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Mannitol in Critical Care and Surgery Over 50+ Years

A Systematic Review of Randomized Controlled Trials and Complications With Meta-Analysis

Zhang, Weiliang, MD*; Neal, Jonathan, BS; Lin, Liang, MD, PhD; Dai, Feng, PhD§; Hersey, Denise P., MS; McDonagh, David L., MD; Su, Fan, MD, PhD*; Meng, Lingzhong, MD#

Journal of Neurosurgical Anesthesiology: July 2019 - Volume 31 - Issue 3 - p 273–284
doi: 10.1097/ANA.0000000000000520
Review Articles
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Objective: Despite clinical use spanning 50+ years, questions remain concerning the optimal use of mannitol. The published reviews with meta-analysis frequently focused on mannitol’s effects on a specific physiological aspect such as intracranial pressure (ICP) in sometimes heterogeneous patient populations. A comprehensive review of mannitol’s effects, as well as side effects, is needed.

Methods: The databases Medline (OvidSP), Embase (OvidSP), and NLM PubMed were systematically searched for randomized controlled trials (RCTs) comparing mannitol to a control therapy in either the critical care or perioperative setting. Meta-analysis was performed when feasible to examine mannitol’s effects on outcomes, including ICP, cerebral perfusion pressure, mean arterial pressure (MAP), brain relaxation, fluid intake, urine output, and serum sodium. Systematic literature search was also performed to understand mannitol-related complications.

Results: In total 55 RCTs were identified and 7 meta-analyses were performed. In traumatic brain injury, mannitol did not lead to significantly different MAP (SMD [95% confidence interval (CI)] =−3.3 [−7.9, 1.3] mm Hg; P=0.16) but caused significantly different serum sodium concentrations (SMD [95% CI]=−8.0 [−11.0, −4.9] mmol/L; P<0.00001) compared with hypertonic saline. In elective craniotomy, mannitol was less likely to lead to satisfactory brain relaxation (RR [95% CI]=0.89 [0.81, 0.98]; P=0.02), but was associated with increased fluid intake (SMD [95% CI]=0.67 [0.21, 1.13] L; P=0.004), increased urine output (SMD [95% CI]=485 [211, 759] mL; P=0.0005), decreased serum sodium concentration (SMD [95% CI]=−6.2 [−9.6, −2.9] mmol/L; P=0.0002), and a slightly higher MAP (SMD [95% CI]=3.3 [0.08, 6.5] mm Hg; P=0.04) compared with hypertonic saline. Mannitol could lead to complications in different organ systems, most often including hyponatremia, hyperkalemia, and acute kidney injury. These complications appeared dose dependent and had no long-term consequences.

Conclusions: Mannitol is effective in accomplishing short-term clinical goals, although hypertonic saline is associated with improved brain relaxation during craniotomy. Mannitol has a favorable safety profile although it can cause electrolyte abnormality and renal impairment. More research is needed to determine its impacts on long-term outcomes.

*Department of Anesthesiology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong

Department of Anesthesiology, The First Affiliated Hospital of Xiamen University, Siming Qu, Xiamen, Fujian, China

School of Medicine, University of Connecticut, Farmington

§Department of Biostatistics, Yale University School of Public Health, Yale Center for Analytical Sciences

#Department of Anesthesiology, Yale University School of Medicine, New Haven, CT

Lewis Science Library, Princeton University, Princeton, NJ

Departments of Anesthesiology & Pain Management, Neurological Surgery, Neurology & Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX

L.M.: conception and design. W.Z., J.N., F.S., and L.M.: drafting the article. All authors: critically revising the article. L.M.: approved the final version of the manuscript on behalf of all authors.

Funded by the Key Projects of Shandong Provincial Natural Science Foundation (ZR2014HZ005, to Fan Su). The authors have no conflicts of interest to disclose.

Address correspondence to: Lingzhong Meng, MD. E-mail: lingzhong.meng@yale.edu.

Received March 9, 2018

Accepted May 22, 2018

Mannitol is a commonly administered hyperosmolar agent for a variety of clinical indications. Introduced into patient care 50+ years ago, it is claimed that mannitol delivers clinical benefits by reducing elevated intracranial pressure (ICP),1–5 enhancing operative conditions for craniotomy,6 and providing renoprotection during kidney transplantation.7,8

Although considered to have a favorable safety profile, questions remain concerning mannitol’s clinical efficacy and the associated impacts on physiology and outcomes. The clinical significance of this uncertainty is increasing, as investigation into hypertonic saline as an alternative osmotherapy has recently grown.9,10 Given the presence of ambiguous research findings and the clinical complexity of patients requiring hyperosmolar therapy, physician preference has traditionally played a significant role in mannitol application.

Quality randomized controlled trials (RCTs) that specifically compare mannitol versus a control therapy are essential to determining the optimal use of mannitol. In this paper, we aim to systematically review and summarize the evidence pertinent to mannitol’s clinical efficacy, based on the RCTs conducted since mannitol’s clinical debut. We also aim to systematically review the reported complications attributed to mannitol administration. Meta-analysis is performed when feasible.

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HISTORY OF MANNITOL

Weed and McKibben11 proposed the hyperosmolar theory for reducing raised ICP in 1919, based on the observation that cerebrospinal fluid pressure decreased following hypertonic saline-induced intravascular osmotic shifts in etherized cats. This discovery prompted the search for an optimal osmotherapy in neurological patients with elevated ICP. Although urea was considered early on,12 mannitol eventually emerged as the agent of choice in the early 1960s.13 Before this introduction into clinical neuroscience, mannitol was investigated as an alternative to inulin to measure glomerular filtration rate14 and as a treatment for edema secondary to nephrosis.15

In 1961, Wise and Chater13 reported that administering mannitol in canines (and a human subject with a brain tumor) lowered cerebrospinal fluid pressure. Wise and Chater16 followed this proof of concept study in rapid succession with a study of 24 human subjects and a publication in 1962 that formally introduced the potential therapeutic indications for intravenous mannitol administration.17 Also in 1962, Shenkin et al18 published a report of 34 patients supporting the use of mannitol for brain relaxation during craniotomy by determining that satisfactory operative conditions were achieved in all cases. Eventually, mannitol replaced urea as the standard of care for brain relaxation because of a more favorable profile in regards to preparation, chemical stability, and safety.19

More recently, hypertonic saline has emerged as an alternative hyperosmolar therapy.20,21 The clinical efficacy of hypertonic saline was demonstrated by Todd et al22 in 1985, with successive research suggesting that it may outperform mannitol for brain relaxation23,24 and ICP reduction.25–27 Despite accumulating research, there is no consensus concerning the optimal osmotherapeutic agent in critical care and surgery. For example, the 2017 Guidelines for the Management of Severe Traumatic Brain Injury recommended mannitol for raised ICP because of the lack of sufficient evidence supporting hypertonic saline as a replacement.28

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APPLIED PHARMACOLOGY AND PHYSIOLOGY

Mannitol, which in alternate settings may be referred to as mannite or manna sugar, is a 6-carbon hexahydric alcohol with a molecular weight of 182.17 g/mol.29 A solution of 20% mannitol provides an osmolality of 1245 mOsm/kg.30 Renal excretion eliminates approximately 80% of administered mannitol, with hepatic metabolism playing a minor role.31 In humans, the distribution and elimination half-lives of mannitol are ~2 and ~71 minutes, respectively; whereas the volume of distribution and total body clearance are ~0.47 L/kg and ~7 mL/min/kg, respectively.31

Mannitol administration exerts a rapid and reliable increase in total serum osmolality. Alterations in osmotic gradients between different compartments, especially between the intracellular and extracellular space and between the intravascular and extravascular space, drive the movement of free water and provide the foundation of mannitol’s osmotherapeutic efficacy.32 The increase in serum osmolality is mitigated by the renal excretion of mannitol33 and dilution secondary to intravascular volume expansion.34 Mannitol also causes considerable diuresis, which modulates changes to serum osmolality by free water and sodium loss.35–37 Depending on the administration rate, serum osmolality normally increases until the infusion is discontinued, with a subsequent decrease driven primarily by the renal elimination of mannitol and changes in serum free water.

The effect of mannitol in neurological patients relies on the integrity of the blood brain barrier, which restricts the passage of mannitol and allows the movement of free water.32 The loss of free water in brain parenchyma (primarily from the intracellular and extravascular spaces) leads to a decrease in brain bulk that in turn leads to brain relaxation when the dura is opened and ICP reduction when the dura is closed.6

Mannitol may also affect the intravascular space of the brain. In cats, mannitol leads to cerebral vasoconstriction, which is likely a regulatory response to the decrease in blood viscosity and the consequential increase in cerebral blood flow (CBF).38 In theory, cerebral vasoconstriction may reduce cerebral blood volume, which in turn may facilitate brain shrinkage.

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EVIDENCE BASED ON RANDOMIZED CONTROLLED TRIALS

Systematic Review With Meta-Analysis

In order to understand the effects of mannitol on clinically relevant outcomes, a systematic literature search of the published RCTs with meta-analysis (when feasible) was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.39 An experienced medical librarian performed a comprehensive search of multiple databases after consulting with the lead authors and performing a Medical Subject Heading (MeSH) analysis of key articles provided by the research team. In each database, we used an iterative process to translate and refine the searches. Both English and foreign language articles were eligible. The formal search strategies used relevant vocabulary terms and synonymous free text words and phrases to capture the concepts of RCT and mannitol.

The databases searched were MEDLINE (OvidSP 1946 to September Week 2 2016), MEDLINE (PubMed, for in-process and nonindexed citations), and Embase (OvidSP 1974 to 2016 September 09). All searches were run on September 9, 2016. The full strategy for OvidSP MEDLINE is detailed in the Supplemental Digital Content File 1, http://links.lww.com/JNA/A65, and additional strategies are available from the authors. Further studies were identified by examining the reference lists of all included articles and searching Google Scholar and PubMed nonsystematically.

The inclusion criteria were (1) mannitol administered intravenously as an intervention, (2) mannitol compared to a control therapy, (3) critical care or perioperative setting, (4) RCT study design, and (5) human subjects. The exclusion criteria were (1) case reports, (2) observational studies, (3) retrospective studies, (4) review articles, (5) nonhuman studies, and (6) mannitol given orally or in an irrigation solution.

The systematic literature search yielded 2413 unique articles which were independently screened by 2 investigators (W.Z. and L.L.), with the conflicts resolved by consulting the senior investigators (F.S. and L.M.). A total of 55 RCTs were identified20,30,43–95 (Supplemental Digital Content File 2, http://links.lww.com/JNA/A66). See Figure 1 for flowchart outlining the study selection process. The risk of bias for each individual study that was eligible for meta-analysis was assessed with a tool developed by the Cochrane Collaboration.40 The domains being assessed and the results of the assessment are detailed in the Supplemental Digital Content File 3, http://links.lww.com/JNA/A67.

FIGURE 1

FIGURE 1

The outcomes of interest included: (1) ICP, (2) cerebral perfusion pressure (CPP), (3) mean arterial pressure (MAP), (4) brain relaxation, (5) serum sodium, (6) intraoperative fluid intake, and (7) intraoperative urine output (Table 1). Because of the methodological heterogeneity, not every clinically relevant outcome could be meaningfully meta-analyzed. We only performed meta-analyses if outcomes were investigated by at least 3 RCTs that used the same patient population and comparable methodologies.

TABLE 1

TABLE 1

The meta-analysis was performed using the Review Manager (RevMan) software (Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). To account for variation or heterogeneity among various studies, the DerSimonian and Laird random-effects statistical model was applied for all analyses. I2 statistic was used to measure the degree of heterogeneity across studies. When I2 was <50%, low heterogeneity was assumed, and the effect was thought to be because of chance. Conversely, when I2 >50%, high heterogeneity was thought to exist. The statistical test of heterogeneity was undertaken by the use of Cochran’s Q-test (eg, χ2 test). For measures of effect sizes, risk ratio (RR) with 95% confidence interval (CI) was calculated for dichotomous outcomes. Standardized mean difference (SMD) with 95% CI was calculated for continuous outcomes. A P-value<0.05 was considered to be statistically significant.

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Traumatic Brain Injury (TBI)

TBI is associated with significant morbidity and mortality. It leads to ~235,000 hospitalizations and ~50,000 deaths per year in the United States.96 The goals of mannitol administration in patients with TBI are to decrease ICP, increase CPP, and reduce the risk of cerebral ischemia and brain herniation.97

The literature search identified 11 RCTs comparing mannitol versus a control therapy in patients with TBI (Supplemental Digital Content File 2, http://links.lww.com/JNA/A66). Meta-analysis was performed for MAP and serum sodium concentration. There was no difference in posttreatment MAP between mannitol and hypertonic saline (SMD [95% CI]=−3.3 [−7.9, 1.3] mm Hg; P=0.16) (Fig. 2A). The serum sodium concentration measured 15 to 120 minutes after administration was significantly lower for mannitol compared with hypertonic saline (SMD [95% CI]=−8.0 [−11.0, −4.9] mmol/L; P<0.00001) (Fig. 2B). Mannitol effectively decreased ICP in patients with TBI, and there was no difference in the magnitude of reduction between mannitol and the control therapy based on the reported data.30,48,49,51,52,54 We did not perform a meta-analysis of ICP because of the heterogeneity of the control therapies among these studies.

FIGURE 2

FIGURE 2

A recent meta-analysis based on 7 RCTs performed in patients with severe TBI concluded that the risk of ICP treatment failure favors hypertonic saline over mannitol (RR [95% CI]=0.39 [0.18, 0.81]; P=0.01).98 The authors were not able to directly meta-analyze changes in ICP because of the significant heterogeneity in the reporting of ICP changes from baseline.98 A different meta-analysis based on 5 RCTs, performed in patients with brain tumors, stroke, or TBI, concluded that hypertonic saline is more effective than mannitol in ICP reduction (RR [95% CI]=1.16 [1.00, 1.33]; P=0.046).99 Another meta-analysis based on 7 studies (6 RCTs and 1 retrospective study) performed in patients with TBI also concluded that hypertonic saline is more effective than mannitol in ICP reduction (SMD [95% CI]=−1.69 [−2.95, −0.44] mm Hg; P = 0.008).27 However, one meta-analysis based on 6 RCTs conducted in TBI patients failed to demonstrate the superiority of hypertonic saline over mannitol (SMD [95% CI]=1.39 [−0.74, 3.53] mm Hg; P=0.152).10

Of note, studies performed in different patient populations were included in 2 meta-analyses,27,99 whereas all previous meta-analyses were based on studies that had used different intervention protocols.10,27,98,99 Moreover, a variety of outcome measures (ie, treatment failure, relative risk, and mean difference) were used by different meta-analyses.10,27,98,99 An additional limitation was that several RCTs reported either the median (range) or the mean (SD) ICP, which could not be readily pooled together for meta-analysis. Although there exist some rules that approximate mean and SD values by certain transformations of median and range values, we opted not to do so because the reporting of different types of summary statistics implicitly suggested inherent study differences. This empirical approximation introduces another source of bias to the synthesis of heterogeneous studies. In conclusion, the predetermined methodology has a heavy influence on both the conduct and results of a meta-analysis.

All RCTs included in our meta-analysis demonstrated the efficacy of both mannitol and hypertonic saline in increasing CPP from the pretreatment level. While some studies found a larger increase in CPP after hypertonic saline than after mannitol administration,48 others failed to identify a difference between these 2 treatments.30,48,49,51 One study found that, although CPP was higher after hypertonic saline treatment, there was no statistically significant difference in mortality between mannitol and hypertonic saline treatments in patients with TBI.48 Nonetheless, a study performed in patients with TBI found that aggressive CPP management was associated with more favorable Glasgow coma scale scores and better chances of survival, even in cases of extremely high ICP.100 A review article focusing on the management of CPP in pediatric patients with head injury concluded that a higher CPP level is associated with more favorable outcomes.101 However, there were insufficient data to allow for a meta-analysis of those essential outcomes.

Mannitol increases CBF in patients with TBI,102 and this effect may be cerebral-autoregulation-functional-status dependent.103 The loss of cerebral autoregulation in patients with severe TBI renders CBF pressure-passive, and thus tight control of CPP is even more crucial for optimal brain perfusion.104 It is important to note that cerebral perfusion is determined not only by CPP and cerebrovascular resistance, a relationship defined by cerebral autoregulation,105 but also by the percentage of distribution of cardiac output (CBF is ~12% to 15% of cardiac output).106 It was also suggested by a study performed in 35 patients with severe head injuries that the decrease in blood viscosity following mannitol administration has significant impacts on CBF.107 Overall, it is likely that the impact of mannitol on CBF is primarily determined by its effects on ICP and CPP; however, changes in intravascular volume, blood viscosity, afterload, and cardiac output may also play a role.

Mannitol leads to a higher urine output than hypertonic saline in patients with TBI,49 implying that both urine output and intravascular volume need to be closely monitored following the administration of mannitol. One study demonstrated that hypertonic saline had a more beneficial effect in reducing oxidative stress than mannitol in patients with TBI 53; however, not only does this observation need to be validated by further research, the clinical significance also remains to be determined.

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Critical Neurological Conditions

Several severe, nontraumatic neurological conditions are frequently associated with increased ICP. One of the therapeutic goals in these patients is to control ICP, with mild cases normally managed medically and severe cases requiring decompressive craniectomy. Mannitol has traditionally been used in these conditions as a hyperosmolar therapy.

The literature search identified 10 RCTs comparing mannitol with a control therapy in patients with ischemic stroke,20,55,61 intracranial hemorrhage,20,57–59,62 and intracranial hypertension related to other etiologies.56,60 However, because of the heterogeneous patient populations and methodologies among these studies, we were not able to meta-analyze the clinically relevant outcomes (Supplemental Digital Content File 2, http://links.lww.com/JNA/A66).

One RCT found that hypertonic saline hydroxyethyl starch was more effective in lowering ICP but less effective in increasing CPP compared with mannitol in stroke patients with intracranial hypertension.20 There were no RCTs comparing the efficacy of mannitol versus a control therapy to decrease ICP in patients with intracerebral hemorrhage. In a canine model of intracranial hemorrhage, no significant difference in ICP change was found among the therapies of 20% mannitol, 3% saline, and 23.4% saline, although it was noted that 3% saline may have a longer duration of action.108

The effects of equiosmolar doses of mannitol and hypertonic saline on CBF, measured by positron emission tomography, were compared in patients with ischemic stroke.61 Mannitol, but not hypertonic saline, seemed to be able to increase CBF in nonischemic brain tissue.61 This finding is corroborated by a nonrandomized human study which demonstrated an increase in the blood flow velocity, measured by transcranial Doppler, in the middle cerebral artery ipsilateral to intracerebral hemorrhage after mannitol administration.109

Compared with hypertonic saline, mannitol consistently decreases serum sodium concentration to a level that is deemed undesirable in neurocritical care (~128 to 129 mmol/L).56,60 However, the mannitol-related hyponatremia does not adversely affect serum osmolality. In fact, mannitol causes a slightly larger increase in serum osmolality compared with hypertonic saline (329 vs. 321 mOsm/L56 and 310 vs. 308 mOsm/L60).

We identified 4 RCTs that investigated mortality or disability associated with mannitol versus a control therapy in stroke patients. Mannitol demonstrated no superiority over control in the following metrics: (1) consciousness, motor capabilities, or sensory capabilities in patients with ischemic stroke,55 (2) Glasgow coma scale score in patients with intracranial hemorrhage,57 and (3) functional disability at 1-month and 3-month follow-up in patients with intracranial hemorrhage.58 The secondary analysis of an RCT conducted in 2839 patients with intracranial hemorrhage concluded that mannitol is a safe therapeutic option, although it might not be associated with improved 3-month mortality or disability.62 In contrast, an RCT conducted in 24 patients with intracranial hemorrhage concluded that mannitol leads to a more significant clinical improvement compared with normal saline.59 The cause of these diverse findings remains to be reconciled.

The Guidelines for the Management of Spontaneous Intracerebral Hemorrhage published in 1999 recommended 20% mannitol (0.25 to 0.5 g/kg) every 4 hours for a duration of <5 days to treat raised ICP, in patients with progressively increasing ICP values or clinical deterioration associated with mass effect.110 Although it was concluded that hypertonic saline might be more effective than mannitol in treating intracranial hypertension based on one meta-analysis,99 the updated Guidelines for the Management of Spontaneous Intracerebral Hemorrhage published in 2015 continued the previous recommendation for mannitol as an acceptable hyperosmolar therapy.111 It should be noted that the aforementioned meta-analysis was based on 5 studies performed in different patient populations (brain tumor, stroke, and TBI).99

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Craniotomy

Craniotomy procedures can be classified as elective or emergent. The primary goal of mannitol administration in elective craniotomy is to optimize operative conditions by brain relaxation.6 Brain relaxation and ICP are related but different entities. Brain relaxation refers to the relation between intracranial content and capacity with the dura opened, whereas ICP refers to the pressure generated as a result of the interaction between intracranial contents and capacity with the cranium closed.6 In contrast to elective cases, the primary goal of mannitol administration in emergent craniotomy is to facilitate ICP management (ie, avoid cerebral herniation injury), especially when the surgical indication is for decompression.

The literature search identified 19 RCTs that compared the effects of mannitol versus a control therapy in patients undergoing craniotomy (Supplemental Digital Content File 2, http://links.lww.com/JNA/A66). Meta-analysis based on 11 RCTs showed that, although mannitol could provide satisfactory brain relaxation, it was less likely than hypertonic saline to do so (RR [95% CI]=0.89 [0.81, 0.98]; P=0.02) (Fig. 3A). Meta-analysis based on 7 RCTs showed that intravenous fluid replacement was much greater in patients receiving mannitol compared with hypertonic saline (SMD [95% CI]=0.67 [0.21, 1.13] L; P=0.004) (Fig. 3B). Meta-analysis based on 8 RCTs showed that mannitol was associated with increased urine output compared with hypertonic saline (SMD [95% CI]=485 [211, 759 mL; P=0.0005) (Fig. 3C). Meta-analysis based on 6 RCTs showed that the serum sodium concentration was significantly lower after mannitol administration than after hypertonic saline administration (SMD [95% CI]=−6.2 [−9.6, −2.9] mmol/L; P=0.0002) (Fig. 3D). Finally, meta-analysis based on 7 RCTs showed that MAP was significantly higher 30 minutes after mannitol administration than after hypertonic saline administration (SMD [95% CI]=3 [0.08, 6] mm Hg; P=0.04) (Fig. 3E).

FIGURE 3

FIGURE 3

Our conclusion that hypertonic saline achieves better brain relaxation versus mannitol for elective craniotomy is supported by 3 different meta-analyses, which include a 2014 study based on 6 RCTs,112 a 2015 study based on 7 RCTs,113 and a 2017 study based on 9 RCTs.24 Although satisfactory brain relaxation is desirable during craniotomy to minimize retraction injury and/or herniation through the skull defect, only a few studies examined the relation between brain relaxation and clinical outcomes. Several studies showed that, although hypertonic saline was associated with better brain relaxation compared with mannitol, there was no difference in length of ICU or overall hospital stay between these treatments.66,74 A recent study performed in patients undergoing elective craniotomy demonstrated that higher doses of mannitol provided better brain relaxation but were also associated with more adverse effects, defined as hyponatremia with Na+ between 125 and 130 mmol/L and hyperkalemia with K+>5.0 mmol/L.114 The authors suggested that the use of 1.0 g/kg mannitol balanced the benefits associated with satisfactory brain relaxation against the risks of undesired side effects.114 The overall evidence suggests that, when poor brain relaxation per se is of primary concern, hypertonic saline is a better therapeutic option than mannitol, and when the dose of mannitol has to be escalated for better brain relaxation, the profile of blood electrolytes needs to be closely watched.

The small but statistically significant difference in MAP between mannitol and hypertonic saline treatments may not be clinically significant. In theory, cerebral autoregulation is better preserved during elective craniotomy than TBI; therefore, CPP fluctuations can be better tolerated during elective craniotomy as long as the CPP is within the autoregulatory range. Moreover, ICP becomes zero during craniotomy with the dura opened, which is different from TBI where the ICP can be dangerously high because of the closed cranium. These facts explain why a small change in MAP is less concerning during elective craniotomy than when treating TBI.

Mannitol has significant but short-lived (~15 to 25 mins) impacts on global hemodynamics during elective craniotomy. On the basis of the transesophageal echocardiography measurements, a single bolus dose of 20% mannitol (1.0 gm/kg) leads to significant increases in left ventricle preload and cardiac output and a significant decrease in afterload without concomitant changes in blood pressure and heart rate.115 This finding is corroborated by a separate study that demonstrated significant mannitol-related increases in stroke volume and cardiac output measured by thoracic bioimpedance plethysmography.116 Both studies were performed in patients undergoing elective craniotomy. The clinical significance of these hemodynamic changes remains to be elucidated.

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Nonneurological Settings

The literature search yielded 14 RCTs comparing mannitol with a control therapy in nonneurological patients (Supplemental Digital Content File 2, http://links.lww.com/JNA/A66). Meta-analysis could not be performed because of the heterogeneity of patient populations, intervention protocols, and outcome measurements among these studies.

Historically, mannitol was used across a wide spectrum of clinical settings including: (1) renoprotection,81,83,84,86,87 (2) treatment of oliguria or anuria,80 (3) prevention of transurethral prostatectomy syndrome,82 (4) enhancement of recovery after coronary artery bypass grafting,90 (5) alleviation of the immunosuppression induced by cardiopulmonary bypass,91 (6) attenuation of postreperfusion syndrome in liver transplantation,95 and (7) optimization of the operative conditions during the repair of orbital blowout fractures.92 On the basis of the RCTs that we collected, modern indications for mannitol, aside from the clinical neuroscience, are primarily related to mannitol’s renal effects.

Mannitol administration in renal transplant has long been used to improve outcomes in kidney allograft recipients.7,117 The beneficial effects may be associated with the expansion of intravascular volume, diminished renal tubular obstruction, enhanced intrarenal vasodilatory prostaglandin and atrial natriuretic peptide release, and oxygen free-radical scavenger properties.7,117–119 However, direct RCT evidence examining the effect of mannitol administration on clinical outcomes after kidney transplantation is lacking.

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SIDE EFFECTS OF MANNITOL

To understand the side effects associated with mannitol administration, we performed a systematic literature search for reported complications attributed to mannitol. Again, a professional librarian searched the same electronic bibliographic databases from inception of the databases until September 12, 2016. The full strategy for OvidSP MEDLINE search is detailed in the Supplemental Digital Content File 4, http://links.lww.com/JNA/A68, and additional strategies are available from the authors. The inclusion criteria were (1) mannitol administered, (2) complications or adverse events occurred and attributed to mannitol, and (3) human subjects.

A total of 65 reports of mannitol-related complications were identified (Supplemental Digital Content File 5, http://links.lww.com/JNA/A69).120–184 Hyponatremia and hyperkalemia were the most commonly reported electrolyte abnormalities. Abnormal electrocardiograms and cardiac arrest associated with hyperkalemia were also reported. Pulmonary edema was the most common pulmonary complication reported, which seemed to be associated with large dose mannitol administration in most cases (eg, 3250 mL of 20% mannitol given to a 7-year-old girl for cerebral edema treatment).134 Most mishaps were renal complications, with most cases diagnosed as acute renal failure. The clinical signs included oliguria, anuria, elevated creatinine, elevated blood urea nitrogen, decreased serum sodium concentration, increased serum potassium concentration, and/or increased serum glucose level. Cerebral complications included intracranial rebleeding, hematoma, brain expansion, and leakage into peritumor edematous areas causing rebound ICP increases. Cardiac complications included cardiac arrest, chest pain, pulmonary embolism, and bundle branch block. The reported gastrointestinal complications were all colonic explosions and associated with large doses of mannitol given orally. Other complications included hypertension, hypotension, and compartment syndrome likely related to mannitol subcutaneous infiltration.

Hypertonic hyponatremia is a well-documented electrolyte abnormality.185–188 The presence of effective solute other than sodium, such as mannitol, in the plasma causes an osmotic shift of water from the intracellular to extracellular space and from the extravascular to intravascular space. The expansion of the proportion of water in the plasma leads to a dilutional decrease in serum sodium concentration.185,187,188 The increased sodium loss from urine following mannitol-induced diuresis fuels the development of hyponatremia.36,37 The etiology of mannitol-induced hyperkalemia is likely multifactorial, with possible explanations including (1) expansion acidosis because of the dilution of the extracellular bicarbonate with a bicarbonate-poor fluid from the intracellular space, (2) solvent drag, which refers to the movement of potassium along with the water out of intracellular space, and (3) hemolysis secondary to red cell crenation; however, this speculation regarding hemolysis is contradictory to some experimental data and clinical experience.189–191

It is important to note that the doses of mannitol administered in many cases were very large, sometimes 10 times larger than what are currently used in clinical practice. Thus, it is possible that the reported complications were dose-related. Indeed, most literature indicates that mannitol is safe as long as the dose is within the recommended range.114 Most patients with reported complications recovered, although a few died; usually because of the progression of the primary disease. The available evidence should be interpreted with caution because it is based on case reports. Therefore, a cause-effect relationship typically cannot be determined.

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CONCLUSIONS

Since being introduced into clinical neuroscience 50+ years ago, mannitol has remained a prominent osmotherapeutic agent. Despite such a long tenure, our understanding of its effects on essential clinical outcomes is still a work in progress. Although >50 RCTs comparing mannitol with a control therapy have been published, meaningful meta-analyses are restrained by the heterogeneity of clinical settings, intervention protocols, and outcome measures. Most evidence centers on mannitol’s physiological effects in neurological patients. The efficacy of mannitol in decreasing ICP and rendering brain relaxation in neurological patients is supported by our meta-analyses. Although potential side effects should not be overlooked, mannitol has a generally favorable safety profile when the recommended doses are used. A shift towards conducting RCTs that focus on long-term outcomes is a priority.

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REFERENCES

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Keywords:

mannitol; randomized controlled trials; complications; systematic review; meta-analysis

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