Editorials

Hyperosmolar Therapy for Intracranial Hypertension:

Time to Dispel Antiquated Myths
Pharmacologic induction of supraphysiologic serum osmolality
(hyperosmolar therapy) with either mannitol or hypertonic saline
(HTS) is the mainstay of medical management for patients with
acute intracranial hypertension, and its efficacy for reduction of intracranial pressure (ICP) has been demonstrated consistently (1).
Despite the absence of supporting evidence, several myths regarding the selection, administration, titration, and complications of
hyperosmolar therapy endure. Regrettably, their perpetuation
risks delaying the delivery or compromising the appropriate use
of this potentially life-saving therapy. This commentary examines
four of the most significant myths regarding hyperosmolar therapy and summarizes briefly the refuting evidence with the goal
of removing unsubstantiated treatment barriers and improving
the evidence-based delivery of appropriate medical therapy to
patients with elevated ICP.

MYTH #1: MANNITOL AND HTS THERAPY

ARE EQUIVALENT
The term hyperosmolar therapy may inadvertently connote
that the ultimate goal is supraphysiologic osmolality without
regard to the agent selected to induce the hyperosmolar state.
Although both mannitol and HTS are effective in reducing brain
water content and ICP (13), animal studies suggest greater
short- and intermediate-term reduction in brain water with
HTS (3). The results of human studies are more ambiguous,
but recent data also suggest that HTS may outperform mannitol
in ICP reduction (3, 4). In addition, HTS is effective at achieving
ICP control when mannitol therapy fails (4, 5). Although overall
superiority may ultimately depend on a variety of clinical factors,
these data refute the notion that all agents for inducing and
maintaining hyperosmolar states are clinically equivalent.

MYTH #2: MANNITOL THERAPY SHOULD BE

TITRATED TO SERUM OSMOLALITY TO AVOID
RENAL INSUFFICIENCY
A common misconception is that the risk of acute renal insufficiency (ARI) among patients receiving maintenance mannitol
therapy is mitigated by maintaining serum osmolality (Sosm) ,
320 mOsm/L, and thus this parameter is frequently used as
a threshold for dose titration. However, recent data demonstrate
no independent association between Sosm and ARI (6). Conversely, the serum osmolal gap (OG, Osmcalculated 2 Osmmeasured)
may be a more predictive metric (7, 8), and ARI is rare when OG
is less than 55 mOsm/L (8). OG is also preferable because its
levels are stable in the ICU population and because, as an unmeasured osmole, mannitol accumulation correlates well with
increasing OG (7). Together, these data suggest that strategies
Author Contributions: N.M.: manuscript design, acquisition of data, and writing
and editing manuscript.
Dr. Nicholas Marko is a neurosurgeon supported by a grant from the William P.
Van Wagenen fellowship program of the American Association of Neurological
Surgeons.
Am J Respir Crit Care Med Vol 185, Iss. 5, pp 467478, Mar 1, 2012
Internet address: www.atsjournals.org

for monitoring and titrating mannitol therapy to OG may be

more clinically relevant than those based on following Sosm.

MYTH #3: ACUTE, INTERMITTENT PERIPHERAL

INFUSION OF HTS CAUSES PHLEBITIS, REGIONAL
NECROSIS, AND INTRAVASCULAR HEMOLYSIS
Peripheral infusion of HTS, even in the acute setting, is often
avoided by clinicians or prohibited by institutions because of concerns for phlebitis, regional necrosis, or intravascular hemolysis.
These practices are likely based on literature regarding infusion
of hypertonic parenteral nutrition, which reveals a duration- and
osmolality-dependent relationship between peripheral infusion
and local vascular complications (9). These data, however, describe the sequelae of long-term peripheral infusion, and there is
no evidence suggesting their generalizability to the practice of
intermittent, peripheral bolus administration of HTS. To the contrary, histologic investigations from animal models demonstrate
no evidence of vascular damage associated with peripheral boluses
(10), and human data from prehospital resuscitation with peripherally administered HTS report no regional vascular complications
(11). In the absence of evidence of clinical complications, and with
both animal and human data suggesting the safety of peripheral
HTS boluses (10, 11), the practice of withholding hyperosmolar
therapy for lack of central venous access appears unjustified.
A related concern is the fear of intravascular hemolysis after
peripheral administration of HTS. This may be grounded in
early in vitro investigations of red blood cell membrane fragility and augmented by more recent evidence of hemolysis when
HTS was administered in a canine model (12). However, the
former results are not reproducible in vitro (13), whereas the latter
are confounded by a uniquely canine deficiency of the red
blood cell membrane Na1/K1-ATPase that increases susceptibility to osmolality-associated hemolysis (14). Accordingly, no modern evidence supports the concern for HTS-induced intravascular
hemolysis with peripheral bolus administration in humans.

MYTH #4: HTS THERAPY MUST BE INITIATED

SLOWLY TO REDUCE THE RISK OF CENTRAL
PONTINE MYELINOLYSIS
Since its characterization in 1959 (15), concerns for iatrogenically
inducing the often-discussed yet rarely witnessed syndrome of
osmotic demyelination (central pontine myelinolysis [CPM])
have engendered a tendency among clinicians toward slow
administration of supraphysiologic sodium solutions. Although
50 years of investigation have yet to identify definitively the etiology of CPM (16), investigators have reported several findings
that appear to mitigate the requisite clinical concern over CPM
when HTS is used to treat elevated ICP. First, CPM typically
occurs in the setting of chronic comorbidities believed to compromise neuronal and glial energy supply and is, therefore, rarely
observed without concomitant chronic alcoholism, malnourishment, liver disease, hypoglycemia, or syndrome of inappropriate
antidiuretic hormone (16). Next, only approximately 22% of modern cases of CPM are associated with intravenous sodium therapy,
and nearly all of these involve correction of profound baseline

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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE

hyponatremia (16). Finally, evidence suggests that bolus infusions

of more than 300 mOsm of sodium given over 20 minutes are
clinically well tolerated (17), even though the resulting increase
in serum sodium significantly exceeds the often-quoted safe rate
of 0.5 mEq/L/hour. In the absence of preexisting hyponatremia
and predisposing comorbidities, there is little evidence to suggest
that rapid elevation of serum sodium with HTS during initiation
of acute hyperosmolar therapy presents a significant CPM risk for
most patients.
This discussion is not intended to be a comprehensive review of
hyperosmolar therapy, and interested readers should consult such
a publication (18) for additional information and for further references. Additionally, the goal is not to encourage the injudicious use
of hyperosmolar therapy, as the modality is not without risk and
because the aforementioned side effects, although highly improbable, are not theoretically impossible. Accordingly, consultation
with an experienced intensivist, neurologist, or neurosurgeon remains invaluable in the management of patients with elevated ICP,
particularly since this represents a rapidly evolving field in which
ongoing appraisal of the literature is necessary. Notwithstanding,
the preponderance of clinical evidence dispels several antiquated
myths associated with hyperosmolar therapy that have persisted
for generations within the collective consciousness of the medical
community. Changes in individual practice and institutional policies grounded in concerns for patient safety but predicated upon
these unsubstantiated myths are long overdue, as appropriate delivery of hyperosmolar therapy reduces morbidity and improves
survival among patients with intracranial hypertension.
Author disclosures are available with the text of this article at www.atsjournals.org.
Acknowledgment: The author thanks Drs. Robert Weil and Andrew Torre-Healey
for their generous contributions to and valuable insights regarding this discussion.

Nicholas F. Marko, M.D.

Cancer Research UK Cambridge Research Institute
Cambridge, United Kingdom
and
Department of Applied Mathematics and Theoretical Physics
University of Cambridge
Cambridge, United Kingdom
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head injuries. J Trauma 1993;35:344348.

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2012

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Copyright 2012 by the American Thoracic Society
DOI: 10.1164/rccm.201109-1698ED

Interferon-l1 and Viral Wheeze in Asthma:

A Gothic Duality?
A recurring theme in Gothic literature is that the human condition is an enigmatic mixture of good and evil. These themes
are central in classics such as Robert Louis Stevensons
Dr. Jekyll and Mr. Hyde, in which the protagonist begins as
a respected pillar of the community, but his darker side
becomes evident as the story unfolds. In this issue of the Journal, Miller and colleagues (pp. 508516) suggest that IFN-l1,

Supported by National Institutes of Health Grants U19 AI070503-01, P01

HL070831, and HHSN272200900052C.

a prototypic antiviral cytokine, may also have an injurious

duality (1).
Previous studies have demonstrated that rhinovirus (HRV)
infections are closely associated with exacerbations of childhood
asthma. Since HRV infections often cause mild or asymptomatic
illnesses, this raises questions as to mechanisms that differentiate
mild colds from severe episodes of wheezing and shortness of
breath in children with asthma. Viral factors could relate to the
great diversity among HRVs, which consist of over 150 different
types in three species (A, B, and C). In fact, there is some evidence
that infections with HRV-C species viruses may be more likely to