Ir J Med Sci DOI 10.1007/s11845-014-1080-9

ORIGINAL ARTICLE

Single bolus 30 % hypertonic saline for refractory intracranial hypertension E. H. Major • P. O’Connor • B. Mullan

Received: 13 October 2013 / Accepted: 3 February 2014 Ó Royal Academy of Medicine in Ireland 2014

Abstract Background In recent years hypertonic saline has attracted increasing interest in the treatment of traumatic intracranial hypertension, and has a number of documented and theoretical advantages over other hyperosmolar agents. To date, no consensus has been achieved on the safest and most effective HTS concentration for administration. Aims The purpose of this paper was to evaluate the efficacy of intravenous bolus administration of highly concentrated (30 %) hypertonic saline (HTS) in the treatment of refractory intracranial hypertension secondary to traumatic brain injury. Methods Patients were treated with an intravenous bolus of 10 ml of 30 % hypertonic saline. Multiple physiological parameters were measured throughout, including intracranial pressure, mean arterial pressure, cerebral perfusion pressure, pulse and inotrope/pressor requirements. Laboratory investigation pre and post HTS administration included: arterial pH, pCO2, HCO3, base excess; serum biochemistry measurements of sodium, potassium, chloride, urea and creatinine; and coagulation studies. Results TBI patients saw a rapid and significant reduction in ICP from a baseline value of 28 ± 5.31 to 18.44 ± 6.17 mmHg at 1 h post HTS, a statistically significant reduction that was maintained for up to 7 h. This response was maintained even with repeated HTS administration, which was also associated with an augmented cerebral perfusion pressure from a baseline of 58.0 ± 6.48 to 76.33 mmHg within 1 h of HTS administration.

E. H. Major (&)  P. O’Connor  B. Mullan Regional Intensive Care Unit, Royal Victoria Hospital, Grosvenor Road, BT12 6BA Belfast, Northern Ireland, UK e-mail: [email protected]

Conclusion No associated harmful biochemical or haematological abnormalities were noted. In conclusion, highly concentrated 30 % HTS appears to be both effective and safe in the management of refractory intracranial hypertension. Keywords Hypertonic saline solutions  Intracranial hypertension  Intensive care  Traumatic brain injuries  Cerebral edema  Mannitol

Introduction Traumatic brain injury (TBI) remains a leading cause of mortality, morbidity and economic cost to societies worldwide [1]. Primary brain insults are associated with a secondary brain injury––a complex cascade of consecutive and concurrent pathophysiological events including cerebral vasospasm, loss of cerebrovascular autoregulation with subsequent damaging alterations to cerebral blood flow (resulting in both hypoperfusion and hyperperfusion), cerebral metabolic dysfunction, vasogenic and cytotoxic oedema, neuronal excitotoxicity, intracranial hypertension, overwhelming oxidative stress activation of numerous immunological and inflammatory pathways [2]. While the primary brain injury is not amenable to therapeutic measures, the secondary events listed above can be ameliorated. Hyperosmolar therapy remains a central pillar in the treatment of traumatic brain injury, particularly in the context of relieving intracranial hypertension (ICP) [3]. The two current hyperosmolar agents in widespread use are mannitol and hypertonic saline (HTS). In recent years HTS has attracted increasing interest and utilisation despite the lack of high-quality studies recommending its use. To date,

123

Ir J Med Sci

no consensus has been achieved on the safest and most effective HTS concentration for administration. HTS has a number of documented and theoretical advantages over mannitol. Firstly, in cases where aetiology results in a largely intact blood brain barrier (BBB), the endothelium is less permeable to saline than to mannitol due to its high reflection coefficient and as such is more osmotically effective [4–6]. There are reports of HTS effectively reducing intracranial pressure (ICP) in patients with intracranial hypertension refractory to mannitol, although not all involved TBI aetiology [7–12]. It remains unclear if this success is solely due to superior osmotic potential. Secondly, use of HTS may avoid well-documented adverse effects of mannitol use, including rebound ICP elevation, intravascular volume depletion with reduced cerebral perfusion pressure (CPP), and renal failure [13, 14]. Finally, the use of concentrated HTS allows clinicians to employ a ‘‘low-volume resuscitation’’ strategy in the haemorhagically shocked trauma patient, an aspect of trauma care attracting ongoing interest. It should be noted that the use of HTS is not restricted to TBI aetiologies only and is being increasingly employed in the management of tumour oedema, post-neurosurgical intracranial hypertension, subarachnoid and intracerebral haemorrhage, venous hypertension and infarction, and acute liver failure [4]. A recent paper by Murphy et al. [5] describes the safe and efficacious use of 30 % HTS in the treatment of elevated ICP in the context of acute liver failure. At our institution 30 % HTS is routinely available and has been used in the treatment of refractory intracranial hypertension. The purpose of this paper was to study the efficacy of 30 % HTS in the treatment of refractory intracranial hypertension in traumatic brain injuries.

Materials and methods Patient selection All patients were previously inpatient of the Royal Victoria Hospital Regional Intensive Care Unit, Belfast, Northern Ireland. A database search was performed utilising the unit’s Philips Medical Systems IntelliVue Clinical Electronic Information Record to identify all patients receiving 30 % HTS in the period from January 2009 to December 2010. From this cohort, a population sample of 20 patients here randomly chosen and their records were examined in detail. 5 patients were excluded on the basis of insufficient data (all patients were in either operating theatre or computed tomography scanner at time of HTS administration with subsequent lack of detailed physiological data). Of the remaining 15 patients, 4 were female and 11 were male, average age was 36 (range 27) years and average weight

123

was 83 (range 106) kg. All patients had suffered traumatic brain injuries (2 patients fell down stairs, 2 falls from height, 4 victims of assault and 7 road traffic collisions), sustaining a diverse range of severe intracranial injuries (3 with subdural and traumatic subarachnoid haemorrhages, 6 with subdural haemorrhages and significant intraparenychmal contusions, 2 with isolated diffuse axonal injuries, 3 with subdural haemorrhages and diffuse axonal injuries, and 1 patient with both extradural and subdural haemorrhages with significant intraparenchymal contusions). All patients had ICP measured via an intraparenchymal wire catheter (Codman MicroSensor, Johnson & Johnson, Raynham, MA, USA), placed in the frontal lobe. All physiological parameters and laboratory investigations were tabulated for the purpose of retrospective analysis. Given the refractory nature of the intracranial hypertension, several other ICP controlling measures were concomitantly employed. All patients were intubated and ventilated and all patients were heavily sedated with a combination of propofol, synthetic opiates (fentanyl) and benzodiazepines (midazolam). Also, 7 received mannitol infusions, 4 had an external ventricular drain (EVD) inserted post intraparenchymal wire manometer insertion, 3 received a thiopentone infusion and 3 underwent a decompressive craniectomy. Dynamic physiological measurements and laboratory investigations Real time recordings of each patient were made via Philips Medical Systems IntelliVue Clinical Electronic Information Record. The following physiological parameters were analysed just prior to HTS administration and at 1 h intervals up to 8 h post HTS administration: ICP, mean arterial pressure (MAP), CPP, pulse and inopressor requirements (noradrenaline in every patient). Laboratory investigation pre and post HTS administration was also analysed, including: arterial blood gas (ABG) measurements of pH, pCO2, HCO3, base excess (BE), sodium and potassium at approximately 2 h pre and 2 and 4 h post HTS administration; serum biochemistry measurements of sodium, potassium, chloride, urea and creatinine at approximately 6 h pre and 4, 10 and 20 h post HTS administration; and coagulation prothrombin time (PT) and activated partial thromboplastin time (APTT) at approximately 10 h pre and 10 and 20 h post HTS administration. Hypertonic saline administration 10 ml of 30 % HTS was administered as a bolus dose over a maximum of 10 min via central venous catheter in response to acute refractory intracranial hypertension

0.6723 0.207 ± .171 0.185 ± .167 0.175 ± .162 0.178 ± .163 0.133 ± .135 Data are presented as mean ± SD

* P \ 0.05,  P \ 0.01, àP \ 0.001 vs. baseline values (time = 0 min)

0.289 ± .400 0.291 ± .400 0.306 ± .395 0.334 ± .385 Noradrenaline requirements (lg/kg/min)

0.9984

0.4286 96.8 ± 10.3

74 ± 24 72 ± 18

93.4 ± 9.4 94.3 ± 9.0

73 ± 20 71 ± 16

98.3 ± 4.4 91.3 ± 7.5

74 ± 17 75 ± 19

89.0 ± 11.5 92.4 ± 4.3

74 ± 19 75 ± 18

95.1 ± 9.3 97.3 ± 10.5 MAP (mmHg)

75 ± 20

70.2 ± 13.7 CPP (mmHg)

Pulse

0.0004 20.1 ± 7.1

76.5 ± 10.8 75.1 ± 12.1 76.0 ± 11.3 81.1 ± 4.5 72.1 ± 11.0 70.1 ± 13.4 73.9 ± 7.2

28.8 ± 5.3 ICP (mmHg)

76.7 ± 9.0

18.8 ± 4.1à 18.6 ± 4.4  17.7 ± 3.4à 19.3 ± 6.3  19.0 ± 3.9à 18.6 ± 6.0à

7h 6h 5h 4h 3h 2h 1h

In total 15 patients were included in the study, incorporating 22 separate administrations of 30 % HTS. Physiological data from patients receiving a single first dose of HTS (n = 15) are presented in Table 1. Traumatic brain injury patients saw a rapid and significant reduction in ICP from a baseline value of 28 ± 5.31 to 18.44 ± 6.17 mmHg at 1 h post HTS. This statistically significant reduction was maintained for 7 h (Fig. 1). Changes in all other physiological variables, including CPP, MAP, pulse and noradrenaline requirements remained insignificant at all times post HTS administration. Similarly, physiological data from patients receiving a subsequent bolus of HTS (more than 8 h from previous dose, n = 7) are presented in Table 2. Traumatic brain injury patients again saw a rapid, significant decrease in ICP from a baseline value of 33.0 ± 5.83 to 16.17 ± 4.88 mmHg 1 h post HTS. This statistically significant reduction persisted for at least 8 h (Fig. 2). In the case of repeated HTS boluses, patients with traumatic brain injuries were also noted to have a significant increase in their CPP at 1, 2 and 5 h post HTS administration (Table 2). Again, all other physiological variables saw no significant alteration.

Time 0

Efficacy

Time

Results

Table 1 Physiological response to single first dose of 30 % HTS administration in patients with refractory intracranial hypertension (n = 15)

Analyses of efficacy and safety were made on patients receiving a single, first dose of HTS. In order to assess continuing efficacy and safety of HTS in recurrent usage we furthermore analysed data from a sub-group of 7 patients who received a second dose of HTS for highly refractory intracranial hypertension more than 8 h after the first (on average 728 ± 241 min post initial HTS administration). Results were analysed using Prism 5 (GraphPad Software) statistical software. Data are reported as mean ± SD unless otherwise stated. Changes in physiological, biochemical and haematological parameters following HTS administration were assessed using one-way repeated measures ANOVA with post-test Bonferroni’s multiple comparison test. P \ 0.05 was considered statistically significant.

8h

Data and statistical analysis

18.4 ± 6.2à

p value (ANOVA)

(defined as an acute rise in ICP [ 20 mmHg which was sustained for [ 5 min despite other ICP controlling measures).

0.0605

Ir J Med Sci

123

123

0.9679 0.283 ± .286 0.296 ± .284 0.275 ± .257 0.267 ± .248 0.26 ± .228 0.250 ± .206

à

P \ 0.01  

Data are presented as mean ± SD

* P \ 0.05

P \ 0.001 vs. baseline values (time = 0 min)

0.234 ± .163 0.271 ± .183 0.287 ± .142 Noradrenaline requirements (lg/kg/min)

0.8212

0.0887 86.7 ± 13.8

76 ± 19 80 ± 30

95.0 ± 11.1 92.8 ± 11.7

82 ± 25 79 ± 18

86.2 ± 12.0 83.7 ± 7.5

80 ± 14 82 ± 19

90.8 ± 9.4 89.5 ± 9.9

76 ± 11 80 ± 14

90.5 ± 10.6 90.7 ± 8.1 MAP (mmHg)

76 ± 11

74.0 ± 8.5 76.3 ± 7.4 58.0 ± 6.5 CPP (mmg)

Pulse

0.0003

0.0121 71.0 ± 11.8 72.7 ± 3.3 74.8 ± 12.4* 69.7 ± 12.8 68.5 ± 5.5 72.5 ± 13.9

15.2 ± 8.0  18.7 ± 11.4* 17.5 ± 8.6* 16.8 ± 8.3* 15.7 ± 7.7 

  à

6h 5h 4h 3h

18.3 ± 7.5  16.3 ± 8.5  16.2 ± 4.9  33.0 ± 5.8 ICP (mmHg)

This paper describes a retrospective analysis of patients receiving highly concentrated HTS for the management of refractory intracranial hypertension. The principle mechanism by which HTS reduces intracranial hypertension is that of simple osmotherapy reducing intraparenchymal brain volume [15–17]. Further mechanisms which have been postulated include: changes in blood rheology (blood fluid dynamics), in particular by erythrocyte dehydration, decreased blood viscosity, and a reduction in endothelial oedema and capillary resistance [13, 18–21]; augmenting cellular structural integrity and cytoskeletal dynamics, stabilising neuronal cell membranes and the neurochemical environment [13]; and through the modulation of the inflammatory response and reduction of leucocyte adhesion to endothelium [13, 22]. It is likely that the utilisation of HTS also augments circulating blood volume and mean arterial pressure (MAP)—thereby inducing a cerebroprotective rise in CPP [15, 23–25]. A wide range of concentrations is seen in the literature, from 1.6 % to 29.2 %, administered both in bolus and infusion form [26], with no widespread agreement on the

2h

Discussion

1h

Real time measurement of sodium, potassium, urea, creatinine, chloride, pH, pCO2, base excess, bicarbonate, prothrombin time, activated partial thromboplastin time was performed as described above. No statistically significant change was observed in any of the above variables at any time point (biochemistry results displayed in Table 3—remainder data not shown), even amongst patients receiving 2 HTS boluses.

Time 0

Safety

Time

Fig. 1 ICP response to single first dose of 30 % HTS administration in patients with refractory intracranial hypertension (n = 15). Data are presented as mean ± SD. * P \ 0.05,   P \ 0.01, à P \ 0.001 vs. baseline values (time = 0 min)

Table 2 Physiological response to repeat dose of 30 % HTS administration in patients with refractory intracranial hypertension (n = 7)

7h

8h

p value (ANOVA)

Ir J Med Sci

62.7 (±15.4)

115.2 (±10.0)

62.5 (±18.4)

114.3 (±9.0) Data are presented as mean ± SD

P values [ 0.05 throughout

65.0 (±22.2) 66.1 (±23.1)

111.1 (±7.8) Chloride

Creatinine 47.0 (±24.8)

113.6 (±6.4) 114.6 (±5.1)

51.00 (±20.5) 49.3 (±25.6)

113.9 (±4.6)

58.5 (±23.0)

112.7 (±6.0) Chloride

Creatinine

Fig. 2 ICP response to repeat dose of 30 % HTS administration in patients with refractory intracranial hypertension (n = 7). Data are presented as mean ± SD. * P \ 0.05,   P \ 0.01, à P \ 0.001 vs. baseline values (time = 0 min)

112.9 (±8.0)

3.8 (±0.6)

7.0 (±2.8) 7.6 (±2.7) 6.6 (±3.1) 6.4 (±3.0) Urea 6.6 (±5.2) 6.3 (±5.2) 4.8 (±2.1) Urea

5.0 (±1.9)

144.3 (±5.2)

3.7 (±0.2)

144.0 (±5.0) 144.4 (±3.6)

3.8 (±0.3) 3.9 (±0.6)

142.0 (±4.0) Sodium

Potassium 3.9 (±0.3)

142.6 (±4.0)

4.2 (±0.6)

4.1 (±0.8)

142.8 (±3.4) 142.9 (±4.0) Sodium

Potassium

144.2 (±3.5)

?20 h ?10 h ?4 h -6 h

3.9 (±0.3)

?20 h ?10 h ?4 h Time Time

-6 h

Repeat dose HTS ([8 h apart) Single first dose only HTS

Table 3 Biochemical response to single first dose (n = 15) and repeated dose (n = 7) of 30 % HTS administration in patients with refractory intracranial hypertension

Ir J Med Sci

safest and most effective HTS concentration for administration. To our knowledge, this study represents the first time highly concentrated 30 % HTS is described for the management of refractory intracranial hypertension, although such highly concentrated solutions are widely used internationally. Highly concentrated HTS has theoretical advantages over less concentrated, higher volume preparations, principally revolving around the modern paradigm of low-volume resuscitation, and as 30 % HTS has an osmolarity of 10.33 mOsm/ml (approximately a tenfold increase on 20 % mannitol), it is an excellent candidate for use where low-volume resuscitation is particularly important. In terms of efficacy, we found that 30 % HTS appears to effectively reduce ICP for up to 8 h in patients whose primary brain injury had a traumatic aetiology. The efficacy of HTS does not appear to diminish on administration of a second bolus. Patients who received a second administration of HTS also had a brief but significant increase in CPP with no change in MAP or inopressor requirements. It is notable that no increase in serum sodium concentration was seen at any time point, even as early as 1 h post-HTS administration. Therefore, the hyperosmolar effect of small volumes of HTS is likely to be rapid yet transient in nature, and appears to have a prolonged effect. It should also be borne in mind that the total amount of sodium administered using small volumes of highly concentrated HTS is less when compared to many other commonly used HTS concentrations and doses. The pharmacokinetics and pharmacodynamics of highly concentrated HTS solutions remain to be fully elucidated however. There are continues safety concerns regarding the use of hypertonic saline, including renal failure, osmotic demyelination syndrome, rebound oedema and increases in ICP, excessive increases in serum osmolality, electrolyte disturbance and non-anion gap acidosis, volume overload,

123

Ir J Med Sci

coagulopathy, thrombophlebitis and tissue necrosis [4, 13, 26, 27]. However, this study of 30 % HTS was associated with no significant biochemical or haematological abnormalities or other adverse effects. In order to overcome the inherent potential bias and confounding of any retrospective study, we felt important that data were analysed in a highly conservative fashion. HTS effects were deemed significant by two-tailed t test only if both a one-way repeated measures ANOVA and post-test Bonferroni’s multiple comparison test indicated significance. This statistical technique has drawn criticism over recent years in that its conservative nature may propagate type II errors [28], i.e. HTS is deemed ineffective in all cases of refractory intracranial hypertension. Despite the use of such stringent statistical methodology, this study found HTS to be effective and safe in the management of refractory hypertension. We do acknowledge the use of separate concomitant ICP controlling measures as described in the ‘‘Materials and methods’’ section is a study weakness, but would argue this represents a ‘‘real world’’ situation inherent to any retrospective study and does not render its findings valueless. Clearly further prospectively designed, controlled trials are vital.

Conclusions In conclusion, this paper strengthens the argument that 30 % HTS is effective and safe in the management of refractory intracranial hypertension in patients with traumatic brain injury. Whether this, in concomitant association with other therapeutic tools, translates into improved clinical outcomes requires further study. Conflict of interest Dr. Major has nothing to disclose. Dr. O’Connor has nothing to disclose. Dr. Mullan has nothing to disclose.

References 1. Brain Trauma Foundation, Surgeons AAON, Surgeons CON et al (2007) Guidelines for the management of severe traumatic brain injury. introduction. J.Neurotrauma 24(Suppl 1):S1–S2 2. Werner C, Engelhard K (2007) Pathophysiology of traumatic brain injury. Br J Anaesth 99:4–9 3. Brain Trauma Foundation, Surgeons AAON, Surgeons CON et al (2007) Guidelines for the management of severe traumatic brain injury. II. hyperosmolar therapy. J.Neurotrauma 24(Suppl 1):S14–S20 4. Ogden AT, Mayer SA, Connolly ES Jr (2005) Hyperosmolar agents in neurosurgical practice: the evolving role of hypertonic saline. Neurosurgery. 57:207–215 (discussion 207–215) 5. Murphy N, Auzinger G, Bernel W et al (2004) The effect of hypertonic sodium chloride on intracranial pressure in patients with acute liver failure. Hepatology 39:464–470

123

6. Fenstermacher JD, Johnson JA (1966) Filtration and reflection coefficients of the rabbit blood–brain barrier. Am J Physiol 211:341–346 7. Horn P, Munch E, Vajkoczy P et al (1999) Hypertonic saline solution for control of elevated intracranial pressure in patients with exhausted response to mannitol and barbiturates. Neurol Res 21:758–764 8. Schwarz S, Georgiadis D, Aschoff A et al (2002) Effects of hypertonic (10%) saline in patients with raised intracranial pressure after stroke. Stroke 33:136–140 9. Schwarz S, Schwab S, Bertram M et al (1998) Effects of hypertonic saline hydroxyethyl starch solution and mannitol in patients with increased intracranial pressure after stroke. Stroke 29:1550–1555 10. Vialet R, Albanese J, Thomachot L et al (2003) Isovolume hypertonic solutes (sodium chloride or mannitol) in the treatment of refractory posttraumatic intracranial hypertension: 2 mL/kg 7.5% saline is more effective than 2 mL/kg 20% mannitol. Crit Care Med 31:1683–1687 11. Suarez JI, Qureshi AI, Bhardwaj A et al (1998) Treatment of refractory intracranial hypertension with 23.4% saline. Crit Care Med 26:1118–1122 12. Worthley LI, Cooper DJ, Jones N (1988) Treatment of resistant intracranial hypertension with hypertonic saline. Report of two cases. J Neurosurg 68:478–481 13. Himmelseher S (2007) Hypertonic saline solutions for treatment of intracranial hypertension. Curr Opin Anaesthesiol 20:414–426 14. Wakai A, Roberts I, Schierhout G (2007) Mannitol for acute traumatic brain injury. Cochrane Database Syst Rev (1): CD001049 15. Schmoker JD, Shackford SR, Wald SL et al (1992) An analysis of the relationship between fluid and sodium administration and intracranial pressure after head injury. J Trauma 33:476–481 16. Zornow MH (1996) Hypertonic saline as a safe and efficacious treatment of intracranial hypertension. J Neurosurg Anesthesiol 8:175–177 17. Berger S, Schurer L, Hartl R et al (1995) Reduction of posttraumatic intracranial hypertension by hypertonic/hyperoncotic saline/dextran and hypertonic mannitol. Neurosurgery. 37: 98–107 (discussion 107–108) 18. Mazzoni MC, Borgstrom P, Intaglietta M et al (1990) Capillary narrowing in hemorrhagic shock is rectified by hyperosmotic saline-dextran reinfusion. Circ Shock 31:407–418 19. Prough DS, Whitley JM, Taylor CL et al (1991) Regional cerebral blood flow following resuscitation from hemorrhagic shock with hypertonic saline. Influence of a subdural mass. Anesthesiology 75:319–327 20. Schmoker JD, Zhuang J, Shackford SR (1991) Hypertonic fluid resuscitation improves cerebral oxygen delivery and reduces intracranial pressure after hemorrhagic shock. J Trauma 31:1607–1613 21. Shackford SR, Zhuang J, Schmoker J (1992) Intravenous fluid tonicity: effect on intracranial pressure, cerebral blood flow, and cerebral oxygen delivery in focal brain injury. J Neurosurg 76:91–98 22. Hartl R, Ghajar J, Hochleuthner H et al (1997) Hypertonic/ hyperoncotic saline reliably reduces ICP in severely head-injured patients with intracranial hypertension. Acta Neurochir Suppl 70:126–129 23. Qureshi AI, Suarez JI (2000) Use of hypertonic saline solutions in treatment of cerebral edema and intracranial hypertension. Crit Care Med 28:3301–3313 24. Suarez JI (2004) Hypertonic saline for cerebral edema and elevated intracranial pressure. Cleve Clin J Med 71(Suppl 1):S9–S13 25. Tollofsrud S, Tonnessen T, Skraastad O et al (1998) Hypertonic saline and dextran in normovolaemic and hypovolaemic healthy

Ir J Med Sci volunteers increases interstitial and intravascular fluid volumes. Acta Anaesthesiol Scand 42:145–153 26. White H, Cook D, Venkatesh B (2008) The role of hypertonic saline in neurotrauma. Eur J Anaesthesiol Suppl 42:104–109 27. White H, Cook D, Venkatesh B (2006) The Use of hypertonic saline for treating intracranial hypertension after traumatic brain injury. Anaesth Analg 102:1836–1866

28. Ninomiya Y, Fujisawa H (2007) A conservative test for multiple comparison based on highly correlated test statistics. Biometrics 63:1135–1142

123

Single bolus 30% hypertonic saline for refractory intracranial hypertension.

In recent years hypertonic saline has attracted increasing interest in the treatment of traumatic intracranial hypertension, and has a number of docum...
422KB Sizes 3 Downloads 0 Views