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Why we do what we do: Hypertonic saline for elevated intracranial pressure
Hypertonic saline is used to treat elevated intracranial pressure in children with traumatic brain injury.
What is it and how does it work?
Technically hypertonic saline is any sodium chloride solution with a greater concentration than normal saline (0.9%, which has 154 mEq/L of NaCl). Available concentrations include 3% (513 mEq/L), 5% (856 mEq/L) and 23.4% (4000 mEq/L). Believe it or not the blood brain barrier is very impermeable to sodium. Giving saline with a NaCl concentration far in excess of the plasma sodium will exert an osmotic effect that will help shift fluid out of the cranial vault – overcoming this baseline lack of permeability. This, can lower intracranial pressure. Aside form the osmotic effect there are also potential benefits on inhibiting inflammation, stimulation of atrial natriuretic peptide and increased cardiac output (maybe by restoring resting membrane potentials?). The effectiveness of hypertonic saline is greatest in the first hour then wanes a bit as sodium rapidly equilibrates across the blood brain barrier.
How do you give it?
There are various strategies and dosing regimens. The effective dose for acute usage – which is how you’ll use it in the Emergency Department on kids – is between 6.5 and 10 mL/kg. The dose I’ve used is:
In general you can expect 3% saline to increase serum sodium by 1 mEq/L for each mL/kg you give. Experts recommend aiming for a serum sodium of 155 mEq/L. You hit a ceiling in decreasing ICP once the serum sodium gets to ≥160 mEq/L. In ICU settings continuous infusions of 3% saline are given at a rate of 0.5 – 1.5 mL/kg/hr. This is in conjunction with ICP monitoring with a goal of <20 mmHg.
Three percent can be given through a peripheral IV. The higher concentrations may be more caustic and are better given through central venous access.
What’s the evidence?
This is by no means a complete listing of all studies on hypertonic saline – but I did limit the choices to humans, and display them here to illustrate some of the evidence, and also highlight that it isn’t quite “ironclad.” They are presented in chronological order.
Hypertonic saline lowers raised intracranial pressure in children after head trauma
Fisher B, Thomas D, Peterson B.
J Neurosurg Anesthesiol. 1992 Jan;4(1):4-10.
This was a randomized controlled crossover trial of only 18 patients and compared 3% and 0.9% saline. ICP was compared over two hours following dosing and patients in the 3% arm had lower ICP and needed fewer “interventions” – thiopental and hyperventilation. A serum sodium increase of approximately 7 mEq/L was noted in the 3% group. The authors did not control for many confounding variables unfortunately.
A prospective, randomized, and controlled study of fluid management in children with severe head injury: lactated Ringer’s solution versus hypertonic saline
Simma B, Burger R, Falk M, Sacher P, Fanconi S.
Crit Care Med. 1998 Jul;26(7):1265-70.
A randomized controlled trial of 35 patients that compared lactated ringers (a hypotonic solution) with hypertonic saline (1.7%) as a continuous infusion over 3 days. The outcomes included ICP, cerebral perfusion pressure, need for other interventions, fluid requirements, intensive care unit length of stay and survival rate. Unfortunately this study was not blinded, but it did show the following;
No difference between groups in survival rate and length of hospital stay
Hypertonic saline required fewer interventions to maintain ICP control (p=0.01)
Hypertonic saline had shorter length of ICU stay (p= 0.04)
Hypertonic saline had shorter duration of mechanical ventilation (p =0.10)
Hypertonic saline had fewer complications (p=0.09 for ≥2 complications)
Prolonged hypernatremia controls elevated intracranial pressure in head-injured pediatric patients
Peterson B, Khanna S, Fisher B, Marshall L.
Critical Care Medicine, 2000
This was a retrospective chart review of 68 patients who received continuous hypertonic saline infusions to reduce ICP by ≤20 mmHg. The authors noted a higher survival rate than expected by injury severity scores (they predicted 41% but 58% survived) and did not see what at the time was called central pontine myelinosis (osmotic demyelination syndrome), subarachnoid hemorrhage or rebound ICP increases.
Use of hypertonic saline in the treatment of severe refractory posttraumatic intracranial hypertension in pediatric traumatic brain injury
Khanna S, Davis D, Peterson B, Fisher B, Tung H, O’Quigley J, Deutsch R.
Critical Care Medicine, 2000
A prospective study of 10 children with elevated ICP resistant to conventional therapy (HOB 30 degrees, normothermia, sedation/analgesia/paralysis etc,.). Children got continuous infusion of 3% saline to keep ICP <20 mmHg. The authors noted a “statistically significant decrease in ICP spike frequency at 6, 12, 24, 48, and 72 hrs (p < .01).” Two of the ten patients developed acute renal failure – but this was also because they were both septic. Ultimately this study is harder to interpret in the context of the ED, since it was focused on patients refractory to other interventions.
Intravenous hypertonic saline use in the pediatric emergency department
Brenkert TE, Estrada CM, McMorrow SP, Abramo TJ.
Pediatr Emerg Care. 2013 Jan;29(1):71-3. doi: 10.1097/PEC.0b013e31827b54c3.
This retrospective chart review included patients who received hypertonic saline of varying doses (3-5 mL/kg) for a variety of conditions including TBI, with concern for increased intracranial pressure, diabetic ketoacidosis with altered mental status, hyponatremia without seizure activity, hyponatremic seizure and altered mental status secondary to a nontraumatic, non-diabetic ketoacidosis cause. They found no evidence of adverse effects but were only able to describe temporal trends in administration patterns.
Hyperosmolar therapy in pediatric traumatic brain injury: a retrospective study
Roumeliotis N, Dong C, Pettersen G, Crevier L, Emeriaud G.
Childs Nerv Syst. 2016 Dec;32(12):2363-2368. Epub 2016 Aug 27.
This retrospective review of patients with severe TBI in a PICU included patients with ICP monitoring and administration of a hyperosmolar agent (20% mannitol or 3 % hypertonic saline) within 48 hours of admission. In the 16 patients included (they excluded 3 times as many) “both mannitol and hypertonic saline were followed by a non-significant decrease in ICP (mannitol, p = 0.055 and hypertonic saline, p = 0.096).” They also noted that “a co-intervention occurred in 69 % of patients within the 4 h post hyperosmolar agent, and eight patients received continuous 3 % saline.”
Effectiveness of Pharmacological Therapies for Intracranial Hypertension in Children With Severe Traumatic Brain Injury–Results From an Automated Data Collection System Time-Synched to Drug Administration
Shein SL, Ferguson NM, Kochanek PM, Bayir H, Clark RS, Fink EL, Tyler-Kabara EC, Wisniewski SR, Tian Y, Balasubramani GK, Bell MJ.
Pediatr Crit Care Med. 2016 Mar;17(3):236-45. doi: 10.1097/PCC.0000000000000610.
A prospective observational study of ICP treatment with a number of different agents in children with severe TBI. They excluded ICP crises confounded by external stimulation or mechanical ventilator adjustments were excluded. The authors analyzed 196 doses of fentanyl, hypertonic saline, mannitol, and pentobarbital administered to 16 children (median: 12 doses per patient). They controlled for patients getting more than one of the meds and noted that ICP was decreased following hypertonic saline and pentobarbital administration; cerebral perfusion pressure was decreased following fentanyl and was increased following hypertonic saline administration. Finally “after adjusting for significant covariates (including age, Glasgow Coma Scale score, and intracranial pressure), hypertonic saline was associated with a two-fold faster resolution of intracranial hypertension than either fentanyl or pentobarbital.”
What about mannitol?
Studies on mannitol began in the 1960s (see Wise et. al). It works by decreasing blood viscosity which leads to reflexive vasoconstriction. This effect lasts for about 75 minutes. It also produces an osmotic gradient that draws fluid away from the brain into the vessels. The side effects include hypovolemia, electrolyte disturbances and renal failure. Animal models (Kaufmann et al) showed that repeated doses aggravated cerebral edema in cats – maybe because mannitol crossed the blood brain barrier and caused injury.
The current best evidence supports the use of hypertonic saline over mannitol. Per the the 2012 guideline for the acute medical management of severe traumatic brain injury in infants, children, and adolescents (Kochanek et al.) hypertonic saline received a Level II recommendation as the first line osmotic agent. This recommendation was based on the following:
Hypertonic saline better preserves intravascular status
It can be administered in a hemodynamically unstable patient
It restores normal cellular resting membrane potential and cell volume
It stimulates release of atrial natriuretic peptide releaseIt inhibits inflammation
It enhances cardiac output
So again, go with hypertonic saline instead of mannitol if you need an osmotic agent for elevated ICP.
Are there any risks?
Yes, but you generally won’t see these happen in the ED, and the benefit on decreasing ICP outweighs the risks, which include:
Rebound increased ICP
Hypernatremia (duh!) which can lead to acute kidney injury
Osmotic demyelination syndrome
Consider hypertonic saline (3% generally, but other concentrations exist) as the first line osmotic agent for use in children with acute elevation of intracranial pressure in the Emergency Department.
Brenkert TE, Estrada CM, McMorrow SP, Abramo TJ. Intravenous hypertonic saline use in the pediatric emergency department. Pediatr Emerg Care. 2013 Jan;29(1):71-3. doi: 10.1097/PEC.0b013e31827b54c3.
Khanna S, Davis D, Peterson B, Fisher B, Tung H, O’Quigley J, Deutsch R. Use of hypertonic saline in the treatment of severe refractory posttraumatic intracranial hypertension in pediatric traumatic brain injury. Critical Care Medicine, 2000
Kochanek PM, Carney N, Adelson PD, Ashwal S, Bell MJ, Bratton S, et al. Guidelines for the acute medical management of severe traumatic brain injury in infants, children, and adolescents – Second edition. Pediatr Crit Care Med. 2012;13(Suppl 1):S1–82.
Peterson B, Khanna S, Fisher B, Marshall L.Prolonged hypernatremia controls elevated intracranial pressure in head-injured pediatric patients. Crit Care Med. 2000 Apr;28(4):1136-43.
Roumeliotis N, Dong C, Pettersen G, Crevier L, Emeriaud G. Hyperosmolar therapy in pediatric traumatic brain injury: a retrospective study. Childs Nerv Syst. 2016 Dec;32(12):2363-2368. Epub 2016 Aug 27.
Shein SL, Ferguson NM, Kochanek PM, Bayir H, Clark RS, Fink EL, Tyler-Kabara EC, Wisniewski SR, Tian Y, Balasubramani GK, Bell MJ. Effectiveness of Pharmacological Therapies for Intracranial Hypertension in Children With Severe Traumatic Brain Injury–Results From an Automated Data Collection System Time-Synched to Drug Administration. Pediatr Crit Care Med. 2016 Mar;17(3):236-45. doi: 10.1097/PCC.0000000000000610.
Simma B, Burger R, Falk M, Sacher P, Fanconi S. A prospective, randomized, and controlled study of fluid management in children with severe head injury: lactated Ringer’s solution versus hypertonic saline. Crit Care Med. 1998 Jul;26(7):1265-70.
Wise BL, Chater N. The value of hypertonic mannitol solution in decreasing brain mass and lowering cerebro-spinal-fluid pressure. J Neurosurg. 1962;19:1038–43.