serum sodium abnormalities during nonexe”>American Journal of Emergency Medicine (2012) 30, 741-748

Original Contribution

Serum sodium abnormalities during nonExertional heatstroke: incidence and prognostic values^?,??,?

Pierre Hausfater ^a,?, Bruno Megarbane ^b, Laurent Fabricatore ^a,

Sandrine Dautheville ^c, Anabela Patzak ^d, Marc Andronikof ^e, Aline Santin ^f, Gerald Kierzek ^g, Benoit Doumenc ^h, Christophe Leroy ⁱ, Jafar Manamani ^j,

Florence Pevirieri ^k, Bruno Riou ^a

^aEmergency Department, Centre Hospitalo-Universitaire Pitie-Salpetriere, Assistance-Publique Hopitaux de Paris, Paris, and UPMC Univ Paris 06 France

^bEmergency Department, Centres Hospitalo-Universitaire Hopital Lariboisiere, Assistance-Publique Hopitaux de Paris,

Paris, Universite Paris VII France

^cEmergency Department, Hopital Tenon, Assistance-Publique Hopitaux de Paris, Paris, France

^dEmergency Department, Hopital Europeen George Pompidou, Assistance-Publique Hopitaux de Paris, Paris, France

^eEmergency Department, Hopital Antoine Beclere, Assistance-Publique Hopitaux de Paris, Paris, France

^fEmergency Department Hopital Henri Mondor, Assistance-Publique Hopitaux de Paris, Paris, France

^gEmergency Department Hopital Hotel Dieu, Assistance-Publique Hopitaux de Paris, Paris, and Universite Paris V France

^hEmergency Department Hopital Bicetre, Assistance-Publique Hopitaux de Paris, Paris, France ⁱEmergency Department Hopital Louis Mourier, Assistance-Publique Hopitaux de Paris, Paris, France ^jEmergency Department Hopital Saint Louis, Assistance-Publique Hopitaux de Paris, Paris, France ^kEmergency Department Hopital Jean Verdier, Assistance-Publique Hopitaux de Paris, Paris, France

Received 3 February 2011; revised 13 May 2011; accepted 19 May 2011

Abstract

Background: Although heatstroke is often associated with dehydration, the clinical significance of serum sodium abnormalities in patients with heat-related illness during heat wave has been poorly documented. Method: We evaluated 1263 patients (age, 82 +- 15 years; body temperature, 40.1?C + 1.2?C) admitted to emergency departments during the August 2003 heat wave in Paris, having a core temperature greater than 38.5?C and measurement of serum sodium concentrations. Patients were classified according to our previously described risk score of death.

Results: Hyponatremia (b135 mmol/L) was reported in 409 (32%) and hypernatremia (N145 mmol/L) in 220 patients (17%). One-year survival was significantly decreased in patients with hypernatremia (45%; P = .004) but not in those with hyponatremia (58%; P = .86) as compared with patients with Serum sodium concentration in the reference range (57%). Using Cox regression, only hypernatremia

^? The other investigators in the study are listed in the Appendix A.

^?? The study was supported by the Direction Regionale de la Recherche Clinique d’Ile de France (Paris, France), grant number CRC 03-150.

^? Competing interests: The authors declare that they have no competing interests.

* Corresponding author. Service d’Accueil des Urgences, Groupe Hospitalier Pitie-Salpetriere, 47-83 boulevard de l’hopital, 75013 Paris, France. Tel.: +33

1 42 17 72 49; fax: +33 1 42 17 72 64.

E-mail address: [email protected] (P. Hausfater).

0735-6757/$ - see front matter (C) 2012 doi:10.1016/j.ajem.2011.05.020

was an independent prognostic factor (hazard ratio, 1.35; 95% confidence interval, 1.09-1.36) when risk score was taken into account. Using logistic regression, 2 variables were independently associated with hyponatremia (heatStroke severity score and blood urea nitrogen-creatinine ratio b100). Conversely, 5 variables were independently associated with hypernatremia (living in an institution, dementia, serum creatinine N120 umol/L, a blood urea nitrogen-creatinine ratio N100, and absence of long-term diuretic intake).

Conclusions: Serum sodium abnormalities are frequently observed in patients with a nonexertional heatstroke during heat wave; however, only hypernatremia should be considered as an independent risk factor of death. Rapid measurement of serum sodium concentration is mandatory to appropriately guide electrolyte resuscitation.

(C) 2012

Introduction

Nonexertional or environmental heatstroke is encountered in tropical areas, but exceptional heat waves have been increasingly reported in temperate countries [1-4], possibly related to climate change [5]. Health consequences of heat waves may be catastrophic resulting in overcrowding of health facilities [6], considerable excess mortality [7], and poor long-term outcome in surviving patients [8-10]. We recently conducted an observational study including patients admitted to an emergency department (ED) during the French heat wave in August 2003 and identified several risk factors associated with mortality [11,12], to help physicians in determining the therapeutic priorities in such a catastroph- ic situation, which lead considerable overload in the ED [6]. Very few studies have described serum sodium abnormalities observed during heatstroke, and their clinical significance has been poorly documented. This point might be of major importance because many patients who present with heat- related illness during a heat wave may not only have dehydration but also have long-term medications that could markedly interfere with serum sodium concentration, including diuretics and psychotropic drugs [13]. Moreover, health authorities messages provided during a heat wave usually include advice regarding either increase in fluid intake or interruption of such medications [14].

Thus, we performed an ancillary study from our core study [11] including patients admitted to ED during the French heat wave of 2003 and in whom plasma sodium concentration was measured on admission. We assessed the incidence and severity of serum sodium abnormalities, looked for variables associated with either hyponatremia or hypernatremia, and assessed their respective prognostic value during heatstroke.

Methods

Patients

This study was an ancillary study of a core Multicenter cohort study of hyperthermic patients admitted to 16 EDs belonging to the teaching hospital network of the Paris area

(Assistance Publique-Hopitaux de Paris, Paris, France) during the heat wave of August 2003 in France [11]. This study was authorized by the Conseil National Informatique et Libertes (Paris, France). Criteria for inclusion in the study were (1) emergency admission in the adult ED of one of the participating centers between August 5, and August 14, 2003; (2) core temperature of 38.5?C or higher. The study period covered the core period of heat wave and of excess short-term mortality rate recorded during this heat wave [6,8]. There were no exclusion criteria, except age younger than 16 years. In the present ancillary study, measurement of serum sodium concentration at admission was used as additional inclusion criteria.

An electronic clinical record form was used to collect data (Telemedecine Technologies, Boulogne, France). Data entered in the database were verified by on-site Clinical monitoring. Inconsistency between data was systematically checked and solved. The complete chart was examined by an expert panel who decided whether the patient had critically ill conditions that might have required admission to the intensive care unit. To assess dependency in this elderly population, the validated activities of daily living (ADL) scale was recorded [15]. The ADL scale range from

0 (worse) to 6 (best, fully autonomous). Patients were followed up until death or until 1 year after admission to the ED. Surviving patients or their family were contacted and interviewed by telephone. If contact could not be made, tracking was attempted through health care providers, particularly general practitioners, or any acquaintances identified in the medical record. When patients were lost to follow-up, an inquiry was sent to the French national registry of death (Institut National de la Statistique et des Etudes Economiques, Paris, France) to obtain information concern- ing the fatality.

We recently developed an heatstroke risk score using 9 independent prognostic factors and assigned several points proportional to their regression coefficient in a Cox model: previous treatment with diuretics (1 point), living in an institution (1 point), older than 80 years (1 point), cardiac disease (1 point), cancer (2 points), core temperature greater than 40?C (2 points), systolic arterial pressure less than 100 mm Hg (4 points), Glasgow Coma Scale less than 12 (5 points), and transportation to hospital by ambulance

(5 points). We defined 3 risk groups: low (0-6 points), intermediate (7-12 points), and high risk (13-22 points) [11]. In some patients, despite some missing values precluded exact calculation of the risk score, the risk score category could be allocated because these missing values were not able to modify it.

Definition of serum sodium abnormalities

Serum sodium concentration (Na) was corrected (Na_c) for blood glucose (BG) level using the following standard formula: Na_c (mmol/L) = Na (mmol/L) + 0.3 (BG [mmol/L]

- 5) [16]. No correction for high protein level was per-

formed because these modifications did not significantly modify serum sodium concentration. The reference range of serum sodium was 135 to 145 mmol/L. Values less than 135 mmol/L were considered as hyponatremia; values less than 125 mmol/L, as severe hyponatremia; and values greater than 145 mmol/L, as hypernatremia.

A value of serum creatinine of 120 umol/L was considered to reflect renal insufficiency. Because Urine analysis was not performed in most patients, blood urea nitrogen-creatinine ratio was used to indicate functional renal failure (ratio N100) [17].

Statistical analysis

Data are expressed as mean +- SD, median and its 25 to 75 interquartile for non-Gaussian variables (Kolmogorov-Smirnov test), or number and percentage. Comparison between groups was performed using analysis of variance and Newman-Keuls test, multiple Kruskal-Wallis test, and the Fisher exact method with the Bonferroni correction when appropriate. We also performed a multiple backward logistic regression to assess variables associated with either hyponatremia (vs normal serum sodium concentra- tion) or hypernatremia (vs normal serum sodium concen- tration) and calculated their odds ratio and 95% confidence interval (CI). To avoid overfitting, we used a conservative approach and included only the significant variables in the univariate analysis (P value of entry <=.10). If the Pearson correlation coefficient between variables was 0.60 or more, only the variable judged to be clinically more relevant was entered into the multivariate model. Continuous variables were transformed in dichotomous variables, using receiver- operating characteristic curves, the threshold being that which minimizes the distance to the ideal point (1 = sensitivity = specificity), as previously described [18]. The discrimination of the final model was assessed using the C- statistic and its calibration using the Hosmer-Lemeshow statistic. Survival was estimated by the Kaplan-Meier method, and differences in survival between groups were assessed by the log-rank test. To verify that plasma sodium is an independent risk factor, multivariate Cox proportional hazards model was used to determine the contribution of

either hyponatremia and hypernatremia; and our risk score was expressed as 3 states (low-, intermediate-, and high- risk scores) [11].

All statistical tests were 2 sided, and P b .05 was required to reject the null hypothesis. Statistical analysis was performed using NCSS 2001 software (Statistical Solutions, Ltd, Cork, Ireland).

Results

Among the 1456 patients included in the core study, serum sodium concentration was performed in 1263 patients (87%) who constituted the study sample. Patients with serum sodium measurement were older (82 +- 15 vs 61 +- 27 years; P b .001), were more frequently female (64% vs 55%; P = .02), lived more frequently in an institution (22% vs 12%; P b .001), had a higher body temperature (40.1?C +- 1.2?C vs 39.8?C +- 1.2?C; P b .001), a lower Glasgow Coma Scale (15 [11-15] vs 15 [13-15]; P = .02), a lower ADL score (5 [2-6] vs 6 [6-6];

P b .001), had a cardiac disease more frequently (27% vs 16%; P b .001), and were more frequently transported to the hospital in an ambulance (93% vs 35%; P b .001). Their survival rate at 1 year was not significantly different (55% vs 67%; P = .13). Because of missing values, the heatstroke risk score could be calculated in only 1062 patients (84%). In 98 additional patients (8%), some missing values precluded exact calculation of the risk score; but the risk score category could be allocated because these missing values were not

Fig. 1 Distribution of serum sodium concentrations (values corrected for BG) in our cohort (n = 1263). The reference range

(N) of serum sodium was 135 to 145 mmol/L. Values less than 135 mmol/L were considered as hyponatremia; values greater than 145 mmol/L, as hypernatremia. Each bar represents a 5 mmol/L range, the lower limit being indicated for hyponatremia and the upper limit for hypernatremia.

Table 1 Comparison of patients with normal and abnormal serum sodium concentrations

Variable	Hyponatremia	Normal serum concentration	Hypernatremia	P
	(n = 409)	(n = 634)	(n = 220)
Age (y)	81 +- 14	80 +- 17	86 +- 11 ?, +	b.001
Age N80 y	281/409 (69)	429/634 (68)	177/220 (79)	.008
Male sex	142/409 (35)	242/634 (38)	69/220 (31)	.16
ADL score	6 (3-6)	6 (3-6)	2 (0-6) ?, +	b.001
Living in an institution	85/409 (21)	112/634 (18)	85/220 (39) ?, +	b.001
Transportation to the hospital in an ambulance	387/409 (95)	574/634 (91)	115/220 (98) ?	b.001
Preexisting disease Hypertension	164/402 (41) ?	192/624 (31)	57/213 (37) +	b.001
Coronary artery disease	88/402 (22)	129/624 (21)	50/213 (23)	.68
Heart failure	45/402 (11)	53/624 (8)	19/213 (9)	.34
Diabetes	46/402 (11)	71/624 (11)	24/213 (11)	1.00
Cancer	39/402 (12)	49/624 (8)	15/213 (7)	.44
neurologic disease	80/402 (20) ?	169/624 (27)	97/213 (45) ?, +	b.001
Dementia	38/402 (9)	71/624 (11)	69/213 (32) ?, +	b.001
Psychiatric disease	29/402 (7)	55/624 (9)	19/213 (9)	.62
Long-term medication Diuretics	133/389 (34)	175/607 (29)	45/213 (21) ?, +	.003
CEI or AII I	89/389 (23)	118/605 (19)	35/214 (16)	.14
?-Blockers	53/389 (14)	72/605 (12)	12/214 (6) ?, +	.01
Calcium inhibitors	68/389 (15)	75/605 (12)	27/214 (13)	.06
Nitrates	61/389 (16)	83/605 (14)	32/214 (15)	.68
Inotropic drugs	31/389 (8)	56/605 (9)	14/214 (6)	.44
Anticoagulant or antiaggregants	134/389 (34)	221/607 (36)	61/214 (28)	.11
Statines	26/389 (7)	25/607 (4)	6/214 (3)	.06
Psychotropic drugs Clinical signs	165/389 (42)	294/607 (48)	127/214 (59) ?, +	b.001
Core temperature (?C)	40.3 +- 1.2	40.1 +- 1.2	39.7 +- 0.9 ?, +	b.001
Core temperature N40?C	204/389 (57) ?	306/634 (48)	75/220 (34) ?, +	b.001
SBP (mm Hg)	113 +- 40	115 +- 38	110 +- 41	.24
SBP b100 mm Hg	79/401 (20)	110/619 (18)	46/213 (22)	.44
Glasgow Coma Scale	15 (11-15)	15 (13-15)	14 (10-15) ?	.001
Glasgow Coma Scale b12	94/371 (25)	126/576 (22)	68/198 (34) ?	.003
Oxygen saturation (%)	93 (90-95)	93 (90-96)	93 (89-95)	.65
Biologic variables (blood)
Sodium (mmol/L)	129 +- 5	139 +- 3	154 +- 7	-
Potassium (mmol/L)	3.8 +- 0.7	3.9 +- 0.7	3.8 +- 0.7	.24
Nitrogen (mmol/L)	9.3 +- 7.2 ?	10.4 +- 6.0	17.8 +- 7.8 ?, +	b.001
Creatinine (umol/L)	115 +- 55	124 +- 67	171 +- 100 ?, +	b.001
Creatinine N120 umol/L	152/404 (38)	255/621 (41)	138/216 (64) ?, +	b.001
Nitrogen/creatinine	83 +- 62	88 +- 54	115 +- 46 ?	b.001
Nitrogen/creatinine N100	75/401 (19) ?	171/605 (28)	129/213 (61) ?, +	b.001
Plasma protein (g/L)	70 +- 9	71 +- 9	76 +- 9 ?	b.001
Glucose (mmol/L)	8.9 +- 4.1	9.4 +- 5.1	9.9 +- 5.9	.12
Bicarbonates (mmol/L)	22.7 +- 3.6 ?	23.9 +- 4.0	24.2 +- 5.0 +	b.001
arterial pH	7.42 +- 0.07 ?	7.40 +- 0.07	7.40 +- 0.08 +	.002
Hemoglobin level (g/dL)	12.8 +- 2.1	12.9 +- 2.0	14.2 +- 2.2 ?	b.001
Leukocytes (G/L)	12 295 +- 6433	12 404 +- 9801	13 198 +- 5415	.40
Platelets (G/L)	225 +- 95	217 +- 94	230 +- 100	.15
Other conditions
Infection	137/408 (34)	219/617 (35)	93/218 (43)	.07
Therapeutic cooling	289/409 (71)	423/634 (67)	151/220 (69)	.41
Admitted to ICU	26/409 (6)	32/634 (5)	7/220 (3)	.23
Critically ill	122/404 (30)	150/630 (24)	72/218 (33) ?	.01
Risk score	10 (7-13) ?	9 (6-12)	10 (7-13) ?	.004

	Table 1 (continued)
	Variable	Hyponatremia (n = 409)	Normal serum concentration (n = 634)	Hypernatremia (n = 220)	P
	Risk score categories Low Intermediate High	67/381 (25) 205/381 (47) 109/381 (28)	163/582 (29) 274/582 (54) 145/582 (18)	41/197 (29) 98/197 (49) 58/197 (29)	.004
	Data are expressed as mean +- SD, median (25-75 interquartile), or number (%). Percentages were measured using pulse oximetry. SBP indicates systolic arterial blood pressure; CEI, converting enzyme inhibitor; AII I, Angiotensin II inhibitors; ICU, intensive care unit. * P b .05 vs normal serum concentrations. + P b .05 vs hyponatremia.

able to modify it. Thus, 271 patients (23%) were in the low- risk group; 577 (50%), in the intermediate-risk group; and 312 (27%), in the high-risk group.

Among the 1263 patients, serum sodium measurement was in the reference range in 634 (50%). Hyponatremia was observed in 409 patients (32%) (extreme, 104 mmol/L), severe hyponatremia in 59 patients (5%), and hypernatremia in 220 patients (17%) (extreme, 175 mmol/L) (Fig. 1). Com- parison between patients with and without serum sodium abnormalities is shown in Table 1. In the multivariate analysis, 2 variables were independently associated with a hyponatremia: heatstroke risk score and blood urea nitrogen- creatinine ratio less than 100 (Table 2; C-statistics, 0.58). When long-term medication with diuretics was forced into the model, its odds ratio was 0.89 (95% CI, 0.66-1.21). Conversely, 5 variables were independently associated with a hypernatremia: living in institution, dementia, serum crea- tinine greater than 120 umol/L, blood urea nitrogen- creatinine ratio greater than 100, and absence of long-term medication with diuretics (Table 2; C-statistics, 0.77). When long-term psychotropic drug intake was forced into the model, its odds ratio was 1.19 (95% CI, 0.81-1.75).

The survival rate at 1 year was significantly lower in patients with hypernatremia (0.45; 95% CI, 0.38-0.51) but

Table 2 Variables associated with hyponatremia or hypernatremia

Odds ratio P

(95% CI)

Variables associated with hyponatremia (n = 932) Risk score

Low Intermediate High

Blood urea nitrogen-creatinine ratio b100

1

-

1.79 (1.27-2.53) b.001

1.94 (1.32-2.85) b.001

1.67 (1.21-2.30) .002

Variables associated with hypernatremia (n = 775)

Blood urea nitrogen-creatinine ratio N100

Serum creatinine N120 umol/L Dementia

Living in an institution

4.10 (2.81-6.00) b.001

3.94 (2.67-5.82) b.001

2.93 (1.88-4.56) b.001

2.12 (1.41-3.19) b.001

Long-term medication with diuretics 0.53 (0.34-0.80) .003

not significantly modified in patients with hyponatremia (0.58; 95% CI, 0.53-0.63) as compared with those with serum sodium concentration in the reference range (0.57; 95% CI, 0.53-0.61) (Fig. 2). The same results were obtained when severe hyponatremia was considered (0.54; 95% CI, 0.40-0.67). When patients were stratified according to the heatstroke risk score [11], survival rate was significantly lower in patients with hypernatremia but not significantly modified in patients with hyponatremia (Table 3). The same results were observed when severe hyponatremia was considered (hazard ratio, 0.90 [0.72-1.09]; P = .62).

To assess morbidity in surviving patients, we determined the proportion of patients with subsequent impairment of their ADL score after 1 year. No significant differences were observed in patients with normal sodium concentration and those with hyponatremia or hypernatremia.

Discussion

Based on our large cohort study, serum sodium abnormalities are frequently observed in patients with heat-

Fig. 2 Kaplan-Meier survival curves in patients with normal (n = 634) serum sodium concentration, hyponatremia (n = 409), and hypernatremia (n = 220). Only the hypernatremic group was significantly different (P = .01 vs normal, P = .01 vs hyponatremia). The difference between normal and hyponatremia was not significant (P = .86) (log-rank test with the Bonferroni correction).

Table 3 Multivariate Cox proportional hazards analysis predicting death (n = 1160)

Variables

Risk score Low Intermediate High

Serum sodium concentration Normal or moderate hyponatremia

Severe hyponatremia Hypernatremia

Hazard ratio (95% CI)

P

1

2.40 (1.75-3.29)

8.49 (6.20-11.63)

- b.001 b.001

1

-

0.90 (0.72-1.09)

1.35 (1.09-1.36)

.62

.007

related illness during a heat wave. Both hyponatremia (32%) and hypernatremia (17%) were noted. However, only hypernatremia was an independent risk factor of death within the first year.

Patients with serum sodium measurement were signifi- cantly different from those patients in whom serum sodium was not measured. They were older and more dependent, as reflected by lower ADL score. In addition, several variables indicated that they experienced more severe consequences of heatstroke, as reflected by higher core temperature and lower Glasgow Coma Scale. Therefore, the incidence of hypona- tremia or hypernatremia reported here might have been less marked in the global population [11]. Very few studies have described serum sodium abnormalities observed during heatstroke; and to our knowledge, their impact on mortality has never been assessed. Interestingly, when considered as a mean, serum sodium concentration is usually reported as normal, although considerable variation may be observed [9,11]. Therefore, most studies [3,19,20] or reviews [1] did not specifically mention these abnormalities. During the 2003 heat wave in Lyon (France) and in Barcelona Spain, Argaud et al [9] and Jimenez-Mejias et al [21] reported a prevalence of 48% and 37%, respectively, for hyponatremia and of 25% and 46%, respectively, for hypernatremia. However, their patients experienced more severe heatstroke because the criteria for inclusion included a core temperature greater than 40?C and central nervous system abnormalities. Hypernatremia and dehydration have been more constantly reported in some series of exertional heatstroke [22], but Carter et al [23] reported a comparable incidence of hypernatremia (17%) in a large series of exertional heatstroke in soldiers.

The clinical significance of serum sodium abnormalities during heatstroke has also been poorly documented. Although a causality link cannot be demonstrated in this observational study, only 2 variables were independently associated with hyponatremia: heatstroke risk score and blood urea nitrogen-creatinine ratio less than 100 (Table 2). Conversely, 5 variables were independently associated with hypernatremia: living in an institution, dementia, serum creatinine greater than 120 umol/L, blood urea nitrogen- creatinine ratio greater than 100, and absence of long-term

medication with diuretics (Table 2). Two of these (dementia, living in institution) are already recognized as risk factors for dehydration in elderly patients, and 2 others (serum creatinine and blood urea nitrogen-creatinine ratio) suggest an association with renal insufficiency, probably at least partly related to functional renal failure. The association of hypernatremia with increased hemoglobin level and protein concentrations (Table 1) clearly suggests that extracellular dehydration occurred. Our results concur with those obtained by Seraj et al [24] using invasive hemodynamic monitoring, who observed that most of the patients with heatstroke were not fluid depleted. Therefore, our study clearly indicates that rapid measurement of serum sodium concentration may be helpful in heatstroke to appropriately guide blood electrolyte resuscitation.

In our core study [11], we demonstrated that the risk of death in heat-related illnesses occurring during a heat wave is predicted by the presence of 11 variables, which either indicate heatstroke severity (core temperature, systolic arterial pressure, consciousness, leukocyte count), greater susceptibility to heatstroke (age, preexisting disease such as cancer and cardiac disease, or long-term medication with diuretics), both (transportation to hospital by ambulance), or heatstroke complication (pulmonary or bloodstream infec- tion). We have derived a risk score by combining points for each of these features available at admission, which accurately classify patients into subgroups at low, interme- diate, and high risk for death. Taken into account this risk score and using the Cox regression model, we observed that only hypernatremia was an independent prognostic factor (Table 3). Although the exact mechanism involved in the deleterious role of hypernatremia cannot be inferred from our observational study, it is probably largely indirect and related to intracellular dehydration and its hemodynamic conse- quences during heatstroke. Consistently, administration of hypertonic sodium has been proved to induce beneficial effects in experimental heatstroke [25]. This effect is comparable with those observed with Fluid loading using starch [26] or hypervolemic hemodilution [27,28] in experimental heatstroke and is considered as further evidence that vigorous hemodynamic support is mandatory in heatstroke [29]. However, a direct deleterious effect cannot be completely ruled out because hypernatremia has been shown to induce a Hypercoagulable state [30] that may further worsen the heatstroke-induced hypercoagulable state [1,31,32]. Although a nonsignificant trend was noted, either hyponatremia or hypernatremia was not associated with additional morbidity in survivors when assessed using the ADL score.

Because heat waves can be catastrophic leading to overcrowding of health facilities [6] and excess mortality [7], most health authorities have published recommendations directed toward health care professionals as well as public [13]. These recommendations include advice to drink frequently even in the absence of thirst. Although they were associated with clear recommendations to associate

food (fruits, raw vegetables, soup, bread) with water aiming to provide mineral salts, it remains a concern that inappropriate application of these recommendations could lead to hyponatremia and its possible deleterious conse- quences [33,34]. Our present study shows that although hyponatremia was frequently observed, it was rarely severe and not responsible for any detectable deleterious effect in our population exposed to heatstroke. Thus, our study supports the relevance of these recommendations [14].

Our study has several limitations. First, the multivariate model identifies an association between variables and serum sodium abnormalities but does not infer causality. Second, some important variables may have been missed because they were recorded in few patients or because of lack of power in case of low prevalence. Third, the effects of some drugs on hyponatremia may have been missed because this adverse effect occurs in only a limited proportion of patients exposed to these drugs or because a drug category (eg, diuretics or psychotropic drugs) may include molecules that induce hyponatremia and others that do not. Lastly, the exact mechanisms involved in hyponatremia could not be deter- mined because urinary analysis was lacking. In the same way, we could only rely on blood urea nitrogen-creatinine ratio to indicate functional renal failure, whereas serum creatinine is a poorer marker of renal insufficiency than estimated creatinine clearance, particularly in an elderly population [35].

In conclusion, in a large cohort of patients with heat- related illness occurring during the August 2003 heat wave in France, we observed that serum sodium abnormalities occurred frequently; but hyponatremia is more frequent than hypernatremia. Only hypernatremia should be consid- ered as an independent risk factor of death. Thus, rapid measurement of serum sodium appears mandatory to appropriately guide electrolyte resuscitation in these patients.

Acknowledgments

We are indebted to Emmanuelle de Magondeau and Christine Lanau for their excellent data monitoring and management. The authors thank Dr David J. Baker, DM, FRCA (Department of Anesthesiology, CHU Necker-Enfants Malades, Paris, France) for reviewing the manuscript.

Appendix A

The other investigators were (in alphabetic order) Stephanie Andre, MD (CHU Cochin-St Vincent de Paul, Paris); Joelle Benkel (CHU Jean Verdier, Bondy); Domi- nique Brun-Ney, MD (CHU Ambroise Pare, Boulogne, currently the Direction de la Politique Medicale, Assistance Publique-Hopitaux de Paris); Enrique Casalino, MD, PhD (CHU Bicetre, Le Kremlin-Bicetre, currently CHU Bichat and Universite Denis Diderot-Paris 7); Alain Davido, MD

(Hopital Europeen Georges Pompidou, Paris); Jean-Francois Dhainaut, MD (CHU Cochin-St Vincent de Paul and Universite Rene Descartes-Paris 5, currently the Agence de l’Evaluation de la Recherche et de l’Enseignement Super- ieur, Paris, France); David Elkharrat, MD (CHU Lariboi- siere, Paris, currently CHU Ambroise Pare, Boulogne, and Universite Paris Ouest); Anika Fichelle, MD (CHU Bichat Claude-Bernard, Paris); Bertrand Galichon, MD (CHU Lariboisiere, Paris); Christine Ginsburg, MD (CHU Co- chin-St Vincent de Paul, Paris); Philippe Hericord, MD (deceased) (CHU Saint Antoine, Paris); Philippe Hoang, MD (deceased) (CHU Avicenne, Bobigny); Ludovic Korchia, MD (CHU Ambroise Pare, Boulogne); Comes Legaut, MD (CHU Antoine Beclere, Clamart); Virginie Lemiale, MD (CHU Henri Mondor, Creteil); Alice Marichez, MD, and Dominique Meyniel, MD (CHU Tenon, Paris); Dominique Pateron, MD, PhD, (CHU Jean Verdier, Bondy, currently CHU Saint-Antoine and Universite Pierre et Marie Curie- Paris 6); Jean-Louis Pourriat, MD, PhD (CHU Hotel Dieu, Paris and Universite Rene Descartes-Paris 5); Bertrand Renaud MD (CHU Henri Mondor, Creteil), Pierre Taboulet,

M.D. (CHU Saint Louis, Paris), Nabila Terbaoui, MD (CHU Bichat Claude Bernard, Paris); Stephane Wadjou, MD (CHU Pitie-Salpetriere); and Patrick Werner, MD (CHU Beaujon, Clichy), all in EDs of Assistance Publique-Hopitaux de Paris, Paris, France.

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