Volume 1 • Number 4 • 2004 • ISSN 1541–6933
A Journal of Acute and Emergency Care
Eelco F.M. Wijdicks, MD
The Official Journal of the
Se Hu ar ma ch , R naJ ea ou d, r an nal d s Do .co wn m lo ad
Neurocritical Care Copyright © 2004 Humana Press Inc. All rights of any nature whatsoever are reserved. ISSN 1541-6933/04/1:435–440
Original Article Introducing Hypertonic Saline for Cerebral Edema
An Academic Center Experience
Lisa L. Larive,1,4 Denise H. Rhoney,1,2, 4 Dennis Parker, Jr., 1,4 William M. Coplin,2,3,4 and J. Ricardo Carhuapoma2,3,4,*
Department of Pharmacy Practice, 2Department of Neurology, 3Department of Neurological Surgery, and 4Neurosciences Critical Care Program,Wayne State University, Detroit, Michigan Abstract
Introduction: Use of hypertonic saline (HTS) is gaining acceptance in the neurosciences critical care unit (NCCU) based on its efficacy in reducing cerebral edema and its favorable hemodynamic profile. In the NCCU, unfamiliarity with the use of HTS may result in implementation difficulties. We report our initial experience using HTS, its ability to achieve a hypernatremic state, and adverse effects. Methods: Analysis of 19 consecutive patients who were admitted to the NCCU and treated with 2 or 3% HTS infusion for cerebral edema (target serum sodium: 145–155 mEq/L ) included patient diagnoses, laboratory data, length of treatment, adverse effects, and outcome at discharge. We compared the adverse effects of those patients to a contemporary cohort of patients who received mannitol as the sole form of osmotherapy. Results: The HTS cohort had a median age of 46 years (range: 18–70). Median GCS and APACHE II scores were 11 (range: 3–15) and 18 (range: 8–30), respectively. Median length of HTS treatment was 5 days (range: 1–17). Target hypernatremia was achieved in 14 patients (74%), 7 of whom achieved hypernatremia within the first 24 hours. The median number of rescue interventions received for ICP control was 3 (range: 1–30). The adverse effects between the HTS and mannitol cohorts were not found to be significantly different. Conclusion: The use of HTS for cerebral edema requires intensive efforts by the medical team to rapidly achieve and maintain a hypernatremic state. The continuous infusion of HTS was used safely. Key Words: Hypertonic saline; brain injury; cerebral edema.
*Correspondence and reprint requests to:
J. Ricardo Carhuapoma, MD, The Johns Hopkins Hospital, Meyer 8–140, 600 North Wolf St., Baltimore, MD 21287
Severe brain injury is often complicated by cerebral edema and increased intracranial pressure (ICP) resulting in secondary neuronal damage. In particular, for the treatment of traumatic brain injury, the Brain Trauma Foundation and the American Association of Neurological Surgeons have published guidelines on the management of elevated ICP (1). These guidelines support the use of nonpharmacological, pharmacological, and surgical modalities to control and maintain ICP. Osmotic therapy, sedation, and analgesia
are initial pharmacological measures, whereas paralytics and barbiturate infusion are reserved for elevations in ICP refractory to first-tier therapies. Although not addressed in the current guidelines, the use of hypertonic saline (HTS) for the treatment of cerebral edema following brain injury is becoming widespread in the neurosciences critical care unit (NCCU). HTS is similar to mannitol as an osmotic agent in that it is capable of establishing an osmotic gradient between the edematous brain tissue and the intravascular space (2). In contrast to mannitol, however, HTS does
436 ________________________________________________________________________________________________Larive et al. not possess such a pronounced diuretic effect and the potential complications of volume depletion and hypotension (2,3). In addition to creating an osmotic gradient, HTS is also an effective plasma expander; it restores resting membrane potentials, stimulates the release of atrial natriuretic peptide, enhances cardiac output, and increases cerebral perfusion pressure (4–6). In animal models, HTS seems capable of decreasing leukocyte adherence and migration and may also alter production of prostaglandins such that HTS could conceivably offer protection against systemic and central nervous system inflammatory processes that follow traumatic and nontraumatic acute brain injury (7,8). Furthermore, some reports suggest that HTS can decrease cerebrospinal fluid production, although the exact mechanism of this is unknown (9). Recent retrospective clinical experience using HTS in the treatment of cerebral edema following brain injury has already been reported (10–14). However, there is limited data regarding the logistical limitations that are encountered when introducing HTS as a novel form of treatment for cerebral edema or elevated ICP in adult patients with brain injury. We report our experience introducing the use of HTS for the treatment of brain edema in the NCCU of a university-affiliated hospital and identify the areas of difficulty we encountered during its implementation. To assess the safety of this treatment modality, we include an analysis of the adverse effects documented during this period with the use of a continuous HTS infusion. tine interventions for increased ICP or symptomatic cerebral edema included midline neutral alignment of head with an elevation of 30º, maintenance of cerebral perfusion pressure (CPP) more than 60 mmHg and normothermia less than 37.5ºC), and analgesia/sedation, if necessary. The type of rescue intervention used for acute worsening of ICP or symptomatic cerebral edema was based on the discretion of the attending NCCU physician and included the use of mannitol, controlled hyperventilation (PaCO2: 25–35 mmHg), and surgery for mass evacuation or decompression. Each time a rescue intervention was used, it was recorded as a discrete event. Intracranial pressure control was defined as 20 mmHg or less during HTS infusion. Intracranial pressure was recorded 1 hour prior to HTS infusion (if available), hourly during the HTS infusion, and 4 hours following the discontinuation of the HTS infusion (if available) or until the ICP monitor was discontinued, whichever came first. CPP, mean arterial pressure (MAP), and CVP also were recorded hourly. All pressure measurements were averaged consecutively in 4-hour blocks to calculate their daily average.
HTS Administration Protocol
The HTS solution used consisted of a 50:50 admixture of sodium chloride and sodium acetate to achieve a 2 or 3% solution. Sodium acetate was added to the solution to prevent hyperchloremic metabolic acidosis from the continuous intravenous administration of a hypertonic sodium chloride infusion. The treatment approach was similar to that described by Bhardwaj and Utalowski (14). Target serum sodium concentration for the HTS infusion was 145–155 mEq/L. A 2 or 3% sodium chloride/acetate concentration was chosen based on the patient’s serum sodium concentration at the start of the infusion and was adjusted to achieve and maintain the sodium target. Serum chemistry was drawn every 6 hours for monitoring during the HTS infusion.
Patients and Methods
With the approval of the Wayne State University Institutional Review Board, we reviewed the medical records of 19 consecutive patients admitted to the NCCU at Detroit Receiving Hospital who received 2 or 3% sodium chloride/acetate solution (HTS) as a continuous infusion for the treatment of symptomatic cerebral edema or increased ICP. In patients with no ICP monitoring, the operational definition of symptomatic cerebral edema used in this study included reduced level of consciousness associated with evidence of brain edema on head computed tomography (CT) scan (e.g., sulci effacement, hypodensity surrounding discrete brain lesions in structures associated with consciousness, abnormal diffuse white matter lucency, lateral shift of midline structures) in the absence of metabolic derangements (e.g., fever, hypoglycemia) that could account for their altered mental status. Demographic data (age and gender), clinical data (Glasgow Coma Scale [GCS] score , APACHE II score , admitting neurological diagnosis, and laboratory data), treatment information (length of HTS infusion, adverse effects), and specific patient outcome measures at discharge (hospital and NCCU lengths of stay) were collected on standardized data abstraction forms.
We evaluated the introduction of HTS to the NCCU of a university-affiliated hospital that had not used this treatment in a systematic manner before the study period. The primary endpoint of the study was to assess the efficiency of achieving a target serum sodium concentration and the time required to achieve the target. Secondarily, we assessed the safety of HTS administration by adverse effects during its use; these included pneumonia (17) (positive sputum culture, fever, leukocytosis, and abnormal chest X-rays), adult respiratory distress syndrome (18), seizures, bacteremia or sepsis (19), acute renal failure (defined as an increase in serum creatinine concentration greater than 1 mg/dL), arrhythmias (e.g., heart block, ectopic beats, atrial flutter or fibrillation, or ventricular tachycardia or fibrillation), metabolic acidosis or alkalosis (acidosis defined as pH less than 7.35 and HCO3 less than 24 mEq/L and alkalosis defined as pH greater than 7.45 and HCO–3 greater than 28 mEq/L), phlebitis (inflammation of the vein or pain/burning at the catheter site during administration of HTS infusion), hypokalemia (measured serum potassium concentration of less than 3.5 mEq/L), hyponatremia after HTS discontinuation (serum sodium concentration less than 135 mEq/L), anemia (a decrease of hemoglobin by 2 g/dL or leading to blood transfusion, precipitated either by frank hemorrhage or hemolysis),
Management of Symptomatic Brain Edema and Elevated ICP
Patients admitted to our NCCU were cared for using a standardized approach that included continuous neurological and cardiovascular monitoring, central venous catheterization for hyperosmolar intravenous fluids administration and central venous pressure (CVP) monitoring, maintenance of serum electrolytes, nutrition, and prophylaxis against deep venous thrombosis and gastrointestinal hemorrhage. Standard rou-
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Hypertonic Saline in the Treatment of Cerebral Edema ______________________________________________________________437 Table 1 Patient Characteristics for HTS and Mannitol Cohorts HTS cohort (n=19)
Age median (range) Male/Female ratioa Diagnosis n (%) Subarachnoid hemorrhage Traumatic brain injury-induced edema Massive ischemic stroke Intracerebral hemorrhage Traumatic subdural hematoma Brain abscess Post. fossa demyelination/edema Metastatic lesions GCS median (range) APACHE II median (range) 46 (18–70) 3.8:1 6 (31.5) 2 (10.5) 2 (10.5) 2 (10.5) — 2 (10.5) 1 (5.6) — 11 (3–15) 18 (18–30)
Mannitol cohort (n=9)
50 (39–90) 1:2 3 (33.3) — 1 (11.1) 3 (33.3) 1 (11.1) — — 1 (11.1) 9 (3–14) 14 (10–28)
ap = 0.028 Abbreviations: HTS, hypertonic saline; GCS, Glasgow Coma Score; APACHE II, Acute Physiology and Chronic Health Evaluation.
Table 2 Hemodynamic Profile During HTS Infusion Day 1
MAP (mean ± SD) in mmHg ICP (mean ± SD) in mmHg CPP (mean ± SD) in mmHg CVP (mean ± SD) in mmHg Total number of patients Number of patients with ICP monitoring 100.3 ± 14.1 15.1 ± 8 88.5 ± 17.4 8.2 ± 2.4 19 13
102.7 ± 17.1 14.1 ± 5.6 92.9 ± 15.3 9 ± 2.1 16 10
103 ± 19.6 14.9 ± 4.7 91.8 ± 18 9 ± 3.6 15 10
101.9 ± 20.3 13.7 ± 5.8 91.2 ± 13.6 9.8 ± 4.4 13 8
98.3 ± 21.4 15 ± 7 88.8 ± 20.6 8.6 ± 2.5 12 7
Abbreviations: MAP, mean arterial pressure; ICP, intracranial pressure; CPP, cerebral perfusion pressure; CVP, central venous pressure; SD, standard deviation.
and coagulopathy (prothrombin time greater than 15 seconds or International Normalized Ratio [INR] greater than 1.5). In addition, patient outcome was assessed using hospital and NCCU lengths of stay (days) and discharge disposition. Age, gender, diagnoses, admission GCS, APACHE II, and adverse events were compared to a contemporary cohort of patients that received mannitol as the sole form of osmotic therapy.
Clinical Features of the HTS and Mannitol Cohorts
Table 1 illustrates the patient characteristics for both the HTS and mannitol cohorts (compared later to assess adverse effects). Between the groups, gender was found to be significantly different (p = 0.028). Specifically for the HTS cohort, the brain injuries varied from penetrating head trauma to massive ischemic stroke. Thirteen of the patients had an ICP monitor in place during the infusion of HTS. CVP was monitored in seven patients. Six patients received concomitant sedation with propofol. Eleven patients (58%) underwent a neurosurgical procedure prior to initiation of HTS infusion, such as aneurysm clipping (n = 5), debridement of gunshot wound (n = 2), traumatic subdural and intracerebral hematoma evacuation (n = 2), and debridement of brain abscess (n = 2).
Data were entered and analysis was performed using SPSS 10.0 for Windows (Chicago, IL). Descriptive statistics were used to describe patient characteristics, hemodynamic data, and patient outcome (length of stay, discharge disposition). Patient characteristics (age, gender, diagnoses, GCS, and APACHE II) and adverse effects were compared between the HTS and mannitol cohorts using Fisher’s exact test. Pearson correlation was used to assess the relationship between ICP and serum sodium concentrations. Linear regression analysis was used to assess the relationship between GCS and serum sodium concentrations. A p-value less than 0.05 was considered statistically significant.
Hypertonic Saline Infusion
Upon initiating the HTS infusion, the mean ICP was 16.6 + 10.9 mmHg (range: 4–38 mmHg), the mean CPP was + 89.3 = 18.8 mmHg (range: 49–116 mmHg), the mean MAP + was 106.7 = 12.8 mmHg (range: 87–135 mmHg), and the mean + baseline serum sodium concentration was 139.5 = 4.3 mEq/L (range: 133–147 mEq/L). Target hypernatremia was achieved in 14 of 19 (74%) patients; 7 (39%) patients achieved the goal serum sodium within the first 24 hours of HTS infusion. The
A cohort of 19 patients was identified as treated with HTS infusion for increased ICP or cerebral edema over 16 consecutive months at the NCCU at Detroit Receiving Hospital.
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438 ________________________________________________________________________________________________Larive et al. Table 3 Adverse Event Profile for HTS Infusion and Mannitol Adverse Event
Pneumonia Bacteremia Dysrhythmia Metabolic acidosis Hypokalemia Hyponatremia after HTS discontinuation
HTS n (%)
5 (26.3) 3 (15.8) 1 (5.3) — 6 (31.6) 1 (5.3)
Mannitol n (%)
— — — 1 (10) 3 (30) N/A
0.07 0.3 0.7 0.3 0.6 0.7
HTS, hypetonic saline; N/A, not applicable.
Adverse Events During the Administration of HTS
Adverse events during the HTS infusion were compared to the contemporary cohort of patients described earlier who received mannitol as the sole form of osmotic therapy. Table 3 shows the comparison of the adverse effects that were evaluated. One patient in the HTS group, who received propofol at a rate of 55 µg/kg/minute, experienced both heart block and bacteremia during the HTS infusion. Acute renal failure was not observed in any of the patients in either group.
Fig. 1. Interaction between mean daily serum sodium concentrations and mean daily GCS at baseline and during 8 days of HTS therapy. GCS = –25.5 + 0.24 × sodium, r = 0.8, p = 0.01.
Patient Discharge Disposition
Patients were discharged to a rehabilitation facility (36.8%), home and nursing home (15.7% each), or another hospital (10.5%). Four patients in the cohort died (21%). The median lengths of stay for both the hospital and NCCU were 14 days (range: 2–46).
median time to the target hypernatremia (145–155 mEq/L) for the entire cohort was 1 day (maximum 5 days). The median length of HTS infusion was 5 days (maximum 17 days). Table 2 shows the daily mean hemodynamic parameters during the first 5 days of HTS infusion. The median starting infusion rate was 1.2 mL/kg/hour (range: 0.34–1.85 mL/kg/hour). The median continuous infusion rate was 1.19 mL/kg/hour (range: 0.34–1.85 mL/kg/hour) and adjusted to a median maximum infusion rate of 1.36 mL/kg/hour (range: 0.34–1.95 mL/kg/hour). During the HTS infusion, the median time spent under 20 mmHg of ICP was 98.2% of the infusion period for all patients (range: 33–100%). The Pearson correlation coefficient for the interaction between serum sodium concentrations and ICP was 0.37 (p = 0.32). Linear regression analysis of the interaction between mean serum sodium concentrations and GCS during the HTS infusion was significant with r = 0.8 and p = 0.01, as illustrated in Fig. 1.
We present our initial experience with the introduction of HTS administered as a continuous infusion for the treatment of cerebral edema and control of ICP in a cohort of 19 patients with brain injury. We found that a hypernatremic state is achievable after a median time of 1 day; however, it took up to 5 days to reach target hypernatremia (145–155 mEq/L) in some cases. We found a significant direct association (r = 0.8, p = 0.01) between the serum sodium concentrations and the GCS in these patients within the first 8 days of HTS therapy. Our cohort of patients was devoid of serious adverse effects related to the HTS infusion. The rationale for a target hypernatremia range of 145–155 mEq/L during the continuous infusion of HTS solutions is that it corresponds to a serum osmolarity of 310–320 mOsm/L (assuming serum glucose and blood urea nitrogen are within the normal range). In our cohort, it took a median of 1 day, ranging up to 5 days, to reach our hypernatremia target. Our treatment approach mirrors the algorithm described by Bhardwaj and Ulatowski (14). They proposed a treatment algorithm using 2 or 3% sodium chloride/sodium acetate (50:50 admixture) administered at a variable rate (1–2 mL/kg/hour) that aimed for target a hypernatremia goal of 145–155 mEq/L (monitoring serum sodium every 4–6 hours) for patients with cerebral edema and/or elevated ICP. Their treatment algorithm describes the use of HTS infusion in patients with cerebral edema, illustrated by CT scan in patients without an ICP monitor in place. Furthermore, Fisher and colleagues compared 0.9% saline with 3% saline for raised ICP in children with head trauma (20). They reported reaching serum sodium
Four patients required a surgical procedure as rescue intervention for elevated ICP or worsening cerebral edema (one traumatic subdural evacuation, one debridement of gunshot wound, and two intracerebral hematoma evacuations). These patients were receiving HTS infusion for 4, 6, 8, and 22 hours prior to surgery, respectively. The median number of rescue interventions received for ICP control or worsening cerebral edema was three (range: 1–30). Of the patients requiring intervention, nine received additional osmotic therapy with mannitol. A median of three doses (range: 1–30) of mannitol was administered to these patients. In one patient, HTS infusion was started as an adjunct 23 hours after the start of barbiturate infusion.
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Hypertonic Saline in the Treatment of Cerebral Edema ______________________________________________________________439 concentrations of 150 mEq/L within 30 and 120 minutes of starting a HTS infusion. A possible explanation for their rapid induction of therapeutic hypernatremia is the administration of repeated boluses of 3% sodium chloride, by which they were able to achieve the target faster and maintain the hypernatremia. Khanna et al. also studied the use of 3% HTS in pediatric head trauma patients and were able to reach therapeutic hypernatremia within the first 24 hours of infusion (21). We interpret our incomplete and delayed achievement of a hypernatremic state as the result of the lack of an aggressive systematic approach to reach the hypernatremic goals defined previously with the use of HTS infusion. One obstacle we faced was the lack of familiarity with this application of HTS in the NCCU. Educational efforts for physicians, nurses, and pharmacists regarding the use of HTS should be emphasized to ensure the targets of HTS therapy are reached. We postulate that boluses of 2 or 3% saline should be administered when the hypernatremic target is not reached within 6 hours from treatment onset, as in the study by Fisher et al. (20). Currently at our institution, we are focused on improving the method by which aggressive the hypernatremic target is reached by stressing that when serum sodium concentrations are below target range, either an increase in the infusion rate should be made or a bolus of HTS should be given. Intervals for measuring serum sodium and the measures that will be taken if the serum sodium is outside of the target range should be addressed early in centers that plan to introduce HTS fluids for ICP control or treatment of cerebral edema. Alternative ways to accelerate the induction of a hypernatremic state (administration of enteral sodium chloride tablets, as well as fludrocortisone to aid with sodium retention) also should be entertained as part of available interventions for serum sodium measured below the target hypernatremic range. The focus of our report was not the effect of HTS on ICP; not all patients had an ICP monitor in place. Other published reports have assessed the relationship between serum sodium concentration and ICP. Khanna et al. (21) reported a significant inverse relationship between serum sodium concentrations and ICP in their study. As stated earlier, the majority of these patients had serum sodium concentrations over 145 mEq/L, and they were allowed to reach concentrations as high as 187 mEq/L. In our cohort, we evaluated the serum sodium concentrations versus ICP and did not find a significant correlation between the two variables (Pearson correlation coefficient = 0.37). This was likely the result of an average ICP of less than 20 mmHg upon initiation of HTS infusion, as demonstrated in Table 2. However, we found a direct association between mean daily serum sodium concentrations and the mean daily GCS. Although there is not a consensus regarding the hypernatremic target, we were able to show that the GCS improved with increasing serum sodium concentrations within and above normal serum sodium concentrations. The association between these two variables is hypothesis-generating only and needs to be assessed in larger prospective trials in which the independent role of hypernatremia on neurological function following brain injury and edema can be determined. The adverse effects compared between our HTS and mannitol cohorts were not significant (Table 3), although there was a trend toward an increased risk of pneumonia in the HTS group. HTS has been reported to decrease leukocyte migration and adherence (7). HTS may be beneficial to decreasing the inflammatory response in the secondary injury cascade of brain injury; however, by this same mechanism it may expose patients to a higher risk of infectious complications. There are limited data in the literature regarding adverse events, and a larger study population is needed to assess the immunomodulatory effects of HTS. One patient in the HTS group who was receiving propofol (55 µg/kg/minute) developed heart block and bacteremia. Both heart block and bacteremia are well-described with propofol, with an incidence of less than 1% when used for intensive care unit sedation (22). A major concern with the use of HTS and raising the serum sodium concentrations and, subsequently, the serum osmolarity is the development of acute renal failure. This is the argument for use of the serum sodium goal of 145 to 155 mEq/L. Serum sodium concentration greater than 155 mEq/L as well as serum osmolarity greater than 320 to 330 mOsm/L are associated with increased risk of renal failure (likely when the hyperosmolar state is the result of dehydration), pulmonary edema, and neurological complications (encephalopathy, seizures, central pontine myelinolysis) (23,24). We did not observe any of these complications in our cohort of patients. In the study by Khanna et al. (21), two patients developed acute renal failure requiring continuous veno-venous hemodialysis, but these cases were attributed to the concurrent episodes of sepsis and multisystem organ failure. Simma et al. (25) reported pneumonia (4 of 15 patients) and acute renal failure (1 of 15) in their HTS group. These two studies did allow serum sodium concentrations to reach levels greater than 160 mEq/L; the issue of whether they play a causative role in the development of acute renal failure remains unclear.
We acknowledge that the small size of our study cohort of patients limits our capacity to generalize our conclusions. The purpose of this study was to evaluate our initiation of HTS use in a NCCU, and there was not a control group per se. However, we compared the adverse effects to a contemporary cohort of patients receiving mannitol to report the safety of using a continuous infusion of HTS. Although our cohort of patients was highly heterogeneous, at the present time we do not have enough evidence to suspect that HTS solutions favorably modify brain edema following a specific form of brain injury. Nevertheless, future larger prospective studies should narrow the inclusion criteria to brain edema following one specific form of brain injury (e.g., severe traumatic brain injury) to minimize selection bias. The observed interaction between serum sodium concentration and GCS is a simple statistical association and could conceivably respond to factors other than HTS infusion. Thus, it should be considered hypothesis-generating only at this point. Although our initial intention was to monitor objective data (e.g., CT scan criteria of brain edema) as evidence of therapeutic response (or lack of it) to treatment with HTS, the inconsistent radiological assessment from patient to patient made this attempt unsuccessful. Finally, we recognize that the lack of universal
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440 ________________________________________________________________________________________________Larive et al. ICP monitoring in the treatment cohort limits the generalization of our results. However, clinical evidence of cerebral edema and not necessarily ICP was used to guide the use of HTS. Therefore, ICP was not an endpoint of this study.
9. 9 10. 10 11. 11 Harnish PP, DiStefano V. Decreased cerebrospinal fluid production by intravenous diatrizoate. Invest Radiol 1984; 19:318–323. Peterson B, Khanna S, Fisher B, Marshall L. Prolonged hypernatremia controls elevated intracranial pressure in head-injured pediatric patients. Crit Care Med 2000;28:1136–1143. Schwarz S, Schwab S, Bertram M, Aschoff A, Hacke W. Effects of hypertonic saline hydroxyethyl starch solution and mannitol in patients with increased intracranial pressure after stroke. Stroke 1998;29:1550–1555. Suarez JI, Qureshi AI, Anish Bhardwaj, et al. Treatment of refractory intracranial hypertension with 23.4% saline. Crit Care Med 1998;26:1118–1122. Qureshi AI, Suarez JI, Castro A, Bhardwaj A. Use of hypertonic saline/acetate infusion in treatment of cerebral edema in patients with head trauma: experience at a single center. J Trauma 1999;47(4):659–665. Bhardwaj A, Ulatowski JA. Cerebral edema: hypertonic saline solutions. Curr Treatment Options Neurol 1999;1:179–187. Teasdale G, Jennett B. Assessment of coma and impaired consciousness. Lancet 1974;2:81–84. Niskanen M, Kari A, Nikki P, et al. Acute physiology and chronic health evaluation (APACHE II) and Glasgow coma scores as predictors of outcome from intensive care after cardiac arrest. Crit Care Med 1991;19(12):1465–1473. Chow AW, Hall CB, Klein JO, Kammer RB, Meyer RD, Remington JS. Evaluation of new anti-infective drugs for the treatment of respiratory tract infections. Infectious Diseases Society of America and the Food and Drug Administration. Clin Infect Dis 1992;15:S62–S68. Bernard GR, Artigas A, Brigham KL, et al. The American-European Consensus Conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Resp Crit Care Med 1994;149:818–824. Franson TR, Zak O, van den Broek P. Evaluation of new antiinfective drugs for the treatment of vascular access device-associated bacteremia and fungemia. The European Working Party of the European Society of Clinical Microbiology and Infectious Diseases. Clin Infect Dis 1993;17:789–793. Fisher B, Thomas D, Peterson B. Hypertonic saline lowers raised intracranial pressure in children after head trauma. J Neurosurg Anesth 1992;4(1):4–10. Khanna S, Davis D, Peterson B, et al. Use of hypertonic saline in the treatment of severe refractory posttraumatic intracranial hypertension in pediatric traumatic brain injury. Crit Care Med 2000;28:1144–1151. Propofol (Diprivan ®). Product package insert, AstraZeneca Pharmaceuticals LP, Wilmington, DE. Kohan DE. Fluid and electrolyte management. In, Manual of Medical Therapeutics. (Dunagon WC, Ridner ML, eds.). Little Brown, Boston, 1989,52–64. Kirby RR, Taylor RW, Ciretta JM. Hyperosmolar states. In, Pocket Companion of Critical Care: Immediate Concerns. (Kirby RR, Taylor RW, Ciretta JM, eds.). JB Lippincott, Philadelphia, 1990, 28–32. Simma B, Burger R, Falk M, Sacher P, Fanconi S. A prospective, randomized, and controlled study of fluid management in children with severe head injury: Lactate Ringer’s solution versus hypertonic saline. Crit Care Med 1998;26:1265–1270.
The osmotic effects and lack of serious adverse events makes HTS an attractive alternative for osmotic therapy for mannitol. The use of HTS for cerebral edema and increased ICP is difficult and requires intensive efforts by the medical team to maintain the hypernatremic hyperosmolar state, maintain euvolemia, and minimize adverse events. Larger, prospective and controlled investigations are needed to determine the optimal infusion concentration, the target serum sodium concentration for ICP control, and the safety versus efficacy of a hypernatremic state.
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W. M. Coplin is supported in part by NIH/NINDS R01 NS38905. The authors thank the ICU attending physicians, residents, fellows, and nursing staff of the Neuroscience Critical Care Unit at Detroit Receiving Hospital for their help in the complex management of these patients.
1. The Brain Trauma Foundation. The American Association of Neurological Surgeons. The Joint Section on Neurotrauma and Critical Care. Guidelines for the management of severe head injury. J Neurotrauma 2000;17:640–734. 2. 2 Zornow MH. Hypertonic saline as a safe and efficacious treatment of intracranial hypertension. J Neurosurg Anesthesiol 1996;8:175–177. 3. 3 Ostensen J, Stokke ES, Bugge JF, Langberg H, Kiil F. Difference between hypertonic NaCl and NaHCO3 as osmotic diuretics in dog kidneys. Acta Physiol Scand 1989;137:177–187. 4. 4 Nakayama S, Kramer GC, Carlsen RC, Holcroft JW. Infusion of very hypertonic saline to bled rats: membrane potentials and fluid shifts. J Surg Res 1985;38:180–186. 5. 5 Arjamaa O, Karlqvist K, Kanervo A, Vainionpaa V, Voulteenaho O, Leppaluoto J. Plasma ANP during hypertonic NaCl infusion in man. Acta Physiol Scand 1992;144:113–119. 6. 6 Dubick MA, Davis JM, Myers T, Wade CE, kramer GC. Plasma ANP during hypertonic saline and dextran on cardiovascular responses and plasma volume expansion in sheep. Shock 1995;3:137–144. 7. 7 Rizoli SB, Kapus A, Fan J, Li YH, Marshall JC, Rostein OD. Immunomodulatory effects of hypertonic resuscitation on the development of lung inflammation following hemorrhagic shock. J Immunol 1998; 161: 6288–6296. 8. 8 Rabinovici R, Yue TL, Krausz MM, Sellers TS, Lynch KM, Feuerstein G. Hemodynamic, hematologic and eicosanoid mediated mechanisms in 7.5 percent sodium chloride treatment of uncontrolled hemorrhagic shock. Surg Gynecol Obstet 1992;175:341–354. 18. 18
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