Epilepsia, 52(11):1949–1955, 2011 doi: 10.1111/j.1528-1167.2011.03259.x
FULL-LENGTH ORIGINAL RESEARCH
Respiratory alkalosis in children with febrile seizures *Sebastian Schuchmann, ySarah Hauck, yStephan Henning, yAnnette Gru¨ters-Kieslich, zSampsa Vanhatalo, *x1Dietmar Schmitz, and {**1Kai Kaila *Neuroscience Research Center, Charite´ – University Medicine Berlin, Berlin, Germany; yOtto Heubner Centrum, Children’s Hospital, University Medicine Berlin, Berlin, Germany; zDepartment of Clinical Neurophysiology, Children’s Hospital, Helsinki University Central Hospital, Helsinki, Finland; xBernstein Center for Computational Neuroscience, Humboldt University Berlin, Berlin, Germany; {Department of Biosciences, University of Helsinki, Helsinki, Finland; and **Neuroscience Center, University of Helsinki, Helsinki, Finland
SUMMARY Purpose: Febrile seizures (FS) are the most common type of convulsive events in children. FS are suggested to result from a combination of genetic and environmental factors. However, the pathophysiologic mechanisms underlying FS remain unclear. Using an animal model of experimental FS, it was demonstrated that hyperthermia causes respiratory alkalosis with consequent brain alkalosis and seizures. Here we examine the acid–base status of children who were admitted to the hospital for FS. Children who were admitted because of gastroenteritis (GE), a condition known to promote acidosis, were examined to investigate a possible protective effect of acidosis against FS. Methods: We enrolled 433 age-matched children with similar levels of fever from two groups presented to the emergency department. One group was admitted for FS (n = 213) and the other for GE (n = 220). In the FS group, the etiology of fever was respiratory tract infection (74.2%), otitis media (7%), GE (7%), tonsillitis (4.2%), scarlet fever (2.3%) chickenpox (1.4%), urinary tract infection (1.4%), postvaccination reaction (0.9%), or unidentified (1.4%). In all patients, capillary pH and blood Pco2 were measured immediately on admission to the hospital. Key Findings: Respiratory alkalosis was found in children with FS (pH 7.46 ± 0.04, [mean ± standard deviation]
Febrile seizures (FS) are generalized tonic–clonic seizures in children age 6 months to 5 years, with a peak incidence at 16–18 months (Annegers et al., 1987; Berg & Shinnar, 1996), and a cumulative incidence between 2% Accepted July 20, 2011; Early View publication September 12, 2011. Address correspondence to Sebastian Schuchmann, Department of Nephrology and Medical Intensive Care, Charit-Universittsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail:
[email protected] 1 These authors contributed equally to this work. Wiley Periodicals, Inc. ª 2011 International League Against Epilepsy
Pco2 29.5 ± 5.5 mmHg), whereas a metabolic acidosis was seen in all children admitted for GE (pH 7.31 ± 0.03, Pco2 37.7 ± 4.3 mmHg; p < 0.001 for both parameters). No FS were observed in the latter group. A subgroup (n = 15; 7%) of the patients with FS had GE and, notably, their blood pH was more alkaline (pH 7.44 ± 0.04) than in the GE-admitted group. During the enrollment period, eight of the patients were admitted on separate occasions because of FS or GE. Consistent with the view that generation of FS requires a genetic susceptibility in addition to acute seizure triggering factors, each of these patients had an alkalotic blood pH when admitted because of FS, whereas they had an acidotic pH (and no FS) when admitted because of GE (pH 7.47 ± 0.05 vs. pH 7.33 ± 0.03, p < 0.005). Significance: The results show that FS are associated with a systemic respiratory alkalosis, irrespective of the severity of the underlying infection as indicated by the level of fever. The lack of FS in GE patients is attributable to low pH, which also explains the fact that children with a susceptibility to FS do not have seizures when they have GE-induced fever that is associated with acidosis. The present demonstration of a close link between FS and respiratory alkalosis may pave the way for further clinical studies and attempts to design novel therapies for the treatment of FS by controlling the systemic acid–base status. KEY WORDS: Febrile seizure, Triggering mechanism, Respiration, Alkalosis.
and 8%, depending on geographic and cultural factors (Nelson & Ellenberg, 1976; Verity & Golding, 1991). FS are suggested to result from a combination of genetic and environmental factors (Baulac et al., 2004; Mulley et al., 2005; Vestergaard et al., 2008). Children with FS have an increased relative incidence of a positive family history for FS (24%) and for epilepsy (4%) (Sadleir & Scheffer, 2007). The pathophysiologic mechanisms that trigger human FS have not been identified. This also means that it has not been possible to develop rational therapies to directly target the disease mechanisms. There are several factors that make
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1950 S. Schuchmann et al. FS-inducing mechanisms difficult to study in humans. Most importantly, FS appear mainly at home and not under hospital conditions. Hence, there is access only to postictal data that are obtained after admission to the hospital, and, consequently, the search for FS mechanisms can rely only on mechanistic evidence from animal studies and on indirect data from humans. pH changes have a central role in the control of seizure activity in the brain. Alkalosis is known to enhance neuronal excitability and to promote epileptiform activity, both in vitro and in vivo (Balestrino & Somjen, 1988; Jarolimek et al., 1989; Helmy et al., 2011; for review, see Kaila & Ransom, 1998). In line with this, hyperventilation (which by definition leads to a net loss of CO2 and to consequent respiratory alkalosis) is a standard method to provoke absence seizures, complex partial seizures, and other epileptiform manifestations in human patients. The hyperventilation-induced electroencephalography (EEG) changes are more pronounced in children than in adults (Flink et al., 2002; Takahashi, 2005). In contrast to this, neuronal excitability and seizure activity are strongly suppressed by various maneuvers that lead to a decrease in brain pH, including exposure to elevated CO2 (Caspers & Speckmann, 1972; de Curtis et al., 1998; Xiong et al., 2000; Schuchmann et al., 2006; Ziemann et al., 2008; Tolner et al., 2011; for a recent review, see Lçscher & Kçhling, 2010). Using an animal model of experimental FS, we have demonstrated that hyperthermia causes respiratory alkalosis (net loss of CO2) with consequent brain alkalosis and seizures (Schuchmann et al., 2006). Moreover, these experimental FS were completely and rapidly (delay of only 20 s) abolished by exposing the rat pups to 5% CO2 in air, suggesting a putative therapeutic approach. So far, it is not known whether this kind of a mechanism plays any role in FS in humans. A first step to obtaining information on this question would require a demonstration of an association between respiratory alkalosis and FS episodes in the affected children. An attractive strategy to search for the presence of such an association in children is to exploit
the natural clinical variation of pediatric infectious diseases with fever. Notably, identical microbiologic etiologies can cause fever with or without FS (Lewis et al., 1979; Millichap & Millichap, 2004; Chung & Wong, 2007). Previous studies have shown that, in children, fever tends to increase respiration rate, which can lead to respiratory alkalosis (O’Dempsey et al., 1993; Gadomski et al., 1994; Taylor et al., 1995). Hence, we hypothesized that precipitation of FS in children with fever may depend on a systemic alkalosis. However, it is obvious that the net effect of a fever-induced hyperventilation on pH will depend on the overall acid–base balance of the individual, not on respiratory patterns only. It is of interest here that gastroenteritis (GE) is known to typically give rise to a metabolic acidosis because of diarrhea and a consequent loss of bicarbonate (Vega & Avner, 1997; Nagler et al., 2006; Madati & Bachur, 2008). Because of the obvious lack of any physiologically ‘‘normal’’ population in clinical studies, we decided to look at acidotic GE patients in an age- and fever-matched cohort as a useful approach to examine a possible relation between systemic pH changes and FS. Specifically, we examined whether age-matched children with identical levels of fever upon admission to hospital for FS or GE show differences in pH, Pco2, and standard base excess (SBE) as measured from capillary blood. Our data point to a tight association between fever-induced respiratory alkalosis and induction of FS, not only at the level of overall statistics, but also at the level of individual patients with a clinical history of FS.
Patients and Methods We enrolled patients between 6 and 60 months of age with fever (>37.8C, see Armon et al., 2003), who were admitted on the basis of clinical diagnosis of FS (FS group, Table 1; see Sadleir & Scheffer, 2007) or GE (GE group, Table 1) at the emergency department of the Otto Heubner Centrum, Children’s Hospital (Charit – University
Table 1. Clinical data for FS and GE groups n (%) FS Infection of the respiratory tract Gastroenteritis (=FS/GE subgroup) Otitis media Tonsillitis Scarlet fever Chickenpox Urinary tract infection Postvaccination Fever of unknown origin GE
Epilepsia, 52(11):1949–1955, 2011 doi: 10.1111/j.1528-1167.2011.03259.x
213 158 (74.2) 15 (7.0) 15 (7.0) 9 (4.2) 5 (2.3) 3 (1.4) 3 (1.4) 2 (0.9) 3 (1.4) 220
Age (month) 29.7 31.6 24.3 34.3 20.9 17.8 28.3 27.7 19.3 29.5 27.6
± ± ± ± ± ± ± ± ± ± ±
15.0 17.1 10.1 14.2 8.1 5.6 10.2 7.3 6.3 7.9 15.7
Temperature (C) 39.3 39.3 38.6 39.4 39.5 39.7 39.3 40.1 38.9 38.8 39.3
± ± ± ± ± ± ± ± ± ± ±
0.7 0.7 0.7 0.6 0.5 0.5 0.7 0.4 0.8 0.5 0.5
pH 7.46 7.46 7.44 7.43 7.49 7.50 7.49 7.50 7.48 7.45 7.31
± ± ± ± ± ± ± ± ± ± ±
Pco2 (mm Hg) 0.04 0.04 0.04 0.05 0.05 0.02 0.03 0.02 0.02 0.02 0.03
29.5 29.4 26.3 27.0 34.0 28.5 32.3 31.5 33.2 37.5 37.7
± ± ± ± ± ± ± ± ± ± ±
5.5 5.3 5.9 4.0 5.6 3.5 4.8 3.8 4.2 2.7 4.3
SBE (mM) )1.1 )1.0 )2.7 )0.9 )0.8 )1.1 )0.7 )0.8 )0.5 )0.6 )9.35
± ± ± ± ± ± ± ± ± ± ±
1.6 1.6 0.6 2.4 0.7 0.5 0.5 0.4 0.6 0.3 2.3
1951 Febrile Seizures and Systemic pH Medicine Berlin) between September 2005 and August 2007. Below, a minority of FS patients with GE are denoted as the FS/GE subgroup. This study was approved by the Ethics Commission of the Charit – University Medicine Berlin. Simple FS was defined as a primary generalized convulsion lasting 15 min) convulsion and/or more than one convulsions in 24 h. Children with complex FS were treated with rectal diazepam (0.3–0.5 mg/kg). Children with a history of afebrile seizure, or with evidence of central nervous system infection and underlying neurological disorders were excluded from the FS group. Children included in the GE group were admitted to the hospital for symptoms of viral GE, such as diarrhea and/or vomiting, and clinical signs of dehydration, with loss of ‡5% of body weight (Webb & Starr, 2005). In addition to the above, information was collected on the FS susceptibility and FS history of the patients. Because none of the patients in the present GE group had any symptoms of FS (see Results), we used the hospital documents to check whether they had experienced FS outside the enrollment period. In addition, we gathered information from hospital documents on previous FS in the patients recruited for this study because of FS. Immediately after admission to the hospital (0.5 h and later; see Fig. 1), blood gas analyses using capillary blood were performed (ABL700; Radiometer, Berlin, Germany) for all patients, and pH, Pco2, and SBE were measured. We used the following standard values: pH 7.35–7.45, Pco2 35–45 mm Hg, and SBE )2 to +2 mM (Boemke et al., 2004; Longmore et al., 2007). To exclude venous blood samples we accepted only samples with a Po2 >50 mm Hg (Adrogu et al., 1989). The patients’ characteristics (i.e., gender, age at presentation, clinical diagnosis, duration of fever, and temperature on admission) were reviewed. All patients were afebrile at the time of discharge. In order to examine the role of pH in FS induction at the individual level where differences in FS susceptibility play a key role (see Baulac et al., 2004), we examined in detail eight patients who were taken twice to the hospital during the enrollment period with admission because of either FS or GE (hence, they belong to both the FS and GE groups defined above). Four of these children were first admitted for FS, and the second admission was because of GE (interval between the two admissions about 6 weeks or more); and the other four children had first GE and then FS (with an interval between the two admissions of about 14 weeks or more). Measured parameters were compared by Student’s t-test, one-way analysis of variance (ANOVA) and Bonferroni multiple comparison test between the different patient groups and subgroups. Mean values € standard deviation
(SD) are provided. The level of statistical significance (p) is given in the text and in Fig. 1.
Results The analyses below are based on 433 children admitted to the hospital either because of FS (213 patients: 93 girls, 120 boys) or because of GE (220 patients: 140 girls, 80 boys). There was an interesting overlap between these two groups, since during the enrollment period, eight of the patients were admitted on separate occasions because of FS or GE. The age range of the two groups was very similar (FS group: 6.0–58.9 month; GE group: 9.0–59.7 months) and the mean age was not significantly different among the groups (p = 0.24). On admission, the mean rectal temperature showed no significant difference (p = 0.79) and the temperature distribution in both groups was comparable (see Fig. 1A). In the FS group, blood gas analyses performed on admission indicated a noncompensated respiratory alkalosis with increased pH, reduced Pco2, and an SBE within the normal range (see Table 1). This association between respiratory alkalosis and FS is intriguing, since our previous work on a rat model showed that experimental FS can be triggered by respiratory alkalosis (Schuchmann et al., 2006). To gain more insight into the relationships among rectal temperature, respiratory alkalosis, and FS, we subdivided the FS group depending on the time of admission to hospital (0.5 h, n = 57; 1 h, n = 102; 2 h, n = 42; 3 h, n = 12). The initially recorded rectal temperature showed a significant decline within the first 2 h after FS onset (0.5 h vs. 2 h p < 0.001; 1 h vs. 2 h p < 0.001; 2 h vs. 3 h p = 0.023). Notably, we observed a progressive fall of the initially alkaline pH, which reached standard levels at 2 h or later after FS onset in the hospital (0.5 h or 1 h vs. 2 h or 3 h, p < 0.001). The above data are summarized in Fig. 1B. We also compared children with simple FS (n = 124) and complex FS (n = 89). No significant difference was found in either body temperature or pH between these two groups, which suggests that differences in the magnitude of the respiratory alkalosis as such do not contribute to the wellknown differences in the clinical picture of simple and complex FS. This is consistent with the view that simple and complex FS reflect distinct types of genetic susceptibility that lead to two distinct types of epileptiform manifestations in response to external/physiologic triggering factors (see Baulac et al., 2004) which, in the present study, could be respiratory alkalosis. Blood analyses in the GE group showed a partially compensated metabolic acidosis with reduced pH, normal Pco2, and reduced SBE. All three parameters differed significantly between the FS and GE groups (p < 0.001). Strikingly, none of the 220 patients admitted because of GE had FS, despite identical levels of fever when compared to the FS group. The association between FS and pH became even Epilepsia, 52(11):1949–1955, 2011 doi: 10.1111/j.1528-1167.2011.03259.x
1952 S. Schuchmann et al. A
B
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more interesting after analyzing the subgroup of patients who had GE but were admitted to the hospital for FS (the FS/GE subgroup; n = 15; 7% of the total GE population). Epilepsia, 52(11):1949–1955, 2011 doi: 10.1111/j.1528-1167.2011.03259.x
Figure 1. (A) Age (left) and body temperature (right) distribution of individuals admitted for FS (red) and for GE (blue). (B) Capillary blood pH of individuals admitted for FS (red, left) and for GE (blue, right). The FS group was divided into four subgroups according to the delay time between FS onset and hospital admission (0.5, 1, 2 or 3 h). The diagram shows mean values ± standard deviation. Gray shading indicates standard blood pH range. (C) Capillary blood pH (upper bar diagram) and Pco2 (lower bar diagram) of individuals admitted for FS (colors indicating the disease) or GE (light blue bar). The bars show mean, minimum, and maximum values; gray shading indicates the clinically normal range of capillary blood pH (upper diagram) and Pco2 (lower diagram) range. The admission criteria (FS and GE with respective n numbers) are also shown on the right, as well as the subgroups within the FS group. Epilepsia ILAE
In the FS/GE subgroup, we found an alkaline blood pH of 7.44 € 0.04 and a reduced SBE compared with other FS subgroups (vs. respiratory tract infection p = 0.004; vs.
1953 Febrile Seizures and Systemic pH otitis media p = 0.041; vs. tonsillitis p = 0.032; vs. scarlet fever p = 0.037; for mean values, see Table 1). Notably, SBE in the FS/GE subgroup was significantly higher than in the GE patients without FS (p < 0.001), which is consistent with the loss of HCO3 as a result of diarrhea in the FS/GE group. The data from this FS/GE subgroup suggested that, irrespective of the nature of the febrile disease, FS are associated with an elevation of systemic pH. We, therefore, examined whether the severity of infection (as reflected in the level of fever) might explain the presence versus absence of FS. In the FS group, the etiology of fever was respiratory tract infection (74.2%), otitis media (7%), GE (7%), tonsillitis (4.2%), scarlet fever (2.3%) chickenpox (1.4%), urinary tract infection (1.4%), postvaccination reaction (0.9%), or unidentified (1.4%). The clinical characteristics of these populations are summarized in Fig. 1C and Table 1. The possibility that FS is linked to the height of fever was excluded by the fact that the average peak body temperature was similar in both the FS and GE groups (Table 1). Notably, the FS/GE subgroup had a slightly lower temperature than the GE group (Table 1; p = 0.038). Taken together, the two comparisons above imply that the level of fever is not a confounding factor in the present analysis of the association of alkalosis and FS. Furthermore, among the patients enrolled in our study, we found 17 children with a documented medical history of earlier febrile seizures (12 in the FS group, 5 in the FS/GE group). Based on both earlier medical reports at the Charit, these children had not had previous FS during mild infections (body temperature
