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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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 References 1. Kamel H, Navi BB, Nakagawa K, Hemphill JC III, Ko NU. Hypertonic saline versus mannitol for the treatment of elevated intracranial pressure: a metaanalysis of randomized clinical trials. Crit Care Med 2011;39:554559. 2. Freshman SP, Battistella FD, Matteucci M, Wisner DH. Hypertonic saline (7.5%) versus mannitol: a comparison for treatment of acute head injuries. J Trauma 1993;35:344348.
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3. Qureshi AI, Wilson DA, Traystman RJ. Treatment of elevated intracranial
pressure in experimental intracerebral hemorrhage: comparison between mannitol and hypertonic saline. Neurosurgery 1999;44:10551063. [Discussion, pp. 10631054.] 4. Mortazavi MM, Romeo AK, Deep A, Griessenauer CJ, Shoja MM, Tubbs RS, Fisher W. Hypertonic saline for treating raised intracranial pressure: literature review with meta-analysis. J Neurosurg 2011. 5. Horn P, Munch E, Vajkoczy P, Herrmann P, Quintel M, Schilling L, Schmiedek P, Schurer L. Hypertonic saline solution for control of elevated intracranial pressure in patients with exhausted response to mannitol and barbiturates. Neurol Res 1999;21:758764. 6. de Assis Aquino Gondim F, Aiyagari V, Shackleford A, Diringer MN. Osmolality not predictive of mannitol-induced acute renal insufficiency. J Neurosurg 2005;103:444447. 7. Garcia-Morales EJ, Cariappa R, Parvin CA, Scott MG, Diringer MN. Osmole gap in neurologic-neurosurgical intensive care unit: its normal value, calculation, and relationship with mannitol serum concentrations. Crit Care Med 2004;32:986991. 8. Visweswaran P, Massin EK, Dubose TD Jr . Mannitol-induced acute renal failure. J Am Soc Nephrol 1997;8:10281033. 9. Timmer JG, Schipper HG. Peripheral venous nutrition: the equal relevance of volume load and osmolarity in relation to phlebitis. Clin Nutr 1991;10:7175. 10. Hands R, Holcroft JW, Perron PR, Kramer GC. Comparison of peripheral and central infusions of 7.5% NaCl/6% dextran 70. Surgery 1988;103:684689. 11. Mattox KL, Maningas PA, Moore EE, Mateer JR, Marx JA, Aprahamian C, Burch JM, Pepe PE. Prehospital hypertonic saline/dextran infusion for post-traumatic hypotension: the U.S.A. multicenter trial. Ann Surg 1991;213:482491. 12. Rocha e Silva M, Velasco IT, Porfirio MF. Hypertonic saline resuscitation: saturated salt-dextran solutions are equally effective, but induce hemolysis in dogs. Crit Care Med 1990;18:203207. 13. Moore GL, Summary JJ, Dubick MA, Ledford ME, Ryan BA, Gonzales A, Wade CE. Effects of hypertonic saline (7.5%)/dextran 70 on human red cell typing, lysis, and metabolism in vitro. Vox Sang 1990;59:227231. 14. Parker JC. Dog red blood cells: adjustment of salt and water content in vitro. J Gen Physiol 1973;62:147156. 15. Adams RD, Victor M, Mancall EL. Central pontine myelinolysis: a hitherto undescribed disease occurring in alcoholic and malnourished patients. AMA Arch Neurol Psychiatry 1959;81:154172. 16. Kleinschmidt-Demasters BK, Rojiani AM, Filley CM. Central and extrapontine myelinolysis: then.and now. J Neuropathol Exp Neurol 2006;65:111. 17. Huang SJ, Chang L, Han YY, Lee YC, Tu YK. Efficacy and safety of hypertonic saline solutions in the treatment of severe head injury. Surg Neurol 2006;65:539546. [Discussion, p. 546.] 18. Torre-Healy A, Marko NF, Weil RJ. Hyperosmolar therapy for intracranial hypertension. Neurocrit Care (In press) 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
A Study To Evaluate Effectiveness of Cold Application and Magnesium Sulphate Application On Superficial Thrombophlebitis Among Patients Receiving Intravenous Therapy in Selected Hospitals Amritsar.