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Fluid therapy in patients with brain injury: what does physiology tell us?

The unique component of the cerebral circulation is the so called blood–brain barrier (BBB). The anatomical structures of the BBB consist of the cerebral vascular endothelial cells, the surrounding pericytes, the basal lamina and the perivascular astrocytes. These form the so-called neurovascular unit [1]. Notably, the endothelial cells are interconnected by tight junctions; thus, any solute transport will be transcellular, as opposed to paracellular, in the peripheral circulation [2]. The specific anatomy of the neurovascular unit allows the brain volume to be kept constant even in the context of marked changes in intravascular volume status.

On the contrary, the BBB has a considerable passive permeability to free water, as opposed to electrolytes and other solutes. An acute drop in plasma osmolality, therefore, results in an acute increase in brain water content [3]. The neuronal cells compensate for the increase in volume by active depletion of intracellular osmotic solutes (so called ‘volume regulatory decrease’) [4, 5]. Thus, excessive water moves to the extracellular space, thereby normalizing cellular volume. When plasma hypo-osmolality eventually resolves, brain water content proportionally decreases, which may lead to demyelinisation in severe cases [6]. Again, the cells react by internalizing osmotic solutes (‘volume regulatory increase’). However, this process is much less efficient than the depletion of solutes [7]. In summary, the critical sequelae of acute changes in osmolality imply that such alterations should be avoided whenever possible in the clinical setting.

The complex regulation of cerebral volume in response to changes in osmolality is of central interest in the context of fluid therapy in patients with intact or disrupted BBBs. The physical composition of resuscitation fluids is of special relevance in this regard [8]. Key determinants include the osmolality and the colloid osmotic pressure of the fluid preparation. In this context, it is of major importance to discriminate between the theoretical osmolarity, which reflects the sum of all potentially dissociable particles expressed in mosmol/l. Conversely, the osmolality represents the number of osmotically active solutes (in mosmol/kg) and thus is the clinically relevant variable. It may either be calculated from the theoretical osmolarity, the water content of the solution and the osmotic coefficient of the solute, or directly measured by freezing point depression. Notably, due to incomplete dissociation of soluble molecules, osmolality is lower than osmolarity in resuscitation fluids.

An iso-osmotic crystalloid fluid (that is, equalling the physiological plasma osmolality of 288 ± 5 mosmol/kg) equally distributes to the intravascular and the interstitial space [9], because the peripheral endothelial cells allow a more or less unrestricted exchange of water and electrolytes. Thus, large amounts of crystalloids are inevitably associated with a dose-dependent formation of extracellular oedema. Notably, the neurovascular unit prevents electrolytes from passively passing between the intravascular space and extravascular space [2]. Therefore, the intracranial volume is not increased even with large amounts of iso-osmotic crystalloid solutions. Hypo-osmotic solutions, in turn, distribute to the whole body water, including the intracellular space [10]. As discussed above, the brain will respond with an initial increase in cellular volume followed by active (thus ATP-consuming) depletion of intracellular solutes. Notably, patients with cerebral pathologies may not be able to compensate for the increase in cellular volume or the associated increase in cerebral oxygen consumption. To prevent the potentially lethal sequelae of brain oedema, hypo-osmotic solutions should generally be avoided for bolus or high-dose resuscitation or in patients with brain pathology.

In an ideal model of the vasculature, iso-oncotic colloid solutions remain in the intravascular space, since the endothelial barrier is not permeable to colloidal compounds [11, 12]. In clinical reality, however, the volume effect of colloids is context-sensitive, depending on volume status and the presence of systemic inflammation [13, 14]. Notably, infusion of colloids should not exert an intrinsic effect on the brain itself beyond its impact on the cerebral circulation. In this context, it is surprising that a clinical comparison of crystalloids (saline 0.9%) and colloids (4% human albumin), the Saline and Albumin Fluid Evaluation (SAFE) study, showed a less favourable outcome (higher 28-day mortality) for patients with traumatic brain injury treated with 4% human albumin [15, 16]. This finding led to the recommendation that colloids should not be used in patients with head injury [17]. When having a closer look at the study drugs, isotonic saline has an osmolality of 286 mosmol/kg, and is thus iso-osmotic. The albumin preparation used in the SAFE study (Albumex 4%, CSL Ltd, Parkville, Victoria, Australia) however, has a nominal osmolality of only 260 mosmol/kg. Measurement of the freezing point depression revealed a measured osmolality of 266 mosmol/kg [8]. However, it is known that the freezing point depression method may overestimate the actual osmolality due to ‘cryoscopic colloid effects’. Taken together, the investigated colloid of the SAFE study represents a severely hypo-osmotic solution. When taking the above mentioned physiologic considerations into account, the SAFE study confirms that hypo-osmotic solutions are deleterious in patients with brain injury, rather than evaluating the colloid compound itself. Notably, these data have been misinterpreted several times in the current literature [1618]. Given this, there is no reliable evidence that colloids themselves are hazardous in patients with brain injury. It is nevertheless important to consider the osmolality of each product prior to their use. Table 1 gives an overview of the physical properties of many resuscitation fluids.

Table 1 Physicochemical characteristics of available resuscitation fluid preparations

In summary, changes in plasma osmolality may be deleterious in patients with brain injury. Resuscitation fluids should therefore be isotonic in terms of osmolality (not osmolarity). Physicians should be familiar with the osmolality of the resuscitation fluids they use.



Blood–brain barrier


Saline and albumin fluid evaluation.


  1. 1.

    Daneman R: The blood–brain barrier in health and disease. Ann Neurol 2012, 72: 648-672. 10.1002/ana.23648

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Brightman MW, Reese TS: Junctions between intimately apposed cell membranes in the vertebrate brain. J Cell Biol 1969, 40: 648-677. 10.1083/jcb.40.3.648

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  3. 3.

    Arieff AI, Llach F, Massry SG: Neurological manifestations and morbidity of hyponatremia: correlation with brain water and electrolytes. Medicine 1976, 55: 121-129. 10.1097/00005792-197603000-00002

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Melton JE, Patlak CS, Pettigrew KD, Cserr HF: Volume regulatory loss of Na, Cl, and K from rat brain during acute hyponatremia. Am J Physiol 1987, 252: F661-F669.

    CAS  PubMed  Google Scholar 

  5. 5.

    Lien YH, Shapiro JI, Chan L: Effects of hypernatremia on organic brain osmoles. J Clin Invest 1990, 85: 1427-1435. 10.1172/JCI114587

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  6. 6.

    Sterns RH, Riggs JE, Schochet SS Jr: Osmotic demyelination syndrome following correction of hyponatremia. N Engl J Med 1986, 314: 1535-1542. 10.1056/NEJM198606123142402

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Lien YH, Shapiro JI, Chan L: Study of brain electrolytes and organic osmolytes during correction of chronic hyponatremia. Implications for the pathogenesis of central pontine myelinolysis. J Clin Invest 1991, 88: 303-309. 10.1172/JCI115292

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  8. 8.

    Van Aken HK, Kampmeier TG, Ertmer C, Westphal M: Fluid resuscitation in patients with traumatic brain injury: what is a SAFE approach? Curr Opin Anaesthesiol 2012, 25: 563-565. 10.1097/ACO.0b013e3283572274

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Reid F, Lobo DN, Williams RN, Rowlands BJ, Allison SP: (Ab)normal saline and physiological Hartmann’s solution: a randomized double-blind crossover study. Clin Sci (Lond) 2003, 104: 17-24. 10.1042/CS20020202

    CAS  Google Scholar 

  10. 10.

    Shackford SR, Zhuang J, Schmoker J: Intravenous fluid tonicity: effect on intracranial pressure, cerebral blood flow, and cerebral oxygen delivery in focal brain injury. J Neurosurg 1992, 76: 91-98. 10.3171/jns.1992.76.1.0091

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Ertmer C, Rehberg S, Van Aken H, Westphal M: Relevance of non-albumin colloids in intensive care medicine. Best Pract Res Clin Anaesthesiol 2009, 23: 193-212.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Ertmer C, Kampmeier T, Van Aken H: Fluid therapy in critical illness: a special focus on indication, the use of hydroxyethyl starch and its different raw materials. Curr Opin Anaesthesiol 2013, 26: 253-260.

    CAS  PubMed  Google Scholar 

  13. 13.

    Rehm M, Orth V, Kreimeier U, Thiel M, Haller M, Brechtelsbauer H, Finsterer U: Changes in intravascular volume during acute normovolemic hemodilution and intraoperative retransfusion in patients with radical hysterectomy. Anesthesiology 2000, 92: 657-664. 10.1097/00000542-200003000-00008

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Rehm M, Haller M, Orth V, Kreimeier U, Jacob M, Dressel H, Mayer S, Brechtelsbauer H, Finsterer U: Changes in blood volume and hematocrit during acute preoperative volume loading with 5% albumin or 6% hetastarch solutions in patients before radical hysterectomy. Anesthesiology 2001, 95: 849-856. 10.1097/00000542-200110000-00011

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R: A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004, 350: 2247-2256.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Myburgh J, Cooper DJ, Finfer S, Bellomo R, Norton R, Bishop N, Kai Lo S, Vallance S: Saline or albumin for fluid resuscitation in patients with traumatic brain injury. N Engl J Med 2007, 357: 874-884.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Reinhart K, Perner A, Sprung CL, Jaeschke R, Schortgen F, Johan Groeneveld AB, Beale R, Hartog CS: Consensus statement of the ESICM task force on colloid volume therapy in critically ill patients. Intensive Care Med 2012, 38: 368-383. 10.1007/s00134-012-2472-9

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Myburgh JA, Mythen MG: Resuscitation fluids. N Engl J Med 2013, 369: 1243-1251. 10.1056/NEJMra1208627

    CAS  Article  PubMed  Google Scholar 

  19. 19.


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Correspondence to Christian Ertmer.

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Ertmer, C., Van Aken, H. Fluid therapy in patients with brain injury: what does physiology tell us?. Crit Care 18, 119 (2014).

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