Exertional Dysnatremia in Collapsed Marathon Runners A Critical Role for Point-of-Care Testing to Guide Appropriate Therapy

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1 Clinical Chemistry / Dysnatremia in Collapsed Marathon Runners Exertional Dysnatremia in Collapsed Marathon Runners A Critical Role for Point-of-Care Testing to Guide Appropriate Therapy Arthur J. Siegel, MD, 1,6 Pierre d Hemecourt, MD, 2,6 Marvin M. Adner, MD, 3 Terry Shirey, PhD, 4 Jeffrey L. Brown, PsyD, 1,6 and Kent B. Lewandrowski, MD 5,6 Key Words: Dysnatremia; Encephalopathy; Exercise-associated hyponatremia; Inappropriate antidiuresis Abstract Dysnatremia may cause life-threatening encephalopathy in marathon runners. Hypernatremia and exercise-associated hyponatremia (EAH) may manifest with mental status changes and, if untreated, progress to coma and death. We reviewed the on-site blood sodium testing and treatment in collapsed runners at the finish-line medical tent at the Boston marathons from 2001 through Dysnatremia was diagnosed in 429 (32.5%) of 1,319 collapsed runners. Hypernatremia was present in 366 (27.7%) and hyponatremia in 63 (4.8%). Hypernatremic runners unable to drink fluids were treated with intravenous normal (0.9%) saline. Hyponatremic runners with seizures or coma received intravenous hypertonic (3%) saline. Sixteen runners with EAH able to drink a concentrated oral hypertonic solution recovered within 30 minutes. Based on on-site sodium testing, dysnatremic runners were treated with appropriate intravenous fluids according to validated standards of care. Hyponatremic runners able to drink an oral hypertonic solution recovered promptly. Exertional dysnatremia may result in life-threatening encephalopathy in collapsed marathon runners. 1 As opposite disorders of body fluid homeostasis, hypernatremia and exercise-associated hyponatremia (EAH) may manifest similarly with confusion and disorientation and may progress, if untreated, to coma and death. On-site whole blood Na+ testing was introduced at the finish-line medical tent of the Boston marathon in 2001 to provide rapid diagnosis for emergency triage to appropriate treatment. 2,3 Administration of intravenous normal (0.9%) saline, which is appropriate for hypernatremia, may induce seizures in cases of EAH, which will respond to hypertonic (3%) saline. 4-6 In contrast with these evidence-based treatments, 7-9 there is no consensus for management of the more prevalent cases of delirium due to EAH, which may progress to seizures following continued intake of hypotonic fluids. Concentrated broth as an oral hypertonic solution was used for runners able to drink fluids beginning in 2005, with results reported herein. Materials and Methods Heparinized blood samples were obtained from collapsed runners in the finish-line medical tent at the Boston marathons from 2001 to 2008 for point-of-care testing using Nova analyzers (Nova Biomedical, Waltham, MA). In addition to intravenous normal (0.9%) and hypertonic (3%) saline for hypernatremia and life-threatening EAH encephalopathy, respectively, concentrated broth (4 bouillon cubes in 4 oz of water representing approximately 9% saline) as an oral hypertonic solution was administered to hyponatremic runners with delirium who were able to take fluids by mouth. 336 Am J Clin Pathol 2009;132: Downloaded 336 from

2 Clinical Chemistry / Original Article Blood Na+ testing before and after treatment was performed on 3 runners in Results Dysnatremia (Na+ >145 meq/l [145 mmol/l] or <135 meq/l [135 mmol/l]) was observed in almost one third of collapsed runners (429/1,319 [32.5%]) who received on-site blood Na+ testing in the finish-line medical tent at the 2001 through 2008 Boston marathons Table 1. Hypernatremia was present in 366 (27.7%) runners including 52 (3.9%) with values more than 150 meq/l (150 mmol/l). Hyponatremia occurred in 63 runners (4.8%), including 26 (2.0%) with values less than 130 meq/l (130 mmol/l). On average, there were 5.8 cases of hypernatremia for each case of EAH. Runners with hypernatremia were treated with intravenous normal (0.9%) saline if unable to drink hypotonic fluids until clinically stable for discharge. Runners with life-threatening EAH were treated with hypertonic (3%) saline before transfer to a hospital. Beginning in 2005, runners with EAH with mental status changes who were able to drink fluids were treated with concentrated broth as an oral hypertonic saline solution approaching a saline concentration of 9%. This strategy resulted in more timely resolution of symptoms compared with restricting hypotonic fluids alone in approximately 16 cases during the subsequent races. Delirium accompanied in some cases by behavioral changes, including muteness, psychomotor agitation with phantom running, and visual or auditory distortions resembling hallucinations, responded with timely normalization of mental status. All such runners were discharged directly from the medical tent without requiring intravenous hypertonic saline or hospital transfer. In 3 cases in 2008, we measured sequential sodium values before and after administration of the oral hypertonic broth, as shown in Table 2. In all 3 cases, the plasma sodium level essentially normalized to the low normal range. Based on these observations, we developed a treatment outline summarizing the appropriate interventions in current use; Table 3 gives the symptoms and treatment for various degrees of hyponatremia and hypernatremia. Discussion Exertional dysnatremia is very common in marathon runners and may cause delirium and progress, if untreated, to coma and death. 1 Following the widespread collapse of runners with dehydration in the 1976 Boston Marathon known as the run for the hoses, intravenous fluid resuscitation with normal (0.9%) saline was undertaken in the finish-line medical tent to facilitate treatment as subsequently validated. 2,3,9 However, this treatment is contraindicated in patients with EAH and may result in cerebral edema and death. On-site whole blood point-of-care Na+ testing was introduced in 2001 to diagnose cases of EAH defined by a blood sodium concentration (Na+) less than 135 meq/l (135 mmol/l). First described in ultradistance runners in 1985, 10 EAH was initially reported in marathon runners in 1999 followed by cases of fatal pulmonary and cerebral edema in Formerly presumed to be rare, EAH was identified in 13% of asymptomatic Boston marathon runners in 2002, with overconsumption of fluids as an independent risk factor. 11 Table 1 Experience With Whole Blood Sodium Testing in Collapsed Runners in the Finish-Line Medical Tent at the Boston Marathons From 2001 Through Total Sodium testing No. of samples ,319 Mean (mmol/l) SD (mmol/l) Minimum (mmol/l) Maximum (mmol/l) No. with hypernatremia mmol/l (23.8) >150 mmol/l (3.94) Subtotal 366 (27.7) No. with hyponatremia mmol/l (2.8) <130 mmol/l (2.0) Subtotal 63 (4.8) Total with dysnatremia 429 (32.5) Sodium values are given in Système International units; to convert to conventional units (meq/l), divide by 1.0. Values for hypernatremia, hyponatremia, and total with dysnatremia in the Total column are the number (percentage of 1,319) of runners. Downloaded from Am J Clin Pathol 2009;132:

3 Siegel et al / Dysnatremia in Collapsed Marathon Runners Subsequent studies on collapsed Boston marathon runners, including a fatal case in that same year, identified a decrease in free water excretion due to inappropriate secretion of arginine vasopressin as a collateral cause of EAH. 12 The pathophysiology of inappropriate antidiuresis explains the efficacy of intravenous hypertonic (3%) saline, which decreases cerebral edema by reversing the flow of water in brain cells. 13 This treatment is known to be effective in the hospital setting and was initiated in the finish-line medical tent in ,12 The essential element in the management of dysnatremia during competitive athletic events is the availability of rapid, on-site, point-of-care electrolyte testing to differentiate hyponatremia from hypernatremia, to assess the severity of the dysnatremia, and to guide appropriate therapy. Because hypernatremia is much more common in collapsed marathon runners than hyponatremia and because administration of normal saline will aggravate hyponatremia in EAH, rapid on-site electrolyte testing is essential for determining appropriate therapy for the minority of collapsed runners with EAH. In contrast with such evidence-based treatment for lifethreatening cases of dysnatremia, 8,9 no consensus exists for management of the more prevalent mild to moderate cases of EAH. Early symptoms, including disorientation and confusion, may progress to seizures with continued intake of hypotonic fluids, as occurred in a runner in 2004 who was triaged away from the medical tent without Na+ testing. Based on the pathophysiology of inappropriate antidiuresis, we initiated treatment beginning in 2005 with concentrated broth by dissolving 4 bouillon cubes in 4 ounces of water, approximating a 9% saline solution, as an oral hypertonic solution for runners able to drink fluids. This intervention resulted in more timely resolution of mental status changes compared with simply restricting hypotonic fluids and eating salty snacks. Psychomotor agitation, including phantom running and cases with auditory or visual distortions, resolved without the need for intravenous hypertonic 3% saline. Blurred or decreased vision cleared on a timely basis in 2 cases, suggesting that the reported complication of cortical blindness following hypotonic encephalopathy may have been averted. 14 In 1 case, atypical or bizarre behavior in a collapsed runner raised the suspicion for EAH, leading to expedited Na+ testing. A psychologist on call in the medical tent assisted in early identification of such cases. Table 2 Sequential Blood Na+ Testing in Three Runners With Delirium Due to Exercise-Associated Hyponatremia Encephalopathy at the 2008 Boston Marathon Oral Hypoglycemic Treatment Sex/Age, y (Finish Pretreatment Sodium Posttreatment Sodium Pretreatment to Time, h:min:s) Level (mmol/l) Level (mmol/l) Posttreatment Time (min) M/45 (2:47:51) F/47 (3:59:36) F/36 (5:20:33) All 3 runners showed clearing of mental status changes with normal Na+ values within the time indicated. Sodium values are given in Système International units; to convert to conventional units (meq/l), divide by 1.0. Table 3 Symptoms and Treatment of Dysnatremia in Collapsed Runners Based on Clinical Manifestations and Results of Blood Na+ Testing Hypernatremia Hyponatremia Mild Severe Mild-Moderate Severe Symptoms Confusion, disorientation Delirium, obtundation Headache, nausea, confusion, Vomiting, seizures, obtundation, disorientation, inability to concentrate respiratory distress, coma Treatment Oral hypotonic fluids; IV normal (0.9%) saline Oral hypertonic fluids plus salty snacks Emergent IV hypertonic (3%) treat until condition (if nausea and vomiting until urination; treat until condition saline (100-mL bolus); repeat stable enough for or sodium level >150 meq/l stable enough for discharge after 5 min if no response discharge [150 mmol/l]); treat until pending transfer to hospital condition stable enough for discharge IV, intravenous. Oral hypertonic saline was the initial treatment for runners with exercise-associated hyponatremia who were able to drink fluids by mouth. Positive clinical responses (as described) precluded the risk of progression and the need for IV hypertonic saline. 338 Am J Clin Pathol 2009;132: Downloaded 338 from

4 Clinical Chemistry / Original Article Based on these promising if anecdotal observations in initial cases, we undertook blood Na+ testing following oral hypertonic treatment as an objective outcome measure. Three cases in 2008 showed essentially normal Na+ values concurrent with a positive clinical response (Table 2). All runners so treated were discharged directly from the medical tent with written instructions to limit intake of hypotonic fluids until the onset of urination and to eat salty snacks. No cases required intravenous hypertonic saline or hospital transfer or exhibited delayed recurrence of symptoms. Table 3 summarizes these interventions. These findings support treatment with hypertonic fluids for EAH encephalopathy by the oral or intravenous route according to the clinical manifestations and severity. Lifethreatening cases with seizures or coma were treated with intravenous (3%) saline, and runners with mental status changes but able to drink fluids were treated safely and effectively with concentrated oral solutions. The positive clinical response relates to a prompt increase in the blood Na+ level, which reverses the osmotic gradient for the flow of water into brain cells. This can be achieved by using various concentrations of hypertonic saline as demonstrated in events in London, England (2%), and Cape Town, South Africa (5%). 15,16 This treatment should be given as soon as possible after the diagnosis is confirmed to decrease acute cerebral edema before progression to brainstem compression. The paradox that hypertonic salt solutions are efficacious for treating EAH encephalopathy but that supplemental salt intake is apparently without value for prevention of EAH warrants explanation. 17 The pathophysiology of inappropriate antidiuresis reconciles this apparent contradiction, under which the renal clearance of free water is limited, while additional salt is excreted in concentrated urine. 18 The view in some sports medicine circles that salt supplements make avid drinking safe may well be incorrect. EAH may occur when the intake of hypotonic fluids exceeds total losses, including a reduced capacity of the kidneys to excrete free water. Recent reports indicate that the risk for EAH remains despite guidelines advising especially slower runners and walkers to drink only to thirst. 19 Life-threatening cases, including fatalities, continue to occur despite evidence-based support for emergency treatment with hypertonic saline On-site point-of-care electrolyte testing is an essential prerequisite to managing dysnatremia in competitive endurance athletic events. Limitations of this study include those inherent in descriptive studies in which the findings are applicable only to the specific race and demographics of the runners involved. Conclusions should also be considered as preliminary in view of the small sample. The incidence and severity of EAH may vary from year to year in a given race and between venues. 23 An algorithm based on these considerations could provide medical teams at other races with a platform to compare with their experiences. Oral hypertonic treatment for mild to moderate EAH encephalopathy deserves systematic study based on these promising if preliminary findings. From 1 McLean Hospital, Belmont, MA; 2 Boston Children s Hospital, Boston, MA; 3 Metro West Medical Center, Framingham, MA; 4 Nova Biomedical, Waltham, MA; 5 Massachusetts General Hospital, Boston; and 6 Harvard Medical School, Boston. Address reprint requests to Dr Lewandrowski: Clinical Chemistry, Gray 5, Massachusetts General Hospital, Fruit St, Boston, MA References 1. Kratz A, Siegel AJ, Verbalis JG, et al. Sodium status of collapsed marathon runners. Arch Pathol Lab Med. 2005;129: Adner MM, Scarlet JJ, Casey J, et al. The Boston Marathon medical care team: ten year experience. Phys Sportsmed. 1988;16: Adner MM, Gembarowicz R, Casey J, et al. Point of care biochemical monitoring of Boston Marathon runners: a comparison of pre-race and post-race controls to runners requiring on site medical attention. 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