Cardiac output changes after osmotic therapy in neurosurgical and neurocritical care patients: a systematic review of the clinical literature

Abstract

Aim

Osmotherapy constitutes a first‐line intervention for intracranial hypertension management. However, hyperosmolar solutes exert various systematic effects, among which their impact on systemic haemodynamics is poorly clarified. This review aims to appraise the clinical evidence of the effect of mannitol and hypertonic saline (HTS) on cardiac performance in neurosurgical and neurocritical care patients.

Method

A database search was conducted to identify randomized clinical trials and observational studies reporting HTS or mannitol use in acute brain injury setting. The primary end‐points were alterations of cardiac output (CO) and other haemodynamic variables, while the impact of osmotic agents on intracranial pressure, brain relaxation, plasma osmolality, electrolyte levels and urinary output constituted secondary outcomes.

Results

Eight studies, enrolling 182 patients in total, were included. HTS exerted a more profound cardiac output augmentation than mannitol, but no distinct difference between groups occurred. Central venous pressure, stroke volume and stroke volume variation were favourably affected by both osmotic agents, whilst the reported changes in blood pressure were inconclusive. HTS infusion yielded a larger intracranial pressure reduction than mannitol but had an equivalent effect on brain relaxation. Mannitol presented a more potent diuretic effect than HTS. Effect on serum osmolality was alike in both osmotic agents, but contrary to HTS‐promoted hypernatraemia, mannitol use induced transient hyponatraemia.

Conclusions

Mannitol or HTS administration seems to induce an enhancement of cardiac performance; being more prominent after HTS infusion. This effect combined with mannitol‐induced enhancement of diuresis and HTS‐promoted increase of plasma sodium concentration could partially explain the effects of osmotherapy on cerebral haemodynamics.

What is Already Known about this Subject

• Osmotherapy with either mannitol or hypertonic saline (HTS) is the recommended first‐line medical intervention for optimizing cerebral perfusion through brain relaxation.

• Mannitol has long been used as osmotic agent for ensuring brain relaxation in neurosurgical patients undergoing craniotomy, but the clinical benefit of mannitol infusion in acute brain injury setting, has not yet been proven according to evidence‐based medicine.

• Recent guidelines suggest the use of HTS as a second‐line therapy in case mannitol fails to reduce intracranial pressure, in patients sustaining traumatic brain injury.

What this Study Adds

• Both mannitol and HTS induce an increase in cardiac output, which is more pronounced after HTS than mannitol administration.

• Mannitol and HTS infusion are associated with a trend towards to mean arterial pressure and heart rate reduction.

• Both osmotic agents induced an intracranial pressure reduction and brain relaxation, an effect that seems to be more prominent in HTS‐treated patients.

Introduction

Elevated intracranial pressure (h‐ICP) has long been identified as a key factor for the development of secondary brain injury in patients with intracranial pathology. Among the various strategies used to reduce the intensity and duration of h‐ICP, osmotherapy with either mannitol or hypertonic saline (HTS) is the recommended first‐line medical intervention for optimising cerebral perfusion through brain relaxation and hence preventing pertinent neurological deterioration 1. The fundamental concept of the effectiveness of hyperosmolar solutes involves an acute augmentation of blood osmolality, combined with blood–brain barrier impermeability to mannitol and sodium, which facilitates water extraction from brain tissue to intravascular compartment 2.

Although water shift achieves a substantial reduction of brain bulk, it can potentially modify cerebral and systemic haemodynamics in an important manner. Possible theories include an increase of systemic intravascular volume, which results in a decrease of serum viscosity with a concomitant augmentation of both cardiac output (CO) and blood pressure; the latter effect leads to a fall of cerebral blood flow due to compensatory cerebral vasoconstriction 3. With mannitol, this is promptly followed by a profound diuresis, often leading to hypovolaemia. Considering that HTS has no diuretic properties, the volume expansion is sustained for a considerable time, thus giving it a distinct superiority in the setting of hypovolaemia (Table 1) 3, 4, 5.

Table 1.

Physiological and clinical effects of mannitol vs. hypertonic saline

	Mannitol	Hypertonic saline
Primary mechanism	• Increases gradient across BBB	• Increases gradient across BBB
	• Rapid reduction of ICP	• Immediate reduction of ICP
	• Duration of effect: up to 6 h	• Duration of effect: up to 4 h
Secondary mechanisms	• Cerebral vasoconstriction	• Mixed immunomodulatory and inflammatory effects
	• Decreases blood viscosity
	• Increases cerebral blood flow
Reflection coefficient	0.9 = mostly impermeable (assuming intact BBB)	1.0 = completely impermeable (assuming intact BBB)
Haemodynamic effects	• Transient expansion of intravascular volume → ↑ cardiac output	• Expands intravascular volume → ↑ cardiac output
	• Brisk osmotic diuresis→ hypovolaemia and hypotension	• Increases mean arterial pressure
	• Peripheral vasodilation	• Transient vasodilation
Advantages over the other	• ↓ CSF production leads to prolonged ↓ ICP	• Superior brain oxygenation and quicker onset
	• Minimum effects on serum Na levels	• More effective osmotically
		• Lack of diuretic effect, ↓risk of
		nephrotoxicity
Adverse effects	• Rebound ↑ ICP	• Hyperkalaemia, hypernatraemia Hyperchloraemic metabolic acidosis
	• Hyperkalaemia, transient dilutional hyponatraemia	• Central pontine myelinolysis
	• Nephrotoxicity	• Acute renal dysfunction

BBB, blood–brain barrier; ICP, intracranial pressure; CSF, cerebrospinal fluid

Mannitol, a nonmetabolized alcohol derivate of mannose, was introduced for clinical use in 1961 and it has been used as osmotic agent for the treatment of brain oedema and h‐ICP and for ensuring brain relaxation in neurosurgical patients undergoing craniotomy 6, 7. However, in patients sustaining an acute brain injury, the clinical benefit of mannitol infusion, its use in traumatic brain injury setting has not yet been proven according to evidence‐based medicine criteria; the treatment of brain oedema is supported by level II evidence 8.

Clinical use of HTS has been introduced for prehospital intravascular volume restoration in patients with severe haemorrhage and is increasingly used for the treatment of brain oedema and h‐ICP 9, 10. Recent guidelines suggest the use of HTS as a second‐line therapy in cases where mannitol fails to reduce ICP 8. Despite hyperosmolar solutions being routinely used in neurosurgical and neurocritical care (NCC) patients for brain relaxation and ICP management 8, 9, 10, 11, 12, 13, 14, there is scanty information on the time course of their haemodynamic effects.

The purpose of this systematic review (SR) is to report clinical evidence of the effects of mannitol or HTS infusion on cardiac performance and systemic haemodynamics as a primary endpoint, with changes of plasma osmolarity, electrolytes concentration and urinary output as secondary outcomes in neurosurgical and NCC patients.

Methods

Search strategy and study selection

This SR was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐analyses) statement recommendations 15 and was registered in the PROSPERO database under the number CRD42017062358. An electronic literature research of PubMed, EMBASE, Cochrane Central Register of Controlled Trials and International Web of Science databases from their inception to 2017 was performed to detect clinical studies pertinent to the administration of mannitol or HTS in neurosurgical or NCC population for h‐ICP management.

For literature search purposes the subject headings “mannitol” and “hypertonic solutions” combined with free text words as “brain injury”, “cerebral oedema”, “neurosurgical procedures”, “craniotomy”, “neurocritical care”, “haemodynamics” or “cardiac output”, were applied. The search strategy is presented in Appendix 1. An ultimate check of the databases was carried out on 10 July 2017. Based on the search strategy applied, two investigators (G.T. and M.C.) independently screened and assessed titles and abstracts of all studies, and identified and discarded those that were obviously irrelevant or duplicates. If eligibility could not be ascertained from the title or the abstract, the full text of the study was retrieved and those deemed suitable were reviewed for eligibility according to the study characteristics and clinical relevance. References in the selected papers were scrutinized for additional articles in a further effort to ensure that relevant publications were not missed. Any disagreement over eligibility was resolved by consensus or by a third investigator (F.B.), as appropriate.

Inclusion and exclusion criteria

To be eligible for this SR, publications had to meet the following inclusion criteria: (i) peer‐reviewed original research articles of any study design (randomized controlled trials, observational studies, and case series), involving prospective or retrospective data collection; (ii) adult population (age >18 years); (iii) provision of complete data with respect to CO change from baseline to the last measurement after termination of the infusion of either mannitol or HTS (single bolus dose or repeated infusion); (iv) availability of full‐text publication in English language.

Data extraction and quality assessment

A dedicated data extraction form was developed for recording all relevant details. The extracted data were as follows: publication details (author, year of publication), study design, details of the study population (underlying brain pathology and number of patients), intervention (mannitol or HTS concentration and dosage), type and timing of haemodynamic monitoring and findings related to primary or secondary outcomes of interest. The primary outcome measure was the effect of mannitol or HTS on cardiovascular variables, such as: CO or cardiac index (CI), mean arterial pressure (MAP), heart rate (HR), central venous pressure (CVP), stroke volume (SV), stroke volume variation (SVV) and systemic vascular resistance (SVR). Secondary outcomes included their impact on ICP, brain relaxation, plasma osmolality, electrolyte imbalance and urinary output. Selected full papers were critically appraised and quality‐assessed, using the Jadad scale 16 and the ROBINS‐1 tool 17 for randomized controlled trials (RCTs) and observational cohort studies, respectively. Additional information on intention‐to‐treat and withdrawal or dropout rate for RCTs were also recorded. The bias risk in each study was judged by Cochrane Collaboration Risk of Bias Tool 18, which incorporates the following domains: sequence generation, allocation concealment, blinding (including participants and personnel, data collectors, outcome assessors), acquisition of data, selective outcome reporting and other sources of bias. Each item was classified as low, unclear or high risk of bias.

Results

Study selection

A total of 6437 records were retrieved from database search, of which 1177 were screened and identified as possible appropriate publications after filtering. After review of titles and abstracts, 122 studies were selected as being potentially eligible for inclusion in this systematic review. Of these, 96 were eliminated as double publications, and 26 were reviewed for possible inclusion in this SR. The full‐text evaluation identified 18 studies as not appropriate, no full‐text publication and non‐observational or RCT studies, and were finally excluded. The selected eight articles consisted of four RCTs 19, 20, 21, 22 and three prospective 23, 24, 25 and 1 retrospective 26 observational studies, that enrolled a total of 182 adult patients. All these studies met the criteria to be included in the final qualitative appraisal, whilst considerable heterogeneity in methodology, as well as under‐reporting of CO as primary outcome endpoint, precluded from further quantitative analysis. The literature review results and study selection process are summarized in Figure 1.

Figure 1.

Flow diagram showing the results of the search and reasons for exclusion of studies. NA, not‐assessed; SAH, subarachnoid haemorrhage

Description of included trials

Five studies were conducted in elective craniotomy setting 20, 21, 22, 23, 26, while the remaining three enrolled NCC patients treated either for subarachnoid haemorrhage 9 or traumatic brain injury 24, 25. Three studies included the administration of either mannitol 23, 25 or HTS 24 as a sole osmotherapy; four trials (two observational and two RCTs) compared mannitol with HTS [combined or not to hydroxyethyl starch (HES)] 20, 21, 22, 24, and in one RCT, the haemodynamic effects of mixed HTS‐HES solution were tested against placebo 19. Haemodynamic effects of mannitol were recorded as primary outcome end‐point in two of the included studies 23, 24. The concentration and dose of HTS and mannitol varied among the included trials in an important manner. In detail, the tested doses for mannitol 20% ranged between 0.6 and 1 g kg^–1 and for HTS 3–7.5% from 1.5 to 5.3 ml kg^–1, with a reported duration of infusion ranging from 10 to 30 min. A considerable variability was recorded in the timing of osmotic agents administration. As for the subgroup of patients subjected to craniotomy surgery, this was defined as 15 min before dura opening 23, 25, 30 min before skull opening 21, during scalp incision 20 or shortly afterwards the drilling for the first burr hole of craniotomy was performed 22.

Outcomes were assessed at different time points after termination of osmotic agent administration (ranging from 1 min to 6 h), while in one RCT systemic haemodynamic parameters were recorded at two different phases during the infusion of the tested drugs 20. The cut‐off ICP values defined as a criterion for osmotherapy application in NCC patients ranged from 15 mmHg 23 to 20 mmHg 26, whereas ethical issues in a placebo‐controlled RCT dictated the administration of an osmotic agent for ICP values <20 mmHg 19. Moreover, a notable discrepancy in the follow‐up period was recorded ranging from 45 min 21, 22, 26 to 6 h 20. The most common tool for continuous non‐invasive estimation of CO was based on pulse contour analysis, which was applied in four studies 19, 20, 21, 22, whereas transthoracic electrical bioimpedance and transoesophageal echocardiography were used alternatively in two other studies 23, 25. CO assessment was accomplished with an invasive approach in only two studies, using a pulmonary artery catheter for this purpose 24, 26.

Quality assessment and risk of bias estimation of the included trials

Methodological quality assessment of the studies included in the SR is summarized in Tables 2 and 3. Among the included RCTs, a notable difference in quality was identified as two were appraised as of high quality 19, 20 and two of low quality. Blinding was performed only in two RCTs 19, 20 among which only one 20 incorporated blinding of all involved personnel and these also reported adequate allocation concealment and a sample size consideration or power calculations.

Table 2.

Critical appraisal of randomized controlled trials assessing osmotic agents in neurosurgical and neurocritical care patients using Jadad score

Author	Design	Jadad score				Concealment of allocation	Intention‐to‐treat analysis
		Total	Randomization	Blinding	Attrition info
Bentsen et al . 19	Single‐centre, double‐blind, placebo‐controlled, RCT	5	2	2	1	Yes	Yes
Hernandez‐Palazon et al . 20	Single‐centre, double‐blind, RCT	5	2	2	1	Yes	No
Li et al . 21	Single‐centre, RCT	1	1	0	0	No	No
Sokhal et al . 22	Single‐centre, RCT	1	1	0	0	No	No

RCT, randomized, controlled trial

Table 3.

Critical appraisal of observational trials assessing osmotic agents in neurosurgical and neurocritical care patients using ROBINS‐1 tool

Author	Confounding	Selection of participants	Classification of interventions	Deviation from intended interventions	Missing data	Measurement of outcomes	Selection of the reported result
Chatterjee et al . 23	Low	Moderate	Low	Low	Low	Low	Low
Munar et al . 24	Serious	Moderate	Serious	Low	No info	Low	Moderate
Oddo et al . 26	Moderate	Low	Low	Moderate	Moderate	Low	Low
Sabharwal et al . 25	Low	Low	Low	Low	Low	Low	Moderate

The risk of bias estimation of the eight studies included in this SR is summarized in Table 4. Most of the studies enrolled are characterized by moderate to high risk of bias, due to under‐reporting of data regarding randomization method or blinding. Publication bias analysis was not pursued, as data reporting CO changes were insufficient to conduct a valid meta‐analysis.

Table 4.

Critical appraisal of bias of the included trials assessing osmotic agents in neurosurgical and neurocritical care patients using Cochrane Collaboration of Risk tool

Study ID	Sequence generation	Allocation concealment	Personnel, participants and outcome assessors blinding	Incomplete outcome data	Selective reporting	Other bias	Final estimation
Randomized controlled trials
Bentsen et al . 19	Low	Low	Low	Low	Low	Low	Low
Hernandez‐ Palazon et al . 20	Low	Low	Low	Low	Low	Low	Low
Li et al . 21	Unclear	Unclear	High	Low	Unclear	High	High
Sokhal et al . 22	Low	Unclear	High	Low	Low	Unclear	Moderate
Observational studies
Chatterjee et al . 23	No	No	No	Low	Low	Low	High
Munar et al . 24	No	No	No	Unclear	Unclear	High	High
Oddo et al . 26	No	No	No	High	Low	High	High
Sabharwal et al . 25	No	No	No	Low	Unclear	Low	High

Primary outcome measures

Data on CO, MAP and HR changes due to mannitol or HTS infusion being extracted from these studies, are pooled and presented in a timeline sequence, starting from the effects during infusion and up to 360 min follow‐up.

Effects on CO

Two studies assessing mannitol as a sole osmotic agent, reported a CO increase lasting up to 15 min 23, 25, while four studies that tested mannitol versus HTS, failed to identify any profound alteration in CO values, after mannitol infusion 20, 21, 22, 26. Nonetheless, a notable augmentation of CO or CI in HTS‐treated patients was a common finding in five out of the six studies involving the use of HTS 19, 20, 22, 24, 26. The increase in CO was recorded either for a some time frame 22, 24, 25 or at all time points of assessment up to 2 h after infusion 19, 26. The increase in CO became apparent upon 6 h post‐infusion in only one RCT, with no particular differences in CO at earlier time points 20. Due to significant heterogeneity and differences in reporting CO changes attributed to the infusion of osmotic agents, this outcome could not be meta‐analysed.

Effects on MAP and HR

All eight selected studies evaluated the effects of mannitol or HTS on MAP. Mannitol induced a consistent MAP deterioration, which became apparent immediately after the end of the infusion and lasted up to 45 min thereafter 21, 22, 25. A trend towards to MAP reduction, was also reported in HTS‐treated patients, but this effect was not of statistical importance 22. The effect of osmotherapy on HR was reported in six studies 19, 21, 22, 23, 24, 25, ranging from a nonsignificant change 19, 22, 23 to a notable either increase or decrease compared to preinfusion values 21, 24, 25. In detail, mannitol‐induced an HR reduction lasting from 25 to 45 min after the end of infusion 25, while an insignificant effect on HR was the common finding in three studies 21, 22, 23. By contrast, the infusion of HTS was associated with an HR augmentation lasting up to 30 min postinfusion and subsequent normalization thereafter 24, an HR reduction lasting up to 60 min postinfusion 21, or no effect on HR. 19, 22

Effects on CVP, SV, SVV and SVR

In line with previous findings, a relative heterogeneity was also encountered in terms of CVP changes. These varied from nonsignificant 20, 26 to notable augmentation up to 15 min and 25 min after termination of HTS or mannitol administration, respectively 22, 23, 24. Five of the selected studies incorporated SV or SVV as reliable indices of systemic haemodynamic status appraisal 20, 21, 22, 23, 25. SV was positively affected by mannitol use for approximately 15 min 23, 25, whilst in one RCT, the use of mannitol or HTS reduced or enhanced SV, respectively 22. Three RCTs 20, 21, 22 applying pulse contour analysis for SVV estimation, showed either a constant decrease 20, 21, or an increase after an initial fall 22 in HTS group, while the single report about the effect of mannitol on SVV revealed that after a brief initial fall, SVV remained in higher levels compared to baseline throughout the study period 22. Despite the limited available evidence on the impact of mannitol or HTS on SVR, it occurred that both drugs induced a significant decline of this parameter, which seemed to be valid for a longer time in HTS‐treated patients 23, 24.

Of note, comparative studies between the two osmotic agents failed to demonstrate any clinically significant difference in CO or CI and the other tested haemodynamic variables during the study course 20, 21, 22, 26.

Secondary outcome measures

Effects on ICP and cerebral perfusion pressure

Data regarding the impact of osmotic agents on ICP or brain relaxation was provided in six studies, enrolling 176 patients 19, 20, 21, 22, 24, 26. In these studies, mannitol or HTS (as a sole agent or combined with HES 6%) consistently induced an ICP reduction with an associated cerebral perfusion pressure increase. Half of these studies identified a relative superiority of HTS over mannitol, in terms of cerebral haemodynamics, with a peak effect being recorded at 60 min after the end of HTS infusion 19, 24, 26. Two RCTs, reported equivalent brain relaxation scores between both osmotic agents 20, 22, as this was assessed by neurosurgeons using the four‐point brain relaxation scale 27, while another RCT, using a three‐point dural tension score for brain relaxation assessment 28, identified a considerable superiority of HTS over to mannitol for brain relaxation attainment 21.

Data from two RCTs 19, 22 and two observational studies 22, 26, involving ICP monitoring, demonstrated that improvement of cardiac performance as a result of osmotic agent administration, was associated with a concomitant optimization of cerebral haemodynamics, an effect more apparent in HTS‐treated patients 19, 22, 24, 26.

Effects on osmolality and electrolytes

Three trials provided complete data with respect to osmolality, which was consistently maintained above baseline value up to 360 min after the infusion of either osmotic agent 20, 21, 24. Nevertheless, the increase in serum osmolality was more prominent after HTS than mannitol infusion 21. Five trials provided details regarding the changes of various electrolytes 20, 21, 22, 24, 26. Serum sodium levels were consistently elevated after HTS administration throughout the study period 20, 21, 22, 24, 26. The magnitude of hypernatraemia was not associated with the osmotic load of HTS solution or the dose administered, whilst serum sodium levels ranged within acceptable limits. On the contrary, mannitol promoted sodium level reduction, reaching levels below the lower limit of normalcy in one trial 20, 22. Chloride and potassium changes were recorded in two studies 22, 24. HTS promoted an increase of chloride with a concomitant transient reduction of potassium; the reverse observed in mannitol group 22, 24.

Evidence on urine output

Data on urine output were recorded in six studies, which consistently showed that mannitol infusion promoted an augmentation of urine output lasting up to 6 h 20, 21, 22, 23, 24, 25. Two RCTs demonstrated that mannitol had a more potent effect on urine output increase than HTS 21, 22. Higher fluid volume infusion emerged as a necessary treatment of mannitol‐induced hypovolaemia 20, 21, 22. The basic characteristics of the reviewed studies and osmotherapy‐related outcomes are shown in Table 5.

Table 5.

Characteristics of the included studies

Study ID	Study design	Setting (No. pts)	Intervention	Type and time haemodynamic monitoring	Primary Outcome		Secondary outcomes
					CO (l min –1 ) or CI (l min –1 m –2 )	Other haemodynamic variables	ICP/CPP or satisfactory BRS score	Plasma osmolality	Electrolytes	Urine output
Bentsen et al . 19	Single‐blind, placebo‐controlled RCT	SAH (n = 20)	(HTS 7.2% + 6% HES 200/0.5) 2 ml kg–1 vs. NS 0.9% 2 ml kg–1	PiCCO 0, 30, 90 and 210 min	Study period: ΔCI higher in HTS‐HES vs. NS (P = 0.025) ΔCI increase peaked at 30 min	ΔHR and ΔMAP in HTS‐HES vs. NS 0.9% (NS)	ΔICP lower in HTS‐HES vs. NS (P = 0.004) ΔICP reduction peaked at 64 min ΔCPP higher in HTS‐HES vs. NS (P = 0.002)	NA	ΔNa increased in HTS‐HES vs. NS (P < 0.0001) ΔNa peaked in HTS‐HES at 30 min	NA
Hernandez‐ Palazon et al . 20	Double‐blind RCT	Craniotomy (n = 60)	HTS 3% 3 ml kg–1 vs. M 20% 3 ml kg–1	FloTrac 0, 30, 120 and 360 min	Increased in HTS at 6 h (P < 0.05) Change over time in M (NS) M vs. HTS all phases (NS)	MAP increased in M at 30 min (P < 0.05) SVV decreased in HTS at 30 min (P < 0.05) CVP changes (NS) MAP‐SVV‐CVP: HTS vs. M at all phases (NS)	HTS 83% vs. M 90% (NS)	Increased in HTS at 30 and 120 min (P < 0.05) and 360 min (P < 0.01) Increased in M in all phases (P < 0.01)	Na decreased in M at 30 min‐returned to baseline at 120 min and increased at 360 min Na increased in HTS in all phases (P < 0.01)	HTS vs. M at 360 min (NS)
Li et al . 21	RCT	Craniotomy (n = 40)	(HTS 7.2% + 6% HES 200/0.5) 250 ml vs. M 20% 250 ml	FloTrac 0, after infusion of 125 ml and 250 ml and 30 min and 60 min	Change over time in HTS‐HES and M (NS) HTS‐HES vs. M in all phases (NS)	HR decreased in HTS‐HES after 250 ml infused (P < 0.05) and up to 60 min (P < 0.01) MAP decreased in M after 125 ml infused (P < 0.05) SVV decreased in HTS‐HES after 250 ml infused (P < 0.05) and up to 60 min (P < 0.01) and decreased in M after 125 ml infused (P < 0.05)	HTS‐HES 95% vs. M: 75% (P < 0.01)	Increased in both HTS‐HES and M in all phases up to 60 min (P < 0.01) Higher in HTS‐HES vs. M up to 60 min (P < 0.01)	NR	Lower in HTS‐HES vs. M at 30 and 60 min (P < 0.01)
Sokhal et al . 22	Double‐blind, RCT	Craniotomy (n = 40)	HTS 3% 5.35 ml kg–1 vs. M 20% 5 ml kg–1	FlowTrac Every 5 min up to 45 min	Increased in HTS at 10 min (P < 0.0001) to 25 min (P < 0.001) Change over time in HTS vs. M (NS)	HR decrease in both groups over time – HTS vs. M in all phases (NS) MAP decreased in both groups up to 15 min (P < 0.0001) – HS vs. M (NS) CVP increased in HTS up to 15 min and in M up to 25 min (P < 0.0001) – HS vs. M (NS) SV: increase in HS and decrease in M – HS vs. M (NS) SVV increased in both groups ‐ HTS increased at 10 min (P < 0.0001)	ICP decreased in both groups (P < 0.001) and HTS vs. M lower at 15 and 20 min (P < 0.05) CCP increased in both groups (P < 0.001)‐ HTS vs. M (NS) Brain relaxation (NS)	NA	Na and Cl increased in HTS and decreased in M from 30‐90 min (P < 0.0001) K decreased in HTS at 30 min (P = 0.001) and increased in M at 60 and 90 min (P < 0.05)	Lower in HTS vs. M
Chatterjee et al . 23	Prospective, pilot	Craniotomy (n = 15)	M 20% 5 ml kg–1	TOE 0, 5, 15, 25, 35 and 45 min	Increased at 5 min (P < 0.01) and 15 min (P < 0.05)	HR and MAP change over time (NS) CVP increased at 5 min (P < 0.001) SV: increased at 5 min (P < 0.001) and 15 min(P = 0.005) SVR decreased at 5 min (P = 0.002) and 15 min (P = 0.008)	NA	NA	NA	Increased at 5 min
Munar et al . 24	Prospective, cohort	TBI (n: 14)	HTS 7.2% 1.5 ml kg–1	PAC 0, 5, 30, 60 and 120 min	Increased at all time points – up to 60 min (P < 0.01)	MAP change over time (NS) CVP and PAOP increased at 5 min (P < 0.05) SVR decreased from 5 to 60 min (P < 0.05)	ICP reduced from 5 to 120 min (P = 0.0001) CPP increased from 5 to 60 min (P < 0.05)	Increased from 5 to 60 min (P < 0.05)	Na increased from 5 to 120 min (P < 0.002) and peaked at 5 min Cl increased from 30 to 120 min (P < 0.008) K decreased at 5 min (P < 0.0001)	24% increase (NS)
Oddo et al . 26	Retrospective, cohort	TBI (n = 12)	HTS 7.5% 250 ml vs. M 25% 0.75 g kg–1	PAC 0, 30, 60 and 120 min	Increased in HS vs. M from 30 min (P = 0.003) to 120 min (P = 0.002)	MAP and CV change over time (NS) and HTS vs. M (NS)	HTS vs. M ICP reduced at 60 and 120 min (P < 0.001) CPP increased at 60 and 120 min (P < 0.05)	NS	Na increased from 30 to 120 min (P < 0.01) in HTS	NA
Sabharwal et al . 25	Prospective, cohort	Craniotomy (n = 11)	M 20% 1 g kg–1	TEB 0, 1, 2, 5, 10, 15, 20, 25, 30, 35, 40 and 45 min	Increased from 1 to 15 min (P = 0.001) and reduced at 40 and 45 min (P < 0.05)	HR lower from 25 to 45 min (P = 0.008) BP lower at all phases (P = 0.001) SV increased from 1 to 15 min (P = 0.003) and reduced at 45 min (P < 0.05)	NA	NA	NA	Increased up to 120 min (P < 0.001) –peaked at 10 min

RCT, randomized controlled trial; SAH, subarachnoid haemorrhage; TBI, traumatic brain injury; M, mannitol; HTS, hypertonic saline; HES, hydroxyethyl starch; TOE, transoesophageal echocardiography; PiCCO, pulse contour cardiac output; TEB, transthoracic electrical bioimpedance; PAC, pulmonary artery catheter; HR, heart rate; BP, blood pressure; MAP, mean arterial pressure; ΔMAP, delta MAP; CVP, central venous pressure; SV, stroke volume; SVR, systemic vascular resistance; CO, cardiac output; CI, cardiac index; SVV, stroke volume variation; ICP, intracranial pressure; CPP, cerebral perfusion pressure; BRS, brain relaxation scale; NR, not reported; NA, not assessed; NS, nonsignificant

Discussion

This SR reports available clinical literature on cardiovascular effects of mannitol or HTS use in neurosurgical and NCC patients. Despite the limited number of studies being suitable for this SR, it is possible to extract some findings: (i) Both mannitol and HTS induced an increase in CO and other recorded systemic haemodynamic variables (CVP, SV, SVV). CO increase was more pronounced after HTS than mannitol administration. (ii) Mannitol and HTS infusion was associated with a trend towards to MAP and HR reduction. (iii) Both osmotic agents induced an ICP reduction and brain relaxation, an effect that seems to be more prominent in HTS‐treated patients. (iv) HTS infusion promoted notably higher plasma sodium levels compared to mannitol, without any differences in serum osmolality, which was increased by both osmotic agents. (v) Mannitol induced a more potent diuretic than HTS.

CO plays a fundamental role in brain perfusion; however, the relationship between changes in CO and cerebral circulation remains largely speculative and it should be integrated into the framework of cerebral autoregulation 29. Overall, cerebral perfusion relates to CO and blood pressure and to their distinct effects on cerebral haemodynamics 29. Therefore, enhancement of cardiac performance and optimization of fluid balance, could improve brain perfusion especially in patients with impaired cardiac function 30, 31. Infusion of osmotic therapies – mannitol and HTS – promote a water shift from intracellular to the extracellular (and thus intravascular) compartments and direct peripheral vasodilation, ultimately leading to CO augmentation 3, 32, 33. Moreover, HTS can directly improve myocardial performance through a reduction in myocyte oedema and an increase in myocardial uptake of calcium with restores transmembrane potential 33, 34. Current evidence confirms CO enhancement after infusion of either mannitol or HTS 32, 33, 34. The different methods used to evaluate systemic haemodynamic changes (pulse contour analysis, pulmonary artery catheter, transoesophageal echocardiography or transthoracic electrical bioimpedance) might be – in part – responsible for the recorded differences. Despite the various monitoring approaches, comparative studies did not report any differences between the two osmotic agents, in terms of their effects on CO or CI 20, 21, 22, 26.

An early but transient decline in MAP after HTS was recorded by a single study, whilst this was a more consistent finding in mannitol‐treated patients in whom hypotension persisted up to 45 min post‐infusion 21, 22, 25. Nonetheless, validity of these findings is questionable as half of the studies reporting changes of blood pressure, failed to show any effect 19, 23, 24, 26. Possibly, differences in fluid therapy are partially responsible for the short‐term drop in blood pressure after mannitol infusion 20, 21, 22.

Intravascular volume expansion induced by the sustained increase in plasma osmolality ‐ being witnessed in both osmotic compounds at all time points of assessment ‐ is also reflected by the augmentation of CVP reported in three out of five studies assessing this parameter 20, 22, 23, 24, 26, an effect being evident up to 15 min after HTS infusion and 25 min after mannitol infusion 22, 23, 24. Since equivolume, equiosmolar solutions were applied, it is conceivable that no noticeable difference in CVP values between mannitol and HTS groups could be demonstrated 20, 22, 26.

A consistent haemodynamic effect was the decline of peripheral vascular resistance accompanied by an enhancement of CO values 23, 24. Hypertonic solutions improve systemic haemodynamics through mechanisms other than changes in serum osmolality, involving myocardial contractility enhancement and capillary systemic vasculature dilatation 33, 35.

Osmotic therapy is routinely used to control h‐ICP in a wide range of acute conditions and thus most of the clinical knowledge on the application of mannitol and HTS has focused on their brain relaxation and ICP‐lowering properties 1, 3. Prior meta‐analyses have suggested that HTS could be equivalent or even more effective than mannitol at reducing ICP 10, 14, 36, 37, 38. However, our SR showed that both osmotic agents are equally effective in brain relaxation or cerebral haemodynamics optimization 19, 20, 21, 22, 24, 26, 38, no clear superiority of either osmotic agent could be demonstrated due to the limited quantity and quality of the available data 20, 21, 22, 26. A more detailed analysis of data from this SR revealed that the fall in ICP and rise in cerebral perfusion pressure are closely related to the improvement on cardiac performance in both groups 19, 22, 24, 26.

Electrolyte abnormalities are the adverse effects most commonly encountered in hyperosmolar therapy with a clinical importance equivalent to its brain relaxation properties 9, 32. In line with previous reports 9, 35, 39, 40, our SR confirmed that the administration of HTS heightened the levels of serum sodium, which was sustained for 6 h, and promoted a temporary reduction of potassium 20, 21, 22, 24, 26. In contrast, mannitol caused a transient acute dilutional hyponatremia 20, 22, 26, with a concomitant stepwise increase of potassium over time 22. However, sodium levels tend to normalize over time, as a result of the diuretic effects of mannitol 28, 34, 35, 41.

While all hyperosmolar agents promote diuresis, HTS exerts a weaker diuretic effect than mannitol, possibly because it stimulates the release of antidiuretic hormones 9, 39, 40. By contrast, mannitol infusion could induce hypovolaemia through an increase in diuresis 13, 20, 21, 22, 23, 24, 25, 28.

Considering that mannitol is used as first‐choice hyperosmolar solution – for its effectiveness of controlling h‐ICP – the potential risk of secondary hypovolaemia due to its diuretic effect, which in turn requires larger fluid replacement to maintain haemodynamic homeostasis, is an issue of concern 9. Considering that hypovolaemia could be detrimental after brain injury, this has led to a resurgence of interest in the use of HTS in NCC setting, as it seems that the advantage of HTS in this setting is the maintenance of blood pressure with low volume resuscitation and thus avoiding potentially iatrogenic ICP increase 8. This aspect is further supported by a recent SR of HTS compared to isotonic solution for perioperative fluid management, which indicates that HTS can reduce the intravenous fluid replacement needs in patients undergoing surgery 41.

Limitations

Several key limitations of this review need to be considered. Only eight studies with a limited number of participants reported the haemodynamic effects of mannitol or HTS and changes of systemic haemodynamics served as primary end‐point in only five of them. It is therefore not surprising that important contextual parameters, such as brain pathologies, methodological approaches, target haemodynamic variables, timeline for haemodynamic variables recording, and approaches for CO evaluation, presented considerable heterogeneity among the included studies. In some of these studies, isolated numerical reporting of CO, MAP and ICP without the appropriate clinical context, baseline haemodynamic status assessment and evaluation of confounding factors, such as the use of vasoactive medications for cerebral haemodynamics optimization, makes interpretation of the findings even more challenging.

Finally, while this study aimed to assess the impact of either osmotic agent on ICP and brain relaxation via alterations of cardiac performance, it should be emphasized that optimization of these pathophysiological end‐points cannot guarantee a satisfactory neurological outcome.

Implication for research

From these review findings, arises an essential and a clear area in need of high‐quality research to address the possible superiority of HTS compared to mannitol, as to cardiac performance enhancement and subsequent improvement of cerebral haemodynamics. Clear reporting of dosing and osmotic load strategy, cointerventions administered, and a priori defined haemodynamic goal are strongly recommended. Furthermore, it remains to be delineated the underlying pathophysiology for CO improvement after HTS administration and the safety of this volume‐expanding effect in patients with brain pathology and concurrent myocardial dysfunction. Given the challenging haemodynamic sensitivities and distinctive needs for optimization of cerebral autoregulation in neurosurgical and NCC patients, the validation of an effective and safe osmotic therapy would prove invaluable in the future care of this unique population.

Conclusions

In this systematic review, we report clinical evidence on the relationship between systemic and cerebral haemodynamic effects after the application of osmotic therapies – mannitol or HTS – in neurosurgical and NCC setting. Although available data suggest that both mannitol and HTS promote an augmentation of CO, this effect seems to be more pronounced after HTS than mannitol administration. Furthermore, mannitol induces an enhancement of diuresis, while HTS engenders an increase of plasma sodium concentration. These effects might be, in part, responsible for the overall therapeutic effects associated with osmotic therapies. Further research is warranted to define optimal time and dosing and the impact on outcome.

Competing Interests

There are no competing interests to declare.

Appendix 1.

Complete research strategy

Searching strategy, combining free text and medical subject headings (MeSH terms) was set up for PUBMED as follows:

1. ((“mannitol”) AND “cardiac output” AND full text[sb] AND Humans[Mesh] AND English[lang] AND adult[MeSH])) OR ((“mannitol”) AND “hemodynamics” AND full text[sb] AND Humans[Mesh] AND English[lang] AND adult[MeSH])) OR ((“mannitol”) AND “craniotomy” AND full text[sb] AND Humans[Mesh] AND English[lang] AND adult[MeSH])) OR ((“mannitol”) AND “neurosurgical procedures” AND full text[sb] AND Humans[Mesh] AND English[lang] AND adult[MeSH])) OR ((“mannitol”) AND “cerebral oedema” AND full text[sb] AND Humans[Mesh] AND English[lang] AND adult[MeSH])) OR ((“mannitol”) AND “brain injury” AND full text[sb] AND Humans[Mesh] AND English[lang] AND adult[MeSH]) OR ((“mannitol”) AND “neurocritical care” AND full text[sb] AND Humans[Mesh] AND English[lang] AND adult[MeSH])) Filters: Full text; Humans; English; Adult: 18+ years

2. ((“hypertonic solutions”) AND “cardiac output” AND full text[sb] AND Humans[Mesh] AND English[lang] AND adult[MeSH])) OR ((“hypertonic solutions”) AND “hemodynamics” AND full text[sb] AND Humans[Mesh] AND English[lang] AND adult[MeSH])) OR ((“hypertonic solutions”) AND “craniotomy” AND full text[sb] AND Humans[Mesh] AND English[lang] AND adult[MeSH])) OR ((“hypertonic solutions”) AND “neurosurgical procedures” AND full text[sb] AND Humans[Mesh] AND English[lang] AND adult[MeSH])) OR ((“hypertonic solutions”) AND “cerebral oedema” AND full text[sb] AND Humans[Mesh] AND English[lang] AND adult[MeSH])) OR ((“hypertonic solutions”) AND “brain injury” AND full text[sb] AND Humans[Mesh] AND English[lang] AND adult[MeSH])) OR ((“hypertonic solutions”) AND “neurocritical care” AND full text[sb] AND Humans[Mesh] AND English[lang] AND adult[MeSH]) Filters: Full text; Humans; English; Adult: 18+ years

Searching strategy, using combination of terms was set up for EMBASE as follows:

• SUBJECT HEADING: ((“mannitol” OR “hypertonic saline”), USED FOR (cardiac output OR hemodynamics OR craniotomy OR neurosurgical procedures OR cerebral oedema OR brain injury OR neurocritical care)).

Searching strategy, using combination of terms was set up for The International Web of Science as follows:

• TOPIC: ((“mannitol” OR “hypertonic saline”) AND (cardiac output OR hemodynamics OR craniotomy OR neurosurgical procedures OR cerebral oedema OR brain injury OR neurocritical care)).

Searching strategy, using combination of terms was set up for The Cochrane Central Register of Controlled Trials (CENTRAL) as follows:

• #1“mannitol”: ti,ab,kw and “cardiac output” in Trials.
• #2“mannitol”: ti,ab,kw and “hemodynamics” in Trials.
• #3“mannitol”: ti,ab,kw and “craniotomy” in Trials.
• #4“mannitol”: ti,ab,kw and “neurosurgical procedures” in Trials.
• #5“mannitol”: ti,ab,kw and “cerebral oedema” in Trials.
• #6“mannitol”: ti,ab,kw and “brain injury” in Trials.
• #7“mannitol”: ti,ab,kw and “neurocritical care” in Trials.
• #8“hypertonic saline”: ti,ab,kw and “cardiac output” in Trials.
• #9“hypertonic saline”: ti,ab,kw and “hemodynamics” in Trials.
• #10“hypertonic saline”: ti,ab,kw and “craniotomy” in Trials.
• #11“hypertonic saline”: ti,ab,kw and “neurosurgical procedures” in Trials.
• #12“hypertonic saline”: ti,ab,kw and “cerebral oedema” in Trials.
• #13“hypertonic saline”: ti,ab,kw and “brain injury” in Trials.
• #14“hypertonic saline”: ti,ab,kw and “neurocritical care” in Trials.

Tsaousi, G. , Stazi, E. , Cinicola, M. , and Bilotta, F. (2018) Cardiac output changes after osmotic therapy in neurosurgical and neurocritical care patients: a systematic review of the clinical literature. Br J Clin Pharmacol, 84: 636–648. doi: 10.1111/bcp.13492.