NFLUENCE OF DlAZEPAM OR LORAZEP DOTRACHEAL INTUBATION IN CHILDHO

3

Chiulli, MD,* Thomas *Department of internal Medicine, *Department of Pediatrics, .?epnni address: Thomas E. Terndrup,

E. Tern

+Departments of Criticai Care & Emergency State University of New York Health Science MD, Department of Critical Care & Emergency Syracuse, NY 13270

q Abstract - Anticonvulsant management of status epi-

status epi~e~ticns in cb~ldre~ s estcd that aggressive ~t~convu~sant management of cause excessive respiratory depression, resultin ewise u~~~~es~ sary ET1 (45). ‘Tbe be~zod~a~ep~n~s dia~,~~~rn ,and ~~~~~~~a~ are widely accepted as effective first-Iike med~cat~o~s for acute management of status ~~~~~~~c~sin both a and children (4-g). A common c~~~~~c~t~o~of aggressive ant~conv~~sant ma~ageme~t is ~e~~~r~to~ depression, often requiring endotra~~~e~~~~~~ba~ion(9-12). ~nt~bation increases intensive care bed ~t~~izat~o~and probably expenses, and may increase rno~b~~~t~ (for example, poste~tnbatio~ strider). W-m been cited as a respiratory tent with those employed iorazepam has been shown to produce mE tory depression nn effective dosage ra There are no studies corn~~~~ the relat depressant comp~ica~~on5 of these age

ptisus; childhood; diazepam;

Status epilepticus is a serious complication of convulsive disorders with significant associated morbidity and Presented aa the Scientific Assembly, American College of Emergency Physicians. Washington, D.C.. September 12, 1989.

&CEIVED: ACCEPTED:

Street.

mortaiity. Permanent neuroiogic seqlaelae have been observed in up to 15% of cb~~~re~after an episode of SE (1). Earlier studies, prior to modem aggressive anticonvulsant and acute care mana~~rne~t~ q~orted ~~~a~i~ rates of up to 50% (2). Aggressive ant~convnisant ma~a~em~~t to template tonic-clonic activity may reduce ~~~~~e~o~shemodynamic , metabolic, and central wous system changes during prolonged seizures (3). wever, the outcome of s been showri to e seizure rather

lepticus (SE) may result m respiratory depression, often requiring endotracheal intubation (ETI). By examining in childhood SE after intravenous diazepam , when adminfstered alone or in combination with phenytoiu, the influence of anticonvulsants on the frequency of ETI during SE was determined. The medical resords of 142 consecutive children younger than I6 years of age admitted from a university hospital ED with seizures during a %lmonth period were retrospectively reviewed. SE was identified in 38 (27%) of eases,Records of children with SE were reviewed for demographic, seizure severity, and management variables. Twelve patients were excluded, ten of whom reseived sonsominant phenobarbital. Patients receiving lorazepam had ET1 rate of 27% (4/15), compared to 73% (g/II) in the diazepam group (P = 0.026, Fisher’s exact). The groups were not significantly different in age, weight, sex? seizure type, seizure duration, and appropriate antisonvulsaut dosage. A prospective, randomized trial comparing lorazepam and diazepam is warranted to confirm the apparent advantage of lorazepam in redusing respiratory depression. J Keywords - status lorazepam; respiratory

Medicine ano Pediz:ws, Center at Syracxse Medicine, XC E. &ams

Clinical Communications: Pediatrics features articles on the assessmentand ~a~a~e~e~~i?i chii&z~d ‘This section is coordinated by Roger Barkin, MD. of the Rose Medica: Center, Denver. Colorado. 6 April 1990: CAL SUBMISSION KECEIVED: 25 June 1990; 24 July 1990 13

~~~~~~~~n~~~~.

14

Donald

with status epilepticus. The present study was designed to obtain preliminary data on the relative respiratory depressant effects of anticonvulsants by determining the rate of endotracheal intubation during status epilepticus in children through a retrospective chart review. The frequency of intubation was compared in those receiving diazepam compared with those receiving lorazepam to determine whether either drug was associated with greater respiratory depression.

ing a depressed respiratory rate or tidal volume, hypoxemia, hypercarbia, and the clinical impression regarding the patients ability to maintain adequate respiration. Personnel responsible for these decisions included emergency department attending physicians and senior pediatric residents. No information on personnel performing or the indication for ET1 could be reliably obtained from this chart review. Dosage recommendations of 0.1 to 0.2 mg/kg/dose for diazepam and 0.05-O. 1 mg/kg/dose for lorazepam were systematically distributed throughout the period of study. Results are expressed as the frequency or mean + standard deviation. Comparisons between treatment groups (lorazepam alone or with phenytoin, diazepam alone or with phenytoin, and either benzodiazepine in combination with phenobarbital) were performed using onefactor analysis of variance for continuous variables (age, weight, duration). Isolation of significant differences between groups was performed using Scheffe’s F test. Chi-square of Fisher’s exact test was performed on nominal variables (etiology, seizure type, frequency of ETI). Significance was considered to be achieved for P < 0.05.

METHODS We performed a retrospective chart review of 142 consecutive cases of children (< 16 years of age), admitted from a single university hospital emergency department (ED) over a 28-month period ending 13 April 1989 with the diagnosis of seizure disorder or status epilepticus. Status epilepticus (SE) was defined as continuous seizure activity for 30 minutes or more, or recurrent seizures without a return to baseline mental status. Records of patients meeting this definition were reviewed for demographics (age, sex, weight), etiology, total seizure duration, seizure type (generalized or focal), anticonvulsant type and dosage, ablation of seizure activity, and the frequency of endotracheal intubation (ETI). Patients who received phenobarbital prior to ET1 were examined as a separated group, since phenobarbital, particularly in combination with the benzodiazepines, may produce profound respiratory depression (20-22). Patients undergoing immediate ETI, prior to anticonvulsant therapy, or not receiving anticonvulsant therapy in the ED were excluded. The influence of chronic anticonvulsant administration on the frequency of ET1 was examined by comparing the frequency of ET1 in those receiving phenobarbital or clonazepam to patients not receiving these agents. Acute management of these children in SE was performed in a standardized fashion Patients were ventilated with a resuscitation bag and mask with supplemental oxygen. After vascular access was established intravenous benzodiazepines were administered over 2 to 3 min per dose until ablation of tonic-clonic activity or transfer of the patient out of the ED. The choice of diazepam or lorazepam administration and ETI was left up to individual physician discretion. No specific recommendations regarding choice of agents were made during the study period. Indications for endotracheal intubation included airway protection, inability to perform adequate bag-mask ventilation, or ongoing respiratory depression. The decision to intubate was based on several factors, includ-

A. Chiulli,

Thomas

E. Terndrup,

Robert

K. Kanter

RESULTS Status epilepticus (SE) was observed in 38 of 142 cases (27%). Of all children in SE, 45% underwent ED ETI. One patient who underwent immediate ET1 and one patient in partial motor SE who received no anticonvulsant therapy in the ED were excluded from further analysis. There was no in-hospital mortality. Ten patients received concominant phenobarbital, along with either lorazepam or diazepam. Patients receiving lorazepam alone or with phenytoin had an ETI rate of 27% (4/15), compared to 73% (8/l 1) in the diazepam alone or with phenytoin group (P = 0.026). After eliminating the 4 cases of focal SE treated with lorazepam, there was still a significant difference in the frequency of ETI in the lorazepam group, 27% (3/11), compared to diazepam, 73% (s/11) (P = 0.043). These two groups were not significantly different in mean age or weight. Seizure type and appropriate anticonvulsant dosage were not significantly different between groups Cumulative preintubation drug dosages for lorazepam 0.14 + 0.09 (mg/kg) and diazepam 0.26 -+ 0.17, were well within recommended dosage limits (Table 1). Seizure activity was ablated prior to leaving the ED in all but two patients. Efficacy was nearly identical in both the diazepam (91%) and lorazepam (93%) groups: each group had one patient who was transferred to the pediatric intensive care unit while still exhibiting intermittent seizure activity.

intikmbon

in Status Epileptiws TaMe 1~ Comparison

of anticonvulsant

Age, yr. (mean it SD.) Weight, kg Type, % generalized Etiology,

groups’

Lorazepam

Diazepam

(n = 45)

(R = 11)

3.9 19 73

+ 2.3 r 7.4

4.6 20 100

t 3.7 z 11

4.2 16 90

2 2.9 L 6.5

NS NS NS

(50) (40) (10) (0) I 472

NS NS NS NS NS

n (“h)

~u~t~era~eutic5 initial seizue Febrile seizure Other Duration, rnln Dosage, nag/kg (% group receiving agent) borazepam Diazepam ~~en~~i~

8 2 3 2 83

(53) (13) (20) (13)

r 70

0.14 + .09 (100) pa,

26

(ii)

2 ($8) 5 (45) 4 (36) (0) 62 f 36

5 4 1 0 253

0.1 (20) 0.24 2 .I2 (80) 10 (2)

Values are expressed as the mean -c SD, number (percent) of patients in each listed graup, each group receiving each anticonvulsant, “Subtherapeuric anticonvulsant level in a patient with an established seizure disorder.

Patients receiving phenobarbital along with either dia~epam or lorazepam had an ETI rate of 40%. The rates of ETI when phenobarbital was combined with diazepam (318; 38%) or loraze$am (l/2; 50%) were not signi~cantl~ different (Table 1)~ The etiology and duration of SE was not significantly different between. the three groups. Thirty seven percent of cases were secondary to subtherapeutic anticonvulsant levels in patients with established seizure disorders, 29% were in those with the initial presentation of a seizure disorder, and 21% for febrile seizures. Seizures were generalized in 49% of cases There were no significant differences in seizure type between groups. The influence of chronic anticonvulsants with respiratory depressive side effects was not found to be significant. Thirty-three percent of patients receiving chronic ~~enob~bital or clonazepam underwent ETI, compared to 44% of those in SE not receiving one of these agents (P = 0.394). Eight of 9 patients receiving chronic anticonvulsant therapy with either phenobarbital (6i6) or clonazepam (X3) had subtherapeutic serum levels.

The frequency of endotracheal intubation (ETI) during status epilepticus (SE) in children who received lorazepam (27%) was significantly lower. compared to those who received diazepam (73%), when either agent was given alone or combined with phenytoin. There were no

and the percent

of pa’~re~ts in

sig~iflca~t differences in age, weight. seizure ~~~at~~n, etiology, or seizure type between ~r~a~~~~t groups. Chronic ad~~is~atio~ of a~ti~~~v~~s~~~s-\n/ith res tory depressive side effects di nat Increase the tiequency of ETI, although 39% of these patients bad snbtherape~tic a~tico~vulsa~t ievels. The overall rate of E than rates observed by o of ET1 during SE sugg 21,23). Mowever, these studies ~~~I~~~~1~~icaII~ stable and unstable patients, adults an cbildre~, use vtious definitions of SE: were from an ra when aBeria1 blood gas analysis or ETI was not routine during SE, and do l-k0 physician experience with ET%. tory depression during tl~~~atme~tof SE is probably more common than ported that over a lo-year peri had a cardiac or respirator tration of hypnotic agents (20). of ET1 frequency during SE al, reported an overall ET1 episodes of childhood SE (1 I) Sba~er et al reported a 33% rate of ETI in 36 adults in E. ~'~rn~~~~~d~a~e~a~ and ~he~ytoi~ to phenobar~ toin (12). The duration of seizure acti.vity was use sure of the severity of seizure activity in this Studies from children demo~s~ate that ~~~~~~eslasting more than 30 minutes result in ~~t~r~t~~~sof bloodbrain barrier and ab~o~al lactate czebros al fluid

16

Donald

lactate-pyruvate ratios suggestive of brain damage (24,25). Studies of bicuculline-induced seizures in baboons demonstrate a series of progressive metabolic acidosis, hypertension followed by hypotension, hyperpyrexia, hypoxemia, increased intracranial pressure, increased creatine phosphokinase leading to renal failure, and an increase in cerebral oxygen consumption leading to ischemia during prolonged seizures (26). Rapid termination of tonic-clonic contractions is desirable to reduce complications during SE (3,6). Unfortunately, the effective first-line anticonvulsants, including the benzodiazepines and barbiturates, may produce profound respiratory depression ( 11,12,2 1) . Some authors have suggested that the morbidity of aggressive management of SE may actually exceed that of the SE itself (45). A reexamination of current recommendations for management of childhood SE may provide insights into reducing complications, particularly those associated with respiratory depression. Both diazepam and lorazepam are similarly effective in ameliorating seizure activity during SE in children and adults. Leppik et al, in a prospective double-blind trial of SE in adults, found adequate seizure control in 89% and 76% of patients treated with lorazepam and diazepam, respectively (10). Other authors have reported similar rates of efficacy for these agents (3,68,10,12-14,19,22,23). While this retrospective study did not provide detailed data to address efficacy, seizure activity was ablated in all but one patient each from the diazepam and the lorazepam groups at the time of departure from the ED. Although both diazepam and lorazepam may cause serious respiratory depression during SE, lorazepam has been found to have minimal effects on respiratory depression (13-19). Lorazepam has been reported to have a low incidence of respiratory depression in a retrospective study of children in SE (14). Diazepam has been cited to cause respiratory depression in SE, particularly in combination with barbiturates (20-22). In the only double-blind prospective trial directly comparing patients treated with diazepam or lorazepam during SE, no significant difference was observed in the occurence of adverse effects, the most common being respiratory depression (10). Only adult patients were enrolled in this study. The results of our study are consistent with the finding that lorazepam has less respiratory depression than diazepam during SE.

Lorazepam is a 3-hydroxyl- 1,4-benzodiazepine, identical in chemical structure to diazepam except for a chloride and hydroxyl substitution on the R2’ and R3 positions, respectively. Both agents rapidly enter the central nervous system after intravenous administration, producing low-frequency (1-5 Hz) electroencephalographic (EEG) activity (27). Lorazepam has a longer duration of seizure and EEG spike-wave suppression (elimination half-life 13 hours) compared to diazepam, making single-agent anticonvulsant administration for SE possible with lorazepam (27). Denaut et al compared the respiratory depression after intravenous lorazepam and diazepam in 20 adults with chronic obstructive lung disease (28), Although both agents caused a mild decrease in minute ventilation, the effects of diazepam lasted longer and resulted in significant hypoxemia. Elliott et al found no significant respiratory or cardiovascular impairment in 15 healthy adults given up to 7.5 mg of lorazepam orally (15). The limitations of this retrospective study are several. The decision to perform ET1 on a seizing child is influenced by several variables that were difficult to examine retrospectively. These include physicians’ experience and skill in performing bag-mask ventilation and their assessments of when to perform ETI. Also, the severity of seizures or rate of anticonvulsant administration may have been different among treatment groups. Since multiple variables influence the decision to perform ETI, including the severity of respiratory depression, a randomized, prospective trial comparing these anticonvulsant medications during childhood SE appears warranted.

A. Chiulli,

Thomas

E. Perndrup,

Roberl

K. Kanter

SUMMARY We found a significantly lower incidence of ET1 during childhood status epilepticus treated with lorazepam (27%) compared to diazepam (73%) when either agent was used alone or with phenytoin. There were no differences between groups in patient characteristics, seizure duration, chronic anticonvulsant administration, or anticonvulsant dosages. This retrospective, pilot study indicates that lorazepam may cause less respiratory depression than diazepam during childhood status epilepticus and may be the preferred initial anticonvulsant agent.

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