weak. Three percent saline infusions appear to be welltolerated in paediatric patients, although the studies sited above are not powered to detect adverse effects (the total number of patients studied is 100). Based on the protocols and reported ranges of sodium concentrations in the original studies reviewed the following would seem prudent: the serum sodium level should be measured within 6 h of administration if bolus doses are given; and re-administration of hypertonic saline should not occur until the serum sodium concentration is < 155 mmol.l )1. With infusions in paediatric patients it appears that a concentration of 170 mmol.l )1 is well tolerated. Thus, serum sodium concentrations should be monitored regularly, and not permitted to exceed this level. Once again, the grade of recommendation for this action is weak. Current evidence suggests that hypertonic saline as currently used in clinical practice, is safe and does not result in major adverse effects (Grade C). Discussion A bolus dose of intravenous hypertonic saline is safe and effective at improving low blood pressure from haemorrhagic hypotensive states. Evidence for its effectiveness in other hypotensive states has not been clearly established. Intracranial pressure reduction can be safely achieved with bolus doses of intravenous hypertonic saline. The evidence suggests that continuous infusions are also effective for this indication. There is no evidence that intravenous hypertonic saline provides a survival benefit in either shock states or in patients with raised intracranial pressure. Comprehensive recommendations on how to use intravenous hypertonic saline are difficult to construct from the current literature. Due to the heterogeneous nature of the clinical studies, it is unclear from the literature what the ideal concentration, formulation or volume of hypertonic saline is. However, if hypertonic saline solutions are to be employed in critical care practice, they should be used within the context of a welldefined algorithm. Such algorithms can be constructed from the current evidence, and the use of one such algorithm has recently been published [98]. Current areas of pre-clinical work are heavily focused on the immune-modulatory effects of hypertonic saline solutions. The clinical applications are significant: a reduction in the incidence of acute lung injury in proinflammatory states is postulated, as is a potential reduction in infectious complications following surgical insult [26, 99]. In terms of shock states and raised intracranial pressure, however, there are still many unanswered questions. A recent research letter published in Anaesthesia reported a survey of the 30 adult and paediatric neurosurgical services in the United Kingdom [100]. Fifteen of the units used hypertonic saline, but in very disparate ways. An American survey of physicians caring for paediatric victims of TBI found that although there was broad agreement about so-called first tier management, there was no consensus as to which osmolality targets should be used when administering hypertonic saline [101]. Areas that require urgent further investigation and clarification include: infusions of hypertonic saline for prevention of rebound ICP, repeated boluses for recurrent ICP, standardisation of dose and formulation, use in Journal compilation Ó 2009 The Association of Anaesthetists of Great Britain and Ireland 999

11 G. F. Strandvik Æ Hypertonic saline in critical care Anaesthesia, 2009, 64, pages non-hypovolaemic shock. Methods of ensuring zero adverse effects, including the appropriate monitoring of serum sodium and osmolality, are urgently required. The timing of administration would appear to be critical. Recent animal work suggests that ultra-early administration of hypersomolar solutions may be the crucial element for benefit in traumatic brain injury [102]. A well-powered, robustly designed study of bolus dose hypertonic saline for two separate populations: raised intracranial pressure and hypovolaemic trauma patients, is needed. Brasel has recently published a proposed protocol for a multi-centre randomised trial aiming at addressing these two questions in the prehospital setting. The study aims to recruit over 5500 patients [103]. However, the question of infusion therapy has, to date, received the least attention. A nationally-co-coordinated study is needed. Infusions aimed at a pre-defined hyperosmolar or hypernatremic target for the first 48 h after injury would be a safe starting point and may provide more robust clinical information. It would seem a sorry state of affairs to be unclear about a potentially simple and inexpensive therapy, which may indeed provide outcome benefit, purely for the lack of a co-coordinated investigative strategy. Conclusion A review of the available literature indicates that hypertonic saline solutions are effective for blood pressure restoration in haemorrhagic, but not other, shock states. There is no survival benefit with hypertonic saline solutions in shock states. Hypertonic saline solutions are effective at reducing intracranial pressure in conditions causing acute intracranial hypertension. There is no survival or outcome benefit with the use of hypertonic saline solutions for raised intracranial pressure. 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13 G. F. Strandvik Æ Hypertonic saline in critical care Anaesthesia, 2009, 64, pages patients in hemorrhagic shock. Middle East Journal of Anesthesiology 2008; 19: Bortolani A, Governa M, Barisoni D. Fluid replacement in burned patients. Acta Chirurgiae Plasticae 1996; 38: Gunn ML, Hansbrough JF, Davis JW, Furst SR, Field TO. Prospective, randomized trial of hypertonic sodium lactate versus lactated Ringer s solution for burn shock resuscitation. The Journal of Trauma 1989; 29: Gong R, Lindberg J, Abrams J, Whitaker WR, Wade CE, Gouge S. Comparison of hypertonic saline solutions and dextran in dialysis-induced hypotension. Journal of the American Society of Nephrology 1993; 3: Van der Sande FM, Luik AJ, Kooman JP, Verstappen V, Leunissen KM. Effect of intravenous fluids on blood pressure course during hemodialysis in hypotensive-prone patients. Journal of the American Society of Nephrology 2000; 11: Schroth M, Plank C, Meissner U, et al. 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