- Email: [email protected]
Burns and epilepsy – review and case report
JBUR-4440; No. of Pages 4 burns xxx (2014) xxx.e1–xxx.e4
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/burns
Case report
Burns and epilepsy – review and case report Alfredo Gragnani a,*, Bruno Rafael Mu¨ller b, Andrea Fernandes Oliveira c, Lydia Masako Ferreira a a
Plastic Surgery Division of EPM/UNIFESP, Sa˜o Paulo, Brazil EPM/UNIFESP, Sa˜o Paulo, Brazil c Postgraduate Program in Translational Surgery, EPM/UNIFESP, Sa˜o Paulo, Brazil b
article info
abstract
Article history:
Decompensation of epilepsy in burned patients may be caused by several factors. Burn is a
Accepted 8 August 2014
classic etiology of systemic inflammatory response syndrome, and evolves into two physiological phases. The first 48 h after injury corresponds to the first phase involving severe
Keywords:
hypovolemic shock. The second phase corresponds to the hypermetabolic response to
Burns
burns. Altered pharmacokinetics of anticonvulsant drugs is observed. Albumin and other
Epilepsy
plasma proteins are reduced, leading to increased free fraction of phenytoin, resulting in
Seizures
greater clearance and a lower total drug concentration. Associated with metabolic changes
Phenytoin
of burned patient, this fact predisposes to seizures in epileptic burned patients. The authors
Hypoalbuminemia
present the case of an epileptic 36-year-old-woman who developed recurrent seizures after a thermal injury, despite using the same medications and doses of anticonvulsant drugs of last 12 years, with controlled epilepsy. # 2014 Elsevier Ltd and ISBI. All rights reserved.
1.
Introduction
The prevalence of epilepsy around the world is estimated at 10/1000 people [1], being the most serious noninfectious chronic neurological condition in the world. Brazilian studies have shown lifetime prevalence of 11.9 to 21/1000 [2]. These patients are at increased risk for burns [3] and other events [4]. Burns as a result of a seizure represent 1.6–10% of admissions to burns units [5–9] and 3.7–15.9% of adult epileptics have been burned due to seizures [10,11]. Several factors may contribute to decompensation of epilepsy that occurs in burned patients as pain, fever [12], hypovolemia and metabolic changes after burns [13]. The
main factors that reduce the seizure threshold is fever, sleep deprivation, abrupt withdrawal of anticonvulsant medication, hyperventilation, intake of alcoholic beverages or stimulants, use of euphoric drugs, use of drugs with convulsant action (e.g. isoniazid), physical or psychological stress, hormonal disorders, flashing lights, repetitive sounds, flashing lights, repetitive sounds, hypoglycemia.
2. Burns and pharmacokinetics changes of drugs Burn is a classic etiology of systemic inflammatory response syndrome (SIRS), which can lead to multiple organ dysfunction
* Corresponding author at: Division of Plastic Surgery of EPM/UNIFESP, Rua Napolea˜o de Barros, 715 – 48 andar, Vila Clementino, Sa˜o Paulo 04024-002, Brazil. Tel.: +55 11 5576 4118/5579 4933. E-mail addresses: [email protected], [email protected] (A. Gragnani). http://dx.doi.org/10.1016/j.burns.2014.08.004 0305-4179/# 2014 Elsevier Ltd and ISBI. All rights reserved.
Please cite this article in press as: Gragnani A, et al. Burns and epilepsy – review and case report. Burns (2014), http://dx.doi.org/10.1016/ j.burns.2014.08.004
JBUR-4440; No. of Pages 4
e2
burns xxx (2014) xxx.e1–xxx.e4
syndrome (MODS) [14,15]. The skin lesion leads to the induction of a local inflammatory process through activation of coagulation, kallikrein–bradykinin cascades, complement and arachidonic acid. These paths lead to the release of different compounds that induce increased local microvascular permeability, vasodilation and generalized cellular edema by cell membrane dysfunction [16]. Thus, disturbance in the homeostasis occurs locally and systemically, which explains the severe hemodynamic alterations observed in major burn [17]. Based on physiological approach, burns evolve into two phases. The first 48 h after injury corresponds to the first phase involving severe hypovolemic shock. The inflammatory process begins in the burned patient rapidly after tissue injury to the skin resulting in local vasodilation, increase of vascular permeability and destruction of the extracellular matrix. These changes induce a rapid flow of albumin from the vascular to the interstitial space, leading a twofold increase in the interstitial volume within the initial hours after injury. In uninjured tissue, edema formation is delayed by several hours (24–36 h) and it is related to the systemic effects of inflammation in combination with a low oncotic pressure (hypoalbuminemia) [17,18]. The fluids leaking from the vascular space induces circulatory failure with low cardiac output and low glomerular filtration rate (GFR), leading to the low urine output and increased systemic vascular resistance in unburned tissues. Circulatory failure may induce organ damage, especially in acute kidney injury when the resuscitation fails. Fluid administration during resuscitation restores blood volume but increases the formation of edema. These physiological changes are temporary and the rate of edema formation decreases after the first 36–48 h. During this phase, the pharmacokinetics is mainly modified by a slower rate of delivery of drugs and decreased renal clearance [17,18]. The second phase (more than 48 h after injury) corresponds to the hypermetabolic response to burns, which is related to the systemic effects of inflammation and oxidative stress. At this stage, after adequate fluid administration, the hemodynamic status of a patient is hyperactive with increased cardiac contractility, high cardiac output and low systemic vascular resistance, as a septic shock state. Regional blood flow is increased, especially in the liver and kidneys, leading to an increased glomerular filtration rate and creatinine clearance (Crcl). The non-renal clearance is also increased by the leakage of exudate in burned areas, but its role in the elimination of drugs remains controversial [17,18]. The hypermetabolic phase is also characterized by the production of acute phase proteins, especially in the liver, wherein the synthesis of constitutive protein (albumin, prealbumin, transferrin, etc.) is shifted for synthesis of acute phase proteins (alpha 1-acid glycoprotein acid, haptoglobin, fibrinogen, alpha 2-macroglobulin, etc.) to help immune response, coagulation and wound healing function. Therefore, the serum albumin level is severely decreased due to decreases hepatic production and leakage during formation of edema and exudate loss [17,18]. Several studies have demonstrated that during this phase, plasma drug delivery is severely changed [18–20].
Regarding the liver, burn may induce hepatic dysfunction [21,22], with decreases in cytochrome P-450 and all activity related to oxidation, reduction and hydroxylation reactions involved in the drug metabolism. Other routes of metabolism, such as conjugation, are not changed [23]. The hypermetabolic phase may develop and persist over several days or weeks. The pharmacokinetic parameters of drugs are affected differently (volume of distribution, protein binding, hepatic clearance, half-life) depending on the time elapsed since the beginning of the lesion. Obviously, some other important factors related to the burned patient may affect the pharmacokinetics, as preexisting comorbidities, age, fluid replacement and presence of sepsis. Clearly, such changes have a large interindividual variability in drug pharmacokinetics [17,18,24]. Bowdle et al. [25] showed altered pharmacokinetics of phenytoin in burned rats. The main changes were increased clearance and volume of distribution, attributed to a greater free fraction compared with control mice (33.4% vs. 27.1%). The decline in plasma protein binding was directly associated with a lower concentration of albumin. The increase in the free fraction and its inverse correlation with the level of albumin were also observed in burned patients, in whom the free fraction was about 2.5 times higher than in healthy individuals. Results showed greater clearance and a lower total drug concentration, while the average concentration of free drug is not altered [25]. Phenytoin is highly bound to plasma proteins (90%), thus the changes in the unbound fraction are of clinical significance [26,27]. The drug has a moderately large volume of distribution. Clinically important displacement can be caused by bilirubin and several drugs particularly sodium valproate, which is often combined with phenytoin. Displacement will lower the total serum concentration but will little affect the free drug concentration. The metabolism of phenytoin to the major metabolite, 5-(p-hydroxyphenyl)-5(phenylhydantoin, is saturable, giving rise to a nonlinear dose–serum concentration relationship. Therefore, the dose range compatible with a therapeutic serum concentration is narrow within subjects, and monitoring serum concentrations is of particular value in dosage tailoring. In renal failure, the binding of phenytoin to plasma proteins is reduced and therefore a lower range of serum drug concentrations is compatible with therapeutic control. In liver disease, protein binding may also be impaired but delayed metabolism may occur in addition. During pregnancy the serum concentration may fall progressively as pregnancy advances, probably due to an increased rate of metabolism [26,28].
3.
Case report
Female, 36 years-old, litter collector, admitted to the Emergency Room (ER) of Sa˜o Paulo Hospital on 08/18/2009, brought by a rescue unit, with a history of having fired into the body with alcohol and flame. Such information was referred by people at the incident scene to the professional who performed the rescue. There, the patient was found with the fire extinguished and generalized tonic-clonic seizure,
Please cite this article in press as: Gragnani A, et al. Burns and epilepsy – review and case report. Burns (2014), http://dx.doi.org/10.1016/ j.burns.2014.08.004
JBUR-4440; No. of Pages 4 burns xxx (2014) xxx.e1–xxx.e4
submitted to orotracheal intubation and covered with a thermal blanket. On admission to the ER, the patient underwent the protocol ATLS (Advanced Trauma Life Support). At the initial examination, the patient was hemodynamically stable at Glasgow Coma Scale 11 T without sedation, pupils were equal in size and reacting normally to light and deep second degree burns in chest and abdomen (3%), anterior face of both thighs (4.5%), neck (1%) and head (3.5%); third-degree burns in upper limbs bilaterally (15%), totaling 27% of body surface burned. At the scene, the patient was covered with dirt in the wounds and other body parts. We performed a head CT that showed no acute changes, with sparse calcifications that a subsequent evaluation classified as a probable sequel of neurocysticercosis. The patient was transferred to the Burn Care Unit of hospital approximately 1 h after entering the ER. Sedation with fentanyl and midazolam and injury care was initiated according the protocol of institution. Hypovolemic shock ensued within the first 48 h of hospitalization that was reversed with intravenous hydration and urine output monitoring. After 1 day, bronchoscopy was performed to investigate a possible inhalation injury, with normal results. On 08/23/2009 the patient was extubated and was able to provide to the medical team with her personal history of epilepsy treated by 12 years with phenytoin 200 mg/day and phenobarbital 200 mg/day, reporting sporadic seizures (about 2 per year). The antiepileptic medications were introduced at the same doses that the patient was using. The patient was submitted to a surgical debridement in 08/ 26/2009 and 08/31/2009 and partial skin graft on 09/02/2009, with good graft integration. On 08/28/2009, the patient developed generalized tonic-clonic seizure that was reversed with intravenous diazepam 10 mg, 5 min after the start of the seizure. New crises happen again in the days 08/30/2009, 09/ 01/2009 and 2 episodes on 09/03/2009, always reversed with diazepam. During this period, the patient began to be accompanied by the Neurology team that increased the phenytoin dose to 300 mg/day, maintaining the same dose of phenobarbital. During admission, she had peaks of fever between 38 and 39 8C and antibiotics according to protocol of the Burn Unit was initialized. The patient had mild electrolyte disturbances with asymptomatic hypocalcemia and hypomagnesemia, which were replaced intravenously. On 09/09/2009, 09/10/2009, 09/11/2009, 09/13/2009 and 09/ 14/2009 she also had seizures, maintaining peaks of fever, despite negative blood cultures for bacteria growth. On 09/15/ 2009 the antibiotic was changed to vancomycin guided by positive blood culture for Sthaphylococus aureus resistant to oxacillin. After 48 h of the vancomycin had no more fever. The patient still underwent seizures during hospitalisation, being initiated clobazam 20 mg/day on 09/16/2009. She maintained seizures daily until 09/18/2009, when television from the patient’s room was removed, physical therapy was intensified with walking and rehabilitation exercises, and less time spent recumbent. The patient had no further seizures and was discharged with referral to return briefly with the Neurology team.
4.
e3
Discussion
Pugh [29] reported a case in which dramatic decreases in the protein binding of phenytoin and phenobarbital were noted in a 57-year-old burn patient with a history of a seizure disorder. Increased free fractions of phenytoin and phenobarbital were noted after the patient developed renal failure. Decreases in the protein binding of phenytoin in patients with hypoalbuminemia and/or uremia have been well documented [29]. Changes in albumin levels or the binding affinity of phenytoin to albumin must be taken into account when administration of phenytoin is necessary. As total phenytoin levels are of little value if significant changes occur, determination of the free concentration is recommended in these patients with a target concentration of 1–2 mcg/ml. Factors that may reduce albumin levels include: burns, hepatic cirrhosis, cachexia, malnutrition, and nephrotic syndrome. Factors that may decrease the affinity of phenytoin to albumin or cause displacement include: interacting drugs, increased bilirubin and renal failure [30]. Sheiner–Tozer equation can be used to adjust the serum phenytoin concentrations based on either reduced albumin levels or presence of renal failure (Crcl < 10 ml/min). Some studies have found considerable underestimation of serum levels while using these equations in some patients. Again, the most accurate assessment can be made by obtaining the actual unbound free level. The adjustment equations are estimations, and should be considered exactly that. Concenestimated = measured total concentration/ tration [(0.2 albumin) + 0.1] [31]. Epileptic patients have considerable risk for decompensation and evolution to epileptic seizures of hard control after suffering severe burns. Therefore, a multidisciplinary approach is necessary to assist these patients. Beyond primary care based on ATLS and specific therapy for burns, effort is needed to avoid factors that reduce the seizure threshold, predisposing to crisis. Adequate pain control is important in all burned patients. But, in epileptics, control must be more aggressive to avoid physical and psychological stress of the painful sensation, which can be a precipitator of seizures. The hyperthermia that occurs secondary to SIRS caused by burns must also be well controlled with antipyretics, avoiding febrile peaks and prolonged hyperthermia. Flashing lights, such as television, should be avoided especially in epileptic patients with prior history of seizures initiated by these mechanisms of photosensitivity. Neurological monitoring by a specialist is essential for both proper treatment as for the management of antiepileptic drugs. The decompensation of epilepsy occurs in burned due to multiple factors. To avoid this complication, these factors must be addressed one by one and controlled as best as possible, reinforcing the need for a multidisciplinary team for the proper care of these patients.
Conflict of interest No competing financial interests exist.
Please cite this article in press as: Gragnani A, et al. Burns and epilepsy – review and case report. Burns (2014), http://dx.doi.org/10.1016/ j.burns.2014.08.004
JBUR-4440; No. of Pages 4
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burns xxx (2014) xxx.e1–xxx.e4
references
[1] Noronha AL, Borges MA, Marques LH, Zanetta DM, Fernandes PT, de Boer H, et al. Prevalence and pattern of epilepsy treatment in different socioeconomic classes in Brazil. Epilepsia 2007;48(5):880–5. [2] Li LM, Sander JW. National demonstration project on epilepsy in Brazil. Arq Neuropsiquiatr 2003;61(1):153–6. [3] Tellez-Zenteno JF, Hunter G, Wiebe S. Injuries in people with self-reported epilepsy: a population-based study. Epilepsia 2008;49:954–61. [4] Beghi E, Cornaggia C, RESt-1 G. Morbidity and accidents in patients with epilepsy: results of a European cohort study. Epilepsia 2002;43:1076–83. [5] Josty IC, Narayanan V, Dickson WA. Burns in patients with epilepsy: changes in epidemiology and implications for burn treatment and prevention. Epilepsia 2000;41(4):453–6. [6] Tempest M. A survey of domestic burns and scalds in Wales during 1955; some observations on their prevention and the social responsibility of the medical profession. Br Med J 1956;1:1387–92. [7] Maisels DO, Corps BVM. Burned epileptics. Lancet 1964;1:1298–301. [8] Bull J, Jackson DM, Walton C. Causes and prevention of domestic burning accidents. Br Med J 1964;2:1421–7. [9] Richards EH. Aspects of epilepsy and burns. Epilepsia 1968;9:127–35. [10] Neufeld MY, Vishne T, Chistik V, et al. Life-long history of injuries related to seizures. Epilepsy Res 1999;34:123–7. [11] Buck D, Baker GA, Jacoby A, et al. Patients’ experiences of injury as a result of epilepsy. Epilepsia 1997;38:439–44. [12] Karande S. Febrile seizures: a review for family physicians. Indian J Med Sci 2007;61(3):161–72. [13] Mukhdomi GJ, Desai MH, Herndon DN. Seizure disorders in burned children: a retrospective review. Burns 1996;22(4):316–9. [14] Schwacha MG. Macrophages and post-burn immune dysfunction. Burns 2003;29(1):1–14. [15] Schwacha MG. Gammadelta T-cells: potential regulators of the post-burn inflammatory response. Burns 2009;35(3):318–26. [16] Arturson G. Forty years in burns research – the postburn inflammatory response. Burns 2000;26(7):599–604.
[17] Blanchet B, Jullien V, Vinsonneau C, Tod M. Influence of burns on pharmacokinetics and pharmacodynamics of drugs used in the care of burn patients. Clin Pharmacokinet 2008;47(10):635–54. [18] Bonate PL. Pathophysiology and pharmacokinetics following burn injury. Clin Pharmacokinet 1990;18(2):118–30. [19] Sawchuk RJ, Rector TS. Drug kinetics in burn patients. Clin Pharmacokinet 1980;5(6):548–56. [20] Boucher BA1, Kuhl DA, Hickerson WL. Pharmacokinetics of systemically administered antibiotics in patients with thermal injury. Clin Infect Dis 1992;14(2):458–63. [21] Jeschke MG, Barrow RE, Herndon DN. Extended hypermetabolic response of the liver in severely burned pediatric patients. Arch Surg 2004;139(6):641–7. [22] Jeschke MG, Micak RP, Finnerty CC, Herndon DN. Changes in liver function and size after a severe thermal injury. Shock 2007;28(2):172–7. [23] Jeschke MG. The hepatic response to thermal injury: is the liver important for postburn outcomes? Mol Med 2009;15(9– 10):337–51. [24] Martyn JA, Abernethy DR, Greenblatt DJ. Plasma protein binding of drugs after severe burn injury. Clin Pharmacol Ther 1984;35(4):535–9. [25] Bowdle TA, Neal GD, Levy RH, Heimbach DM. Phenytoin pharmacokinetics in burned rats and plasma protein binding of phenytoin in burned patients. J Pharmacol Exp Ther 1980;213(1):97–9. [26] Richens A. Clinical pharmacokinetics of phenytoin. Clin Pharmacokinet 1979;4(3):153–69. [27] Tokola RA, Neuvonen PJ. Pharmacokinetics of antiepileptic drugs. Acta Neurol Scand Suppl 1983;97:17–27. [28] Perucca E. Plasma protein binding of phenytoin in health and disease: relevance to therapeutic drug monitoring. Ther Drug Monit 1980;2(4):331–44. [29] Pugh CB. Phenytoin and phenobarbital protein binding alterations in a uremic burn patient. Drug Intell Clin Pharm 1987;21(3):264–7. [30] Dager WE, Inciardi JF, Howe TL. Estimating phenytoin concentrations by the Sheiner–Tozer method in adults with pronounced hypoalbuminemia. Ann Pharmacother 1995;29(7–8):667–70. [31] Martin E, Tozer TN, Sheiner LB, Riegelman S. The clinical pharmacokinetics of phenytoin. J Pharmacokinet Biopharm 1977;5(6):579–96.
Please cite this article in press as: Gragnani A, et al. Burns and epilepsy – review and case report. Burns (2014), http://dx.doi.org/10.1016/ j.burns.2014.08.004
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/burns
Case report
Burns and epilepsy – review and case report Alfredo Gragnani a,*, Bruno Rafael Mu¨ller b, Andrea Fernandes Oliveira c, Lydia Masako Ferreira a a
Plastic Surgery Division of EPM/UNIFESP, Sa˜o Paulo, Brazil EPM/UNIFESP, Sa˜o Paulo, Brazil c Postgraduate Program in Translational Surgery, EPM/UNIFESP, Sa˜o Paulo, Brazil b
article info
abstract
Article history:
Decompensation of epilepsy in burned patients may be caused by several factors. Burn is a
Accepted 8 August 2014
classic etiology of systemic inflammatory response syndrome, and evolves into two physiological phases. The first 48 h after injury corresponds to the first phase involving severe
Keywords:
hypovolemic shock. The second phase corresponds to the hypermetabolic response to
Burns
burns. Altered pharmacokinetics of anticonvulsant drugs is observed. Albumin and other
Epilepsy
plasma proteins are reduced, leading to increased free fraction of phenytoin, resulting in
Seizures
greater clearance and a lower total drug concentration. Associated with metabolic changes
Phenytoin
of burned patient, this fact predisposes to seizures in epileptic burned patients. The authors
Hypoalbuminemia
present the case of an epileptic 36-year-old-woman who developed recurrent seizures after a thermal injury, despite using the same medications and doses of anticonvulsant drugs of last 12 years, with controlled epilepsy. # 2014 Elsevier Ltd and ISBI. All rights reserved.
1.
Introduction
The prevalence of epilepsy around the world is estimated at 10/1000 people [1], being the most serious noninfectious chronic neurological condition in the world. Brazilian studies have shown lifetime prevalence of 11.9 to 21/1000 [2]. These patients are at increased risk for burns [3] and other events [4]. Burns as a result of a seizure represent 1.6–10% of admissions to burns units [5–9] and 3.7–15.9% of adult epileptics have been burned due to seizures [10,11]. Several factors may contribute to decompensation of epilepsy that occurs in burned patients as pain, fever [12], hypovolemia and metabolic changes after burns [13]. The
main factors that reduce the seizure threshold is fever, sleep deprivation, abrupt withdrawal of anticonvulsant medication, hyperventilation, intake of alcoholic beverages or stimulants, use of euphoric drugs, use of drugs with convulsant action (e.g. isoniazid), physical or psychological stress, hormonal disorders, flashing lights, repetitive sounds, flashing lights, repetitive sounds, hypoglycemia.
2. Burns and pharmacokinetics changes of drugs Burn is a classic etiology of systemic inflammatory response syndrome (SIRS), which can lead to multiple organ dysfunction
* Corresponding author at: Division of Plastic Surgery of EPM/UNIFESP, Rua Napolea˜o de Barros, 715 – 48 andar, Vila Clementino, Sa˜o Paulo 04024-002, Brazil. Tel.: +55 11 5576 4118/5579 4933. E-mail addresses: [email protected], [email protected] (A. Gragnani). http://dx.doi.org/10.1016/j.burns.2014.08.004 0305-4179/# 2014 Elsevier Ltd and ISBI. All rights reserved.
Please cite this article in press as: Gragnani A, et al. Burns and epilepsy – review and case report. Burns (2014), http://dx.doi.org/10.1016/ j.burns.2014.08.004
JBUR-4440; No. of Pages 4
e2
burns xxx (2014) xxx.e1–xxx.e4
syndrome (MODS) [14,15]. The skin lesion leads to the induction of a local inflammatory process through activation of coagulation, kallikrein–bradykinin cascades, complement and arachidonic acid. These paths lead to the release of different compounds that induce increased local microvascular permeability, vasodilation and generalized cellular edema by cell membrane dysfunction [16]. Thus, disturbance in the homeostasis occurs locally and systemically, which explains the severe hemodynamic alterations observed in major burn [17]. Based on physiological approach, burns evolve into two phases. The first 48 h after injury corresponds to the first phase involving severe hypovolemic shock. The inflammatory process begins in the burned patient rapidly after tissue injury to the skin resulting in local vasodilation, increase of vascular permeability and destruction of the extracellular matrix. These changes induce a rapid flow of albumin from the vascular to the interstitial space, leading a twofold increase in the interstitial volume within the initial hours after injury. In uninjured tissue, edema formation is delayed by several hours (24–36 h) and it is related to the systemic effects of inflammation in combination with a low oncotic pressure (hypoalbuminemia) [17,18]. The fluids leaking from the vascular space induces circulatory failure with low cardiac output and low glomerular filtration rate (GFR), leading to the low urine output and increased systemic vascular resistance in unburned tissues. Circulatory failure may induce organ damage, especially in acute kidney injury when the resuscitation fails. Fluid administration during resuscitation restores blood volume but increases the formation of edema. These physiological changes are temporary and the rate of edema formation decreases after the first 36–48 h. During this phase, the pharmacokinetics is mainly modified by a slower rate of delivery of drugs and decreased renal clearance [17,18]. The second phase (more than 48 h after injury) corresponds to the hypermetabolic response to burns, which is related to the systemic effects of inflammation and oxidative stress. At this stage, after adequate fluid administration, the hemodynamic status of a patient is hyperactive with increased cardiac contractility, high cardiac output and low systemic vascular resistance, as a septic shock state. Regional blood flow is increased, especially in the liver and kidneys, leading to an increased glomerular filtration rate and creatinine clearance (Crcl). The non-renal clearance is also increased by the leakage of exudate in burned areas, but its role in the elimination of drugs remains controversial [17,18]. The hypermetabolic phase is also characterized by the production of acute phase proteins, especially in the liver, wherein the synthesis of constitutive protein (albumin, prealbumin, transferrin, etc.) is shifted for synthesis of acute phase proteins (alpha 1-acid glycoprotein acid, haptoglobin, fibrinogen, alpha 2-macroglobulin, etc.) to help immune response, coagulation and wound healing function. Therefore, the serum albumin level is severely decreased due to decreases hepatic production and leakage during formation of edema and exudate loss [17,18]. Several studies have demonstrated that during this phase, plasma drug delivery is severely changed [18–20].
Regarding the liver, burn may induce hepatic dysfunction [21,22], with decreases in cytochrome P-450 and all activity related to oxidation, reduction and hydroxylation reactions involved in the drug metabolism. Other routes of metabolism, such as conjugation, are not changed [23]. The hypermetabolic phase may develop and persist over several days or weeks. The pharmacokinetic parameters of drugs are affected differently (volume of distribution, protein binding, hepatic clearance, half-life) depending on the time elapsed since the beginning of the lesion. Obviously, some other important factors related to the burned patient may affect the pharmacokinetics, as preexisting comorbidities, age, fluid replacement and presence of sepsis. Clearly, such changes have a large interindividual variability in drug pharmacokinetics [17,18,24]. Bowdle et al. [25] showed altered pharmacokinetics of phenytoin in burned rats. The main changes were increased clearance and volume of distribution, attributed to a greater free fraction compared with control mice (33.4% vs. 27.1%). The decline in plasma protein binding was directly associated with a lower concentration of albumin. The increase in the free fraction and its inverse correlation with the level of albumin were also observed in burned patients, in whom the free fraction was about 2.5 times higher than in healthy individuals. Results showed greater clearance and a lower total drug concentration, while the average concentration of free drug is not altered [25]. Phenytoin is highly bound to plasma proteins (90%), thus the changes in the unbound fraction are of clinical significance [26,27]. The drug has a moderately large volume of distribution. Clinically important displacement can be caused by bilirubin and several drugs particularly sodium valproate, which is often combined with phenytoin. Displacement will lower the total serum concentration but will little affect the free drug concentration. The metabolism of phenytoin to the major metabolite, 5-(p-hydroxyphenyl)-5(phenylhydantoin, is saturable, giving rise to a nonlinear dose–serum concentration relationship. Therefore, the dose range compatible with a therapeutic serum concentration is narrow within subjects, and monitoring serum concentrations is of particular value in dosage tailoring. In renal failure, the binding of phenytoin to plasma proteins is reduced and therefore a lower range of serum drug concentrations is compatible with therapeutic control. In liver disease, protein binding may also be impaired but delayed metabolism may occur in addition. During pregnancy the serum concentration may fall progressively as pregnancy advances, probably due to an increased rate of metabolism [26,28].
3.
Case report
Female, 36 years-old, litter collector, admitted to the Emergency Room (ER) of Sa˜o Paulo Hospital on 08/18/2009, brought by a rescue unit, with a history of having fired into the body with alcohol and flame. Such information was referred by people at the incident scene to the professional who performed the rescue. There, the patient was found with the fire extinguished and generalized tonic-clonic seizure,
Please cite this article in press as: Gragnani A, et al. Burns and epilepsy – review and case report. Burns (2014), http://dx.doi.org/10.1016/ j.burns.2014.08.004
JBUR-4440; No. of Pages 4 burns xxx (2014) xxx.e1–xxx.e4
submitted to orotracheal intubation and covered with a thermal blanket. On admission to the ER, the patient underwent the protocol ATLS (Advanced Trauma Life Support). At the initial examination, the patient was hemodynamically stable at Glasgow Coma Scale 11 T without sedation, pupils were equal in size and reacting normally to light and deep second degree burns in chest and abdomen (3%), anterior face of both thighs (4.5%), neck (1%) and head (3.5%); third-degree burns in upper limbs bilaterally (15%), totaling 27% of body surface burned. At the scene, the patient was covered with dirt in the wounds and other body parts. We performed a head CT that showed no acute changes, with sparse calcifications that a subsequent evaluation classified as a probable sequel of neurocysticercosis. The patient was transferred to the Burn Care Unit of hospital approximately 1 h after entering the ER. Sedation with fentanyl and midazolam and injury care was initiated according the protocol of institution. Hypovolemic shock ensued within the first 48 h of hospitalization that was reversed with intravenous hydration and urine output monitoring. After 1 day, bronchoscopy was performed to investigate a possible inhalation injury, with normal results. On 08/23/2009 the patient was extubated and was able to provide to the medical team with her personal history of epilepsy treated by 12 years with phenytoin 200 mg/day and phenobarbital 200 mg/day, reporting sporadic seizures (about 2 per year). The antiepileptic medications were introduced at the same doses that the patient was using. The patient was submitted to a surgical debridement in 08/ 26/2009 and 08/31/2009 and partial skin graft on 09/02/2009, with good graft integration. On 08/28/2009, the patient developed generalized tonic-clonic seizure that was reversed with intravenous diazepam 10 mg, 5 min after the start of the seizure. New crises happen again in the days 08/30/2009, 09/ 01/2009 and 2 episodes on 09/03/2009, always reversed with diazepam. During this period, the patient began to be accompanied by the Neurology team that increased the phenytoin dose to 300 mg/day, maintaining the same dose of phenobarbital. During admission, she had peaks of fever between 38 and 39 8C and antibiotics according to protocol of the Burn Unit was initialized. The patient had mild electrolyte disturbances with asymptomatic hypocalcemia and hypomagnesemia, which were replaced intravenously. On 09/09/2009, 09/10/2009, 09/11/2009, 09/13/2009 and 09/ 14/2009 she also had seizures, maintaining peaks of fever, despite negative blood cultures for bacteria growth. On 09/15/ 2009 the antibiotic was changed to vancomycin guided by positive blood culture for Sthaphylococus aureus resistant to oxacillin. After 48 h of the vancomycin had no more fever. The patient still underwent seizures during hospitalisation, being initiated clobazam 20 mg/day on 09/16/2009. She maintained seizures daily until 09/18/2009, when television from the patient’s room was removed, physical therapy was intensified with walking and rehabilitation exercises, and less time spent recumbent. The patient had no further seizures and was discharged with referral to return briefly with the Neurology team.
4.
e3
Discussion
Pugh [29] reported a case in which dramatic decreases in the protein binding of phenytoin and phenobarbital were noted in a 57-year-old burn patient with a history of a seizure disorder. Increased free fractions of phenytoin and phenobarbital were noted after the patient developed renal failure. Decreases in the protein binding of phenytoin in patients with hypoalbuminemia and/or uremia have been well documented [29]. Changes in albumin levels or the binding affinity of phenytoin to albumin must be taken into account when administration of phenytoin is necessary. As total phenytoin levels are of little value if significant changes occur, determination of the free concentration is recommended in these patients with a target concentration of 1–2 mcg/ml. Factors that may reduce albumin levels include: burns, hepatic cirrhosis, cachexia, malnutrition, and nephrotic syndrome. Factors that may decrease the affinity of phenytoin to albumin or cause displacement include: interacting drugs, increased bilirubin and renal failure [30]. Sheiner–Tozer equation can be used to adjust the serum phenytoin concentrations based on either reduced albumin levels or presence of renal failure (Crcl < 10 ml/min). Some studies have found considerable underestimation of serum levels while using these equations in some patients. Again, the most accurate assessment can be made by obtaining the actual unbound free level. The adjustment equations are estimations, and should be considered exactly that. Concenestimated = measured total concentration/ tration [(0.2 albumin) + 0.1] [31]. Epileptic patients have considerable risk for decompensation and evolution to epileptic seizures of hard control after suffering severe burns. Therefore, a multidisciplinary approach is necessary to assist these patients. Beyond primary care based on ATLS and specific therapy for burns, effort is needed to avoid factors that reduce the seizure threshold, predisposing to crisis. Adequate pain control is important in all burned patients. But, in epileptics, control must be more aggressive to avoid physical and psychological stress of the painful sensation, which can be a precipitator of seizures. The hyperthermia that occurs secondary to SIRS caused by burns must also be well controlled with antipyretics, avoiding febrile peaks and prolonged hyperthermia. Flashing lights, such as television, should be avoided especially in epileptic patients with prior history of seizures initiated by these mechanisms of photosensitivity. Neurological monitoring by a specialist is essential for both proper treatment as for the management of antiepileptic drugs. The decompensation of epilepsy occurs in burned due to multiple factors. To avoid this complication, these factors must be addressed one by one and controlled as best as possible, reinforcing the need for a multidisciplinary team for the proper care of these patients.
Conflict of interest No competing financial interests exist.
Please cite this article in press as: Gragnani A, et al. Burns and epilepsy – review and case report. Burns (2014), http://dx.doi.org/10.1016/ j.burns.2014.08.004
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references
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Please cite this article in press as: Gragnani A, et al. Burns and epilepsy – review and case report. Burns (2014), http://dx.doi.org/10.1016/ j.burns.2014.08.004