Fluid therapy in neurointensive care patients: ESICM consensus and clinical practice recommendations

Abstract

Objective

To report the ESICM consensus and clinical practice recommendations on fluid therapy in neurointensive care patients.

Design

A consensus committee comprising 22 international experts met in October 2016 during ESICM LIVES2016. Teleconferences and electronic-based discussions between the members of the committee subsequently served to discuss and develop the consensus process.

Methods

Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles generated. The consensus focused on three main topics: (1) general fluid resuscitation and maintenance in neurointensive care patients, (2) hyperosmolar fluids for intracranial pressure control, (3) fluid management in delayed cerebral ischemia after subarachnoid haemorrhage. After an extensive literature search, the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system were applied to assess the quality of evidence (from high to very low), to formulate treatment recommendations as strong or weak, and to issue best practice statements when applicable. A modified Delphi process based on the integration of evidence provided by the literature and expert opinions—using a sequential approach to avoid biases and misinterpretations—was used to generate the final consensus statement.

Results

The final consensus comprises a total of 32 statements, including 13 strong recommendations and 17 weak recommendations. No recommendations were provided for two statements.

Conclusions

We present a consensus statement and clinical practice recommendations on fluid therapy for neurointensive care patients.

Introduction

Fluid therapy is a fundamental component of neurointensive care (NIC), with general (volume resuscitation and maintenance) and “neurospecific” indications [intracranial pressure (ICP) control, management of delayed cerebral ischemia (DCI)]. Questions about fluid therapy in NIC patients—such as optimal composition and volume, and choice and dose of hyperosmolar fluids to control ICP—remain and there is limited high quality evidence to guide fluid management and define physiologic triggers and monitoring endpoints of fluid therapy.

Our objective in developing this consensus was to provide guidance to clinicians caring for NIC patients. We addressed three issues: (1) general fluid management in NIC, (2) hyperosmolar fluids for ICP control and (3) fluid therapy for the management of DCI. In view of the low levels of evidence identified, treatment recommendations do not represent standard of care but rather are the summary of current best clinical practice.

Methodology

Definitions

NIC patients were adult critically ill comatose (GCS < 9) patients following severe traumatic brain injury (TBI), high-grade aneurysmal subarachnoid haemorrhage (SAH), severe arterial ischemic stroke (AIS) or intracerebral haemorrhage (ICH).

Registration

The methodological plan for this systematic review was registered on PROSPERO (ID 42016052123 (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=52123).

Sponsorship

No funding was provided. The European Society of Intensive Care Medicine (ESICM) provided logistical support for the first meeting.

Conflict-of-interest policy

There was no industry input into guideline development, and no consensus panel member received honoraria.

Selection of committee members

Participants were members of ESICM, Neurocritical Care Society (NCS) and Latin America Brain Injury Consortium (LABIC). Chairs and co-chairs were selected by ESICM NIC section. An external member (DP) provided methodological expertise for the GRADE process.

Question development

We did not follow the standard Delphi model, but generated the initial ideas and developed the main questions in a face-to-face meeting, during which methodology for literature search, grading of evidence, and the process for reaching the consensus were illustrated.

The focus was the management of NIC patients during the critical care episode, but aspects of pre-hospital management were included when considered important. The guideline panel was divided into three sections, according to the questions addressed:

  1. 1.

    General fluid management (volume resuscitation and maintenance)

  2. 2.

    Hyperosmolar fluids for ICP control

  3. 3.

    Fluid therapy for the management of DCI

Topic selection was the responsibility of consensus chairs (MO, GC) and co-chairs (GM, NS, RH), with input from panel members from each group. All questions were structured in the PICO (population, intervention, comparison and outcomes) format.

Search strategy, data analysis and grading of the evidence

The search strategies and grading of the evidence, including advanced statistical approach such as meta-analyses and meta-regression, are described in detail in the electronic supplementary material (ESM) (ESM_Methodology).

Consensus methodology

The consensus was developed using a modified Delphi process based on the integration of evidence from the literature review and expert opinions. The results of the GRADE assessment of the evidence were made available to the panel through web-based files. The chairs integrated the initial questions with literature revision and grading, and formulated four mutually exclusive questions and 35 questions (clustered in five different sections) requiring a score ranging from 1 (strongly disagree) to 10 (strongly agree). These questions were submitted to each panel member through a web-based system. In addition to providing an overall score (1–10) for each question or cluster of questions, the experts were also invited to provide comments to clarify their answers. The responses were analysed by a non-voting member of the panel (DP). Answers providing scores were analysed as medians and 20th and 80th percentiles. Further, scores were clustered into low (1–3), intermediate (4–7) and high (8–10), and analysed with correspondence analysis. Both approaches were used to identify answers that provided clear-cut responses from the experts, particularly those polarized on agreement or disagreement. Correspondence analysis was used to assess if individual panel members provided specific response patterns, particularly when intermediate positions were taken. The results of the analyses were returned to the panel anonymously for information (the name of each member was replaced with a numeric code), and the same list of questions was then resubmitted to the panel in a second round of voting.

Based on the analysis of the second round of questions, consensus statements were formulated by the chairs, selecting questions with higher degrees of agreement, and then resubmitted to the panel for review. Answers were analysed with correspondence analysis to identify heterogeneity among panel members. In order to minimize the risk of misinterpretations of some questions and statements, individual panel members who had provided heterogeneous answer patterns were invited to review their responses and confirm or correct their vote.

After the final round of voting, the consensus was finalised as follows:

  • A strong recommendation (in favour or against) was made when more than 80% of voting members supported this position for a particular question.

  • When votes in favour or against (a mix of strong and weak options) reached the 80% threshold, a weak recommendation was made.

  • When the 80% threshold was not reached a “no recommendation” option was adopted.

If panel members had minor concerns about one question, they could declare reservation. No blocking option was permitted in the case of major concerns, but a stand aside position was adopted with the reasons for any concerns reported.

Finally, a total of 32 treatment recommendations were formulated, which represent the balance between desirable and unwanted effects, resource implications and quality of evidence [1]. Quality of evidence influenced the strength and direction of recommendations, but in the presence of low or very low scientific evidence, we considered the possibility of providing not only weak but also strong recommendations based on expert opinions.

Additional considerations

The consensus focused on human studies only and did not include animal data. Regarding clinical practice, this consensus selected specific questions and conditions, but was not intended to cover generic issues related to sodium/osmolarity management or specific disorders (diabetes insipidus, SIADH, cerebral salt wasting syndrome), for which the reader may refer to separate reviews [2, 3]. For laboratory safety limits and precise timing of electrolyte/osmolarity follow-up, the reader must follow clinical judgment and general good clinical practices.

This consensus addressed fluid therapy in stable NIC patients, i.e. without circulatory shock, acute bleeding, or poly-trauma, and was restricted to the early ICU phase but did not apply to later ICU care. Additional acute cerebral conditions (infectious encephalitis, hypoxic-ischemic brain injury after cardiac arrest) were not addressed. Because cerebral perfusion pressure (CPP) depends on invasive ICP monitoring (which may not be available everywhere), only arterial blood pressure/mean arterial pressure (MAP) and ICP were considered, but we did not treat CPP separately.

Results

Each section is organized as follows. For every question, the analysis of available evidence based on the GRADE process is reported: when studies were too heterogeneous to be combined in an overall body of evidence, the individual GRADE is reported (GRADE details for each question can be found in ESM_GRADE).

At the end of each section, treatment recommendations are reported.

A summary of all treatment recommendations is shown in Table 1.

Table 1 Summary of recommendations for fluid therapy in neurointensive care (NIC) patients (see “Methodology” for details)

Randomized controlled trials (RCTs) with report of specific outcomes tested are summarized in Table 2.

Table 2 Summary of randomized controlled trials on fluid therapy in neurointensive care patients

Fluids for the general management of NIC patients

Analysis of available evidence

Question 1: Is there evidence to prefer albumin to crystalloids? (ESM, SG1 Q1 GRADE)

One multicentre RCT in AIS patients found comparable 90-day outcome for high-dose (25%) albumin (n = 422) vs. normal saline (NS) (n = 419) [4]. One single-centre observational study in AIS patients (n = 82) found that high-dose albumin was associated with better outcome [OR 1.81 (95% CI 1.11–2.94)] [5].

GRADE for both studies: high quality evidence (against).

A subgroup analysis of the SAFE trial found higher mortality (33.2% vs. 20.4%) for low-dose (4%; osmolality 260 mOsm/l) albumin (n = 214) vs. NS (n = 206) after TBI [6]. Excess mortality was higher in severe TBI patients [41.8% vs. 22.2%; RR 1.88 (95% CI 1.31–2.70)], with no significant difference in moderate TBI patients.

GRADE: low quality evidence (against).

One multicentre propensity score study (n = 5400) [7] and one retrospective single-centre study (n = 42) [8] in SAH patients found that high-dose albumin vs. crystalloids was associated with better neurological outcome.

GRADE for both studies: very low quality evidence (in favour).

Question 2: Is there evidence to prefer colloids to crystalloids? (ESM SG1 Q2 [Q6 Q7] GRADE)

One propensity score study (n = 123) in SAH patients found that colloids (plasma, dextran, starch and/or albumin) had no impact on DCI/cerebral infarcts, but were associated with worse NIH Stroke Scale at 6 weeks [9].

GRADE: low quality evidence (against).

Another study on SAH patients recruited in two RCTs (n = 160) found that cumulative daily colloid dose (4% gelatin or 6% pentastarch) was associated with worse 6-month Glasgow Outcome Score (GOS) [adjusted OR 2.53 (95% CI 1.13–5.68)] while crystalloids (L/day) were associated with better GOS [adjusted OR 0.27 (95% CI 0.11–0.67)] [10].

GRADE: very low quality evidence (against).

In severe TBI patients, Cox proportional hazard modeling of single-centre data (n = 171) found no association between cumulative pentastarch dose and mortality [11].

GRADE: very low quality evidence (against).

Question 3: Is there evidence to prefer buffered crystalloids to standard crystalloids? (ESM SG1 Q3 [Q8] GRADE)

Two small single-centre RCTs, one in SAH patients (n = 36) [12] and another in TBI patients (n = 41) [13], found that, compared to NS, buffered crystalloids reduced hyperchloraemia rate (a secondary outcome in our revision design). The studies had a sufficiently homogenous design to allow a meta-analysis (RR 0.57, 95% CI 0.37–0.75, p < 0.001). The body of evidence was downgraded because of the high degree of imprecision due to small sample size and the risk of inflated effect [14].

GRADE: low quality evidence (in favour).

In addition, one RCT in TBI patients (n = 34, two centres) found that Ringer’s lactate (RL) reduced serum sodium and osmolarity compared to hypertonic saline (HTS) [15].

GRADE: very low quality evidence (in favour).

No study considered robust outcomes such as survival or neurological outcome therefore no recommendation regarding the choice of one specific crystalloid solution (e.g. normal saline vs. buffered solutions) was given.

Question 4: Is there evidence to prefer infusion of hypertonic fluids (given as resuscitation solutions) to infusion of isotonic fluids? (ESM SG1 Q4 GRADE)

All studies were performed in TBI patients.

One RCT comparing a bolus infusion (250 mL) of 7.5% HTS vs. RL (n = 113 patients in each group) in the pre-hospital setting reported no differences in 6-month mortality and GOS [16].

GRADE: high quality evidence (against).

In an RCT (n = 64) comparing 7.5% HTS/6% dextran solutions with NS (given as a single 250-mL resuscitation dose), Baker et al. found no significant difference in 30-day mortality and GOS [17].

GRADE: low quality evidence (against).

In a small RCT (n = 34, two centres), Shackford et al. compared 1.6% HTS to RL for resuscitation and found no significant difference in GOS at hospital discharge [15].

GRADE: very low quality evidence (against).

Treatment recommendations

  • We recommend crystalloids as preferred maintenance fluids in NIC patients (Strong recommendation).

  • We recommend against the use of colloids, glucose-containing hypotonic solutions and other hypotonic solutions, or albumin as maintenance fluids in NIC patients (Strong recommendation).

  • We recommend against the use of high-dose (20–25%) albumin in acute ischemic stroke patients (Strong recommendation).

  • We suggest using crystalloids as first-line resuscitation fluids in NIC patients with low blood pressure (Weak recommendation).

  • We suggest against the use of synthetic colloids as resuscitation fluids in NIC patients with low blood pressure (Weak recommendation).

  • We recommend against the use of glucose-containing hypotonic solutions and other hypotonic solutions as resuscitation fluids in NIC patients with low blood pressure (Strong recommendation).

  • We recommend against the use of low-dose (4%) albumin as resuscitation fluid in NIC patients with low blood pressure (Strong recommendation).

  • We suggest against the use of high-dose (20–25%) albumin as resuscitation fluid in NIC patients with low blood pressure (Weak recommendation).

  • We suggest against the use of hypertonic saline solutions as resuscitation fluids in NIC patients with low blood pressure (Weak recommendation).

  • We suggest targeting normovolaemia during fluid replacement in NIC patients (Weak recommendation).

  • We recommend the use of a multimodal approach, guided by the integration of more than a single haemodynamic variable, to optimize fluid therapy in NIC patients (Strong recommendation).

  • We recommend considering using arterial blood pressure and fluid balance as the main endpoints to optimize fluid therapy in NIC patients (Strong recommendation).

  • We suggest integrating other variables (such as cardiac output, SvO2, blood lactate, urinary output) to optimize fluid therapy in NIC patients (Weak recommendation).

  • We recommend against the use of central venous pressure (CVP) alone as an endpoint for guiding fluid therapy in NIC patients (Strong recommendation).

  • We suggest against the use of restrictive fluid strategies (aiming for an overall negative fluid balance) in NIC patients (Weak recommendation).

  • We suggest using fluid balance as a safety endpoint for fluid therapy in NIC patients (Weak recommendation).

  • We suggest monitoring electrolytes (Na+, Cl) as a safety endpoint for fluid therapy in NIC patients (Weak recommendation).

  • We suggest monitoring measured osmolarity as a safety endpoint for fluid therapy in NIC patients (Weak recommendation).

  • We recommend against the use of CVP as safety endpoint for fluid therapy in NIC patients (Strong recommendation).

Hyperosmolar fluids for the management of elevated ICP

Analysis of available evidence

Question 1: Are hyperosmolar fluids effective in reducing ICP? (ESM SG2 Q1 GRADE)

RCTs

One RCT (60 patients, 2 centres) in severe TBI patients showed that 48-h continuous prophylactic infusion of half-molar hypertonic lactate (HTL) vs. NS was more effective in preventing elevated ICP (> 20 mmHg) [% ICP reduction 30% (95% CI − 50.4 to − 4.8%); number needed to treat 3 (95% CI 2–21)] [18].

Observational studies

Despite limitations (small sample size, no adjustments for confounders), a high number of before–after observational studies investigating the effectiveness of mannitol (MAN) and HTS in reducing ICP were identified [19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45], allowing a meta-analysis to examine whether a common trend could be found. PubMed search code, selection criteria, meta-analysis and meta-regression are reported in detail in the ESM (ESM_Hyperosmolar Fluids).

Mannitol

By meta-analysis, MAN was associated with a 10.9 mmHg ICP reduction (95% CI 8.2–13.5 mmHg, p < 0.001, Fig. 1). Heterogeneity was high (I2 = 69%; 95% CI 45–90%, p < 0.001), but sensitivity analysis using high correlation between before and after measurements was consistent with these findings (ESM_Hyperosmolar Fluids, Fig. 3).

Fig. 1
figure1

Meta-analysis, examining the efficacy of mannitol in reducing ICP, assuming low correlation between before and after ICP measurements. Observed outcome = ICP reduction (mmHg) by mannitol

By meta-regression, for every 1 mmHg increase in baseline ICP, MAN bolus yielded an additional 0.53 mmHg ICP reduction (p < 0.001, Fig. 2). The heterogeneity estimate dropped to 20% (p = 0.255). However, the degree of imprecision was high and this finding should be interpreted with caution. The meta-regression assuming high correlation provided similar results, but heterogeneity was highly significant (p < 0.001), (ESM_Hyperosmolar Fluids, Fig. 4).

Fig. 2
figure2

Meta-regression, showing the magnitude of mannitol effect on ICP reduction, according to initial pretreatment ICP, and assuming a low correlation between before and after ICP measurements. Studies included in the meta-regression are (1) Marshall [31]; (2) Helbok [25]; (3) Muizelaar [34]; (4) Mendelow [32]; (5) Rosner [38]; (6–9) Miller [33], (10) Launey [28]; (11) Oddo [35]; (12) Ware [45]; (13) Francony [23]; (14) Scalfani [40]; (15) Diringer [21]; (16) Ichai [47]

Mannitol dose

By meta-regression, the extent of ICP reduction did not correlate with MAN dose (0.42 mmHg per 100 mg/kg, p = 0.478, Table 3). However, by multivariable analysis after adjusting for initial ICP, the relationship of MAN dose with ICP became statistically significant (0.78 mmHg for every 100 mg/kg increase, p = 0.003, Table 3); this was confirmed by the less conservative sensitivity analysis (data not shown).

Table 3 Meta-regression analysis, using ICP reduction as dependent variable

These results should be treated with great caution because the low numbers of studies included in the analysis may generate spurious results although the use of random effects methods limits this risk [46].

Hypertonic saline

By meta-analysis, HTS was associated with an average 8.8 mmHg ICP reduction (95% CI 6.5–11.1 mmHg, p < 0.001, ESM_Hyperosmolar Fluids, Fig. 1), but heterogeneity was high (I2 = 77%, 95% CI 45–94, p < 0.001). The meta-regression using baseline ICP with post-HTS ICP reduction produced a statistically significant result (slope 0.343, p = 0.040), despite heterogeneity (I2 = 56%, CI 0–91%, ESM_Hyperosmolar Fluids, Fig. 2) and two studies with Cook distances of 3.4 and 1.8 that strongly influenced the slope.

Hypertonic saline dose

Dose was not a predictor of ICP reduction: however, the inclusion of dose and initial ICP in a multivariate meta-regression approach generated statistically significant slopes (Table 3). As for mannitol, the same caution in interpreting these results should be applied.

In summary, there is evidence to suggest that HTL, MAN and HTS are associated with a reduction in ICP.

GRADE: low quality evidence (in favour).

Question 2: Is there evidence that hyperosmolar fluids have different efficacy (more or less effective) in reducing ICP? (ESM SG2 Q2 GRADE)

A total of nine RCTs were identified, comparing different hyperosmolar fluids administered as infusion boluses to treat elevated ICP: six were performed in TBI patients [20, 23, 47,48,49,50], two in a heterogeneous population of TBI and SAH patients [51, 52], and one in AIS patients [42]. Four studies compared MAN to HTS [20, 23, 42, 48], and one MAN vs. HTL [47].

One small observational study provided very low evidence in favour of the superiority of HTS over MAN [53], but did not give information on osmotic doses, precluding comparisons on their effectiveness.

With the exception of one observational study [42] that was graded very low, evidence from all these RCTs was equally graded as low.

RCTs comparing hypertonic fluids given in equiosmolar doses (7 studies, N = 186 patients)

One study (n = 9, crossover design, single-centre) found that 7.5% HTS/6% dextran vs. 20% MAN produced a greater ICP reduction at 60 min [− 5 mmHg (95% CI − 10.8 to – 3), p 0.014] [51], while four studies (n = 20 [23], n = 47 [20], n = 38 [48], n = 29 [49]) found that 7.5%, 3%, 15% HTS and 20% MAN, respectively, were equally effective in reducing ICP. One study (n = 9) investigating ICP reduction using 7.5% HTS/6% dextran and 20% MAN did not compare the two groups with formal statistical tests and received a very low evidence grading [42].

Ichai et al. (n = 34, single-centre) found that half-molar HTL was more effective than 20% MAN in reducing elevated ICP, but, although the difference in ICP decrease at 4 h in favour of HTL was statistically significant, it was of limited clinical relevance (2.7 mmHg) [47].

RCTs comparing hypertonic fluids given in non-equiosmolar doses (2 studies, n = 52 patients)

In these studies, osmotic load was higher for HTS than for MAN, therefore favouring HTS. Vialet et al. (n = 20, single-centre) found that 7.5% HTS was more effective than half the osmotic dose of 20% MAN in reducing the daily number of episodes of elevated ICP > 25 mmHg (6 vs. 13) [50]. The other study (n = 32) found a statistically significant ICP percentage reduction with HTS/HES 200/0.5 vs. 15% MAN [52].

GRADE for all these studies: low quality evidence (in favour or against according to specific study findings).

Question 3: Is there evidence for using hyperosmolar fluids without ICP monitoring? (ESM SG2 Q3 GRADE)

One RCT performed in ICH patients (n = 24) found that MAN and HTS had comparable effects on midline shift reduction assessed by magnetic resonance imaging [54]. A second RCT in patients with severe AIS (n = 9) found that MAN and HTS had comparable effects on cerebral blood flow (CBF) increase measured by positron emission tomography (PET) [55].

GRADE: very low quality evidence (against).

Several observational studies investigated the effects of MAN or HTS in patients monitored with transcranial Doppler (TCD) [26, 44, 56], PET [21, 40], xenon-CT [44, 57, 58], CT scan (to measure brain volume and shift, water content) [29, 59,60,61,62] or EEG [63].

GRADE: very low quality evidence (in favour or against according to specific study findings).

Question 4: Is there evidence that hyperosmolar fluids improve outcome? (ESM SG2 Q4 GRADE)

RCTs

RCTs were heterogeneous and could not be combined into a meta-analysis.

One multicentre RCT performed in TBI patients (n = 226) found that pre-hospital resuscitation with HTS or NS had similar 6-month outcome assessed by GOS-E [16].

GRADE: high quality evidence (against).

There were three additional RCTs. One was performed in TBI patients (n = 60; two centres) and found that prophylactic half-molar HTL did not improve 6-month GOS compared to NS despite significantly reducing episodes of ICP increase greater than 20 mmHg [18]. In a further study in TBI patients, HTL for treatment of elevated ICP was associated with better 12-month GOS compared to MAN (69% vs. 35%), although this difference was not statistically significant (p = 0.055) [47]. A third RCT in TBI patients found no mortality difference between 20% MAN and 7.5% HTS [20].

These three RCTs were downgraded for methodological limitations.

GRADE: low quality evidence (against).

Observational studies

One propensity score matched study in ICH patients included in the INTERACT-2 trial found no significant outcome difference between MAN-treated (n = 1533) and non-MAN treated (n = 993) patients [64].

GRADE: low quality evidence.

One study reported that MAN negatively affected neurological outcome in AIS or ICH patients [65], while in another HTS/dextran improved survival of hypotensive TBI patients [66].

GRADE: very low quality evidence.

Asehnoune et al. found increased survival in TBI treated with continuous infusion of HTS [67]: this study was published after closing the consensus process and therefore could not be included.

Treatment recommendations

  • We suggest the use of mannitol or hypertonic saline for reducing increased ICP (Weak recommendation).

  • We are unable to provide any recommendation on the use of hypertonic lactate as first-line osmotic solution for reducing increased ICP (No recommendation).

  • We suggest considering a predefined trigger for starting osmotherapy to treat elevated ICP (Weak recommendation).

  • We recommend a combination of clinical and neuromonitoring variables for starting osmotherapy to treat elevated ICP (Strong recommendation).

  • We recommend a combination of neurological worsening (defined as a decrease of 2 points of the GCS motor score, or loss of pupillary reactivity or asymmetry, or deterioration of head CT findings) and ICP > 25 mmHg as a trigger for starting osmotherapy to treat elevated ICP (Strong recommendation).

  • We suggest using an ICP threshold > 25 mmHg independent of other variables as a trigger for starting osmotherapy to reduce ICP (Weak recommendation).

  • We are unable to provide any recommendations about whether an ICP threshold of 20–22 mmHg, independent of other variables, should be used as a trigger to start osmotherapy to reduce ICP (No recommendation).

  • We recommend against the use of an ICP threshold of 15 mmHg independent of other variables as a trigger for starting osmotherapy to reduce ICP (Strong recommendation).

  • We suggest monitoring measured serum osmolarity and electrolytes to limit side effects of osmotherapy (Weak recommendation).

  • We suggest monitoring ICP response to hyperosmolar fluids to limit the side effects of osmotherapy (Weak recommendation).

  • We suggest monitoring the effects of hyperosmolar fluids on arterial blood pressure and fluid balance as secondary variables to limit the side effects of osmotherapy (Weak recommendation).

Fluids for the management of cerebral ischemia

Analysis of available evidence

Question 1: Is there enough evidence to prefer specific fluids (crystalloids/colloids) in the prevention of cerebral ischemia (CBF or clinical) improve outcome? (ESM SG3 Q1 GRADE)

Only studies focused on the prevention of vasospasm and delayed cerebral ischemia (DCI) and its consequences on the outcome of SAH patients were considered.

RCTs

Triple H therapy (4 L/day hypervolaemic hypertensive haemodilution fluid therapy, including colloids and crystalloids) vs. normovolaemia (2 L/day crystalloids) did not affect the proportion of patients with TCD evidence of vasospasm, regional CBF, or 1-year GOS (n = 32 patients, two centres) [68]. However, in the context of triple H therapy, the net impact of colloids could not be measured. Lennihan et al. (n = 82 patients, single-centre) similarly found that prophylactic hypervolaemic therapy (including colloids and crystalloids) vs. normovolaemia had no impact on CBF, vasospasm and cerebral infarction [69].

GRADE: very low quality evidence (against).

Observational studies

Because studies (n = 12) were limited by single-centre design, small sample size, heterogeneous treatment protocols and diverse outcomes, it was not possible to combine them into a single body of evidence. Detailed reporting of grading process was made for six studies, after adjustment for confounding factors. Several studies found that higher fluid volumes and positive fluid balance were associated with worse morbidity and neurological outcomes [7, 70, 71]; however, only one specified that colloids were used to achieve hypervolaemia [4].

When specifically addressing DCI therapy, Ibrahim and Macdonald (n = 123 patients) found that colloid administration and positive fluid balance were associated with worse outcome [9]. Another study (n = 288 patients) also found that positive fluid balance was associated with worse functional outcome [72]; however, there was no mention about whether colloids were used to reach a positive balance, and it was of limited use for evidence provision.

Among studies not performing statistical adjustment for confounders, six examined the effect of fluids on CBF and CBF surrogates. In one, hypervolaemia (colloids and crystalloids) modestly increased regional CBF but without improving brain tissue oxymetry (PbtO2) [73], whereas in others volume expansion with HTS was associated with better PbtO2 as well as CBF [57, 74, 75]. Volume expansion with albumin correlated with CBF decrease [76], while NS had no effect on CBF [77].

GRADE for studies: very low quality evidence (in favour or against according to the study findings).

Question 2: Does fluid therapy in the management of cerebral ischemia influence outcome? (ESM SG3 Q2 GRADE and ESM_SG3_AllQs GRADE ischemia)

Although the main focus was on SAH patients, studies on severe ischemic stroke patients were also included when relevant for the topic of cerebral ischemia.

A multicentre RCT in AIS patients (n = 1267) found that haemodilution (by venesection followed by dextran replacement) did not change 6-month outcome compared to standard treatment [78].

GRADE: moderate quality evidence (against).

In AIS patients (observational study, N = 193) daily fluid intake greater than 1650 mL was associated with malignant brain oedema [OR 13.86 (95% CI 5.11–37.60)] [79].

GRADE: very low quality evidence (against).

Additional observational studies (not performing any statistical adjustment for confounders, including small sample sizes and heterogeneous design, to be assessed with a meta-analytical approach) are listed below for, at best, hypotheses-generating purposes:

  • CBF In patients with SAH and vasospasm, boluses of NS (n = 6) [80] or HTS (n = 35) [44] significantly improved CBF, whilst hypervolaemia (albumin, dextran and 10% glycerol) normalized CBF in the cerebral hemisphere where perfusion was reduced because of vasospasm [81]. In contrast, volume expansion with colloids and albumin [82] and isovolaemic haemodilution obtained by venisection and infusion of albumin and dextran [83] did not increase CBF.

  • Clinical endpoints Two studies found that hypervolaemia (albumin, glycerol, dextran or plasma) targeted to haemodynamic monitoring endpoints (Swan-Ganz catheter) led to neurologic improvement and absence of progression to infarction in most patients [84, 85]. Several limitations (small sample size, absence of an instrumental diagnosis of vasospasm, no specific definition of treatment, and lack of adjustment for confounding factors) preclude any definitive conclusions.

Question 3: Is there enough evidence to prefer colloids to crystalloids in the management of cerebral ischemia? (ESM SG3 Q3 GRADE)

One observational study (n = 160 SAH patients) found that higher colloid dose (L/day) was associated with unfavourable 6-month GOS [OR 2.53 (95% CI 1.13–5.68)] [10].

GRADE: very low quality evidence (against).

Question 4: Is brain monitoring useful as a trigger or endpoint to guide fluid therapy in the management of cerebral ischemia? (ESM SG3 Q4 GRADE)

One study in SAH patients (n = 10) found that albumin (250 mL fluid bolus) increased cardiac index and improved PbtO2 [86], but the limited sample size raises internal and external validity issues despite use of a multivariable approach to account for multiple measurements.

GRADE: very low quality evidence (in favour).

Question 5: Should a change in neurological status trigger a modification in fluid management away from normovolaemia? (ESM SG3 Q5 GRADE)

Two studies investigated treatment of new neurological symptoms in SAH patients with hypervolaemia (albumin, glycerol, dextran or plasma); in a subset of patients treatment was guided by pulmonary artery catheter. Neurologic improvement and absence of progression to infarction led the authors to conclude that hypervolaemic therapy was effective [84, 85]. However, these two studies have serious limitations (small sample size, vasospasm diagnosed by means of clinical symptoms, no specific definition of treatment, lack of adjustment for confounding factors).

GRADE for both studies: very low quality evidence (in favour).

Question 6: Is there a place for early goal-directed fluid therapy in the management of cerebral ischemia? (ESM SG3 Q6 GRADE)

One RCT in SAH patients (n = 160), comparing fluid management targeted to maintain high global end-diastolic volume index (GEDI), measured by transpulmonary thermodilution, with standard management found no effect on DCI and poor 3-month outcome rates [87]. However, a predefined analysis of high-grade SAH patients that were stratified at randomization demonstrated a statistically significant reduction in both outcomes. A recalculation (DP) during preparation of this consensus, using the same statistical methods as the authors (see ESM), found that neither result was statistically significant (p = 0.101 for DCI and p = 0.054 for 3-month poor outcome).

GRADE: moderate quality evidence (against).

Three observational studies using logistic regression model found that transpulmonary thermodilution (with the use of Cardiac Function Index [88] and GEDI [89, 90]) were associated with improved outcome.

GRADE: very low quality evidence (in favour).

Treatment recommendations

  • We recommend assessing the efficacy of fluid infusion in SAH patients with delayed cerebral ischemia using a multimodal approach that includes arterial blood pressure and reversal of neurological deficit as main endpoints (Strong recommendation).

  • We suggest that reduction in transcranial Doppler CBF velocities, improvements of cerebral perfusion and reduction of mean transit time on CT perfusion should be used as secondary endpoints when assessing the efficacy of fluids for reversal of delayed cerebral ischemia in SAH patients (Weak recommendation).

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Correspondence to Mauro Oddo.

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Oddo, M., Poole, D., Helbok, R. et al. Fluid therapy in neurointensive care patients: ESICM consensus and clinical practice recommendations. Intensive Care Med 44, 449–463 (2018). https://doi.org/10.1007/s00134-018-5086-z

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Keywords

  • Evidence‐based medicine
  • Guidelines
  • Fluid therapy
  • Traumatic brain injury
  • Subarachnoid haemorrhage
  • Intracerebral haemorrhage
  • Stroke
  • Mannitol
  • Hypertonic
  • Neurointensive care