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July2008 Vol.45 Issue:      2 Table of Contents
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Electroneurophysiological Monitoring as an Early Severity Predictor in Acute Anticholinesterase Poisoned Patient and the Effect of Oxime Therapy Manipulation

Mahmoud K. Elguindi1, Heba M. Halawa2, Iman M. Bayoumy3

 

Departments of Poison Control Center1, Forensic Medicine and Clinical Toxicology2,

Neurology3, Ain Shams University Hospitals

 



ABSTRACT

Introduction: The neuromuscular transmission failure in acute anticholinesterases (e.g. organophosphorus compounds and carbamates) poisoning occurs because of inactivation of the enzyme acetylcholinesterase located in the neuromuscular junction, and is distinguished by single electrical stimulus induced repetitive responses and decrement response upon high rate repetitive nerve stimulation (RNS). Oxime therapy with its action at different sites in the neuromuscular junction would alter the neuroelectrophysiological findings in acute anticholinesterases poisoning. The aim of this study is to evaluate the usefulness of RNS as a prognostic indicator of severity in acute anticholinesterase poisoning and the recovery process and its use as a guide for oxime therapy continuation or discontinuation. Subjects and Methods: The study was conducted on 32 patients with acute organophosphorus poisoning admitted to the poison control center, Ain Shams University Hospitals during the period from January 2007 to June 2007.Patients were subdivided into group I (mild group n=6), group II (moderate group n=20), and group III (severe group n=6). All the cases were clinically evaluated, pseudocholinesterase levels were estimated and RNS was done before and after oxime therapy. Results: The patients were classified according to the decremental response into 3 categories, type 1 response(initial improvement and subsequent lack of improvement),type 2responce(Initial improvement and subsequent normalization of neuromuscular transmission)and type 3 response (lack of improvement with initial dose of toxogonin). In conclusion RNS is a sensitive prognostic test which can be used as an early predictor of acute anticholinesterase poisoning for grading its severity, and assessment of obidoxime (Toxogonin) therapy. As therapeutic benefit of obidoxime is limited by its short duration of action, it is recommended to be administered for a longer period of time under neuroelectrophysiological guidance. (Egypt J. Neurol. Psychiat. Neurosurg., 2008, 45(2): 443-458)




INTRODUCTION

 

Organophosphorus pesticide self-poisoning is an important clinical problem in rural regions of the developing world, and kills an estimated 200 000 people every year. Unintentional poisoning kills far fewer people but is a problem in places where highly toxic organophosphorus pesticides are available1. The total area of agricultural land in Egypt is around 7.6 million feddans. Working in agricultural field is about 34% of the total employment. Several pesticides including, organochloride, organophosphorus, carbamate, and pyrethroid insecticides, fungicides, and herbicides are commonly used in citrus, vegetable and other crop-growing areas to increase agricultural productivity2.

Anticholinesterases (e.g. organophosphorous (OP) compounds and carbamates) are irreversible inhibitors of the enzyme acetylcholinesterase (AchE), binding of esteratic site of the enzyme. They inhibit both cholinesterase and pseudocholinesterase activity, causing accumulation of acetylcholine (Ach) at synapses with resultant over stimulation of neurotransmission3. The clinical features are due to excess Ach at the muscarinic and nicotinic receptors with initial stimulation, and then exhaustion of cholinergic synapses. There are three phases in Anticholisnesterase toxicity. Acute cholinergic crises (first 48- 72hs), intermediate syndrome (IMS) and delayed polyneuropathy4. The acute cholinergic phase, is the most serious, usually passes off within 48-72hs but complete clinical recovery may take up to a week. Treatment is supportive with oximes, atropine and mechanical ventilation in addition to gastric decontamination5.

Obidoxime is the antidote of choice in cases of Anticholinesterases toxicity. It is known to antagonize the effects of Anticholinesterases at the neuromuscular junction6.

In the present study neuroelectrophysiological monitoring of patients with Anticholinesterases poisoning will be evaluated and the decrement response of patients after oxime therapy will be reported. Electrophysiological monitoring using repetitive nerve Stimulation (RNS) is suggested to predict the clinical outcome of cases of Anticholinesterases poisoning. A number of conflicting studies were found about the neuroelectrophysiologic changes during Anticholinesterases toxicity  reporting decrement response at low frequency (3hz) suggesting a postsynaptic defect7. However, Wadia et al. (1987)8, found no decremental response at low and intermediate frequency (3,10 Hz) but only at high frequency (30Hz). Other studies9,10 showed decrement response at intermediate frequency.

In view of these conflicting studies we designed to study the neuroelectrophysiological changes by using repetitive nerve stimulation (RNS) in patients with anticholinesterases poisoning in an attempt to find out its usefulness as a guide for the treating physician during oxime therapy. The test will be used to predict the severity of poisoning , the duration of therapy, and in addition to assess the development of intermediate syndrome and delayed polyneuropathy.

 

SUBJECTS AND METHODS

 

Subjects:

This study was conducted on 32 patients diagnosed as organophosphate poisoning, admitted in the poison control center, Ain Shams University in the period between January 2007 and June 2007.

 

Methods:

Inclusion Criteria:

(i)         History of oral ingestion or dermal exposure to an Anticholinesterases.

(ii)       Characteristic symptoms and signs of muscarinic and nicotinic stimulation.

(iii)      Reduced level of serum cholinesterase levels (using the calorimetric method).

 

Exclusion Criteria:

(i)         Patients on mechanical ventilation due to difficult transfer of the patients from the poison control center to the neurology department.

(ii)         Other factors that decrease serum cholinesterase levels as pregnancy, hepatic disease, malnutrition and metastatic carcinoma11.

 

Patients were subjected to:

1.             Clinical evaluation:

a.      Complete history taking with special stress on the mode of poisoning and the period between intoxication and hospitalization.

b.      Thorough clinical examination stressing on symptoms and signs of muscarinic and nicotinic stimulation .The patients were examined for any change in the pupil size, vital signs (heart rate, respiration, blood pressure and temperature), skin manifestations. Special focus was done on the neurological manifestations as muscular weakness, easy fatigue, fasciculations, hypotonia, coma and convulsions, in addition to other muscarinic symptoms as salivation lacrimation, bronchorrhea, gastrointestinal and urinary symptoms.

2.             Laboratory investigations:

The level of serum cholinesterase was estimated by using calorimetric method according to Waber12 (normal level 1900-3800 u/l).

3.             Neuroelectrophysiological studies:

         The 2 Mk – conter point – DANTEK amplifier system was used to estimate distal latency, conduction velocity and to perform repetitive nerve stimulation test (RNS) of the median, ulnar, common peroneal and posterior tibial nerves conduction studies. Train of a supramaximal stimuli delivered at 3, 20 and 30 Hz (low, intermediate and high speeds respectively) were used.

RNS test was performed before, 30 minutes after toxogonin intravenous administration and then every 24 hours till recovery or failure of response.

The median compound muscle action potential (MAP) amplitude (base to negative peek). The presence or absence of repetitive response and the ratios of the amplitude of the fifth response to the first  CMAP response during (RNS) at 3, 20 and 30 Hz were noted. This ratio effectively measure the derangement produced by Anticholinesterase toxicity13.

4.             Obidoxime dosage and duration of therapy:

Toxogonin was given to the patients in a dose ranging from 1 to 10 intravenous ampoules, according to clinical response (each ampoule contains 250 mg obidoxime). Neuroelectro-physiological studies were performed before, 30 minutes and then daily after obidoxime intravenous injection. Treatment with further doses of obidoxime depends upon the initial response of the patient. If the initial dose is not associated with any improvement in the decrement response no further doses were given. On the other hand, if the initial dose, produced clinical improvement and decrease in the decremental response, the dose was continued (by i.v drip 750 mg/24h). Daily treatment was continued until neuroelectrophysiological tests failed to demonstrate any benefit of administration of obidoxime or return to normal.

The treatment comprised the coadministration of atropine and obidoxime in an initial dose of 1amp in all patients. Neuroelectrophysiological studies were performed before and after oxime therapy.

 

The patients were classified according to Ellenhorn et al.14 into 3 groups:

-        Group A: Mild poisoning (n=6): The patients had mild cholinergic signs few spontaneous fasciculation and no obvious weakness during the course of illness.

-        Group B: Moderate poisoning (n=20): The patients had miosis, muscular weakness moderate cholinergic symptoms and fasciculation.

-        Group C: Severe poisoning (n=6): The patients had severe weakness, flaccid paralysis, pulmonary crepitations, cyanosis, coma grade I, bradycardia and autonomic disturbances.

Statistical Analysis:

Data collected were tabulated & introduced to PC for statistical analysis. Data analysis were performed using the 11th  version of SPSS (Statistical Package for Social Sciences). Qualitative data is presented in form of frequency tables (number and percent), while quantitative data is presented in the form of mean ± standard deviation. The statistical tests used included independent sample t-test, and Freidman test.

 

RESULTS

 

The studied groups of patients include 14 males and 18 female aged between 6 and 46 years (mean age 20.2 years). All cases were suicidal attempts except one who was accidental poisoning.

The patients were subdivided into three groups according to the severity of clinical findings.

Group A mild poisoning (n=6): The mean pseudocholinesterase level on admission was 970.5±87.3 then increased to 2014.3±361.7 on the 3rd day .The mean delay time was 3.6±2.1 hours and the mean atropinization dose 3.1±1.4 mg.

Group B moderate poisoning (n=20): The mean pseudocholinesterase level  was 318.3±68.4 on admission and increased to 1344.1±217.4 on the 3rd day. The mean delay time was 6.6±3.2hours and the mean atropinization dose 7.1±2.7 mg.

Group C severe poisoning (n=6): The mean pseudocholinesterase level on admission was 188±71.3 and increased to 857.8±95.11 by the 3rd day.

The mean delay time was 7.6±4.2 hours and the mean atropinization dose 18.3±5.9 mg.

 

Clinical Manifestations

Hypothermia was found in 53% of the cases especially in the moderate and severe cases. Hypotension was observed in 44% of the cases especially in the severe cases while hypertension was observed only in 6% of the cases. Also bradycardia was more common than tachycardia being observed in 62.5% of the cases.  Tachypnea and bronchorrhea were more commonly observed than bradypnea being 44%, 37.5% and 28% of the cases respectively. Miosis was observed in 87.5% of the cases. Skin manifestations as pallor and sweating was observed in 47% and 50% of the cases (Table 1).

Neurological manifestations as easy fatigability, weakness, hypotonia and fasciculations were the commonest to be observed especially in the moderate and severe cases while coma and delayed neuropathy were the least to be observed. All patients had nausea, vomiting and diarrhea. Abdominal colic was very common as it occurred in 94% of the cases. The occurrence of Intermediate syndrome with recurrence of cholinergic manifestations was noticed in 16% of the cases with higher incidence in the severe group (Table 2).

 

Neuroelectrophysiological Studies

RNS test was performed for all cases just before, after 30 minutes of  toxogonin initial dose then every 24 hours till recovery .In this study median, ulnar, common peroneal and posterior tibial nerves conduction were studied at 3, 20 and 30 Hz .

The decremental response of the patients was classified into 3 categories according to their initial improvement and /or in response to cholinesterase reactivation by toxogonin.

-        Type 1 response: (Initial improvement and subsequent lack of improvement) was observed in 5 patients who had high decremental responses to high rate stimulation (30 Hz). The decrement responses returned to normal following toxogonin therapy. Toxogonin induced neuroelectrophysiologic improvement during the subsequent 2 days with parallel clinical improvement. On the 3rd day these 5 patients developed recurrence of cholinergic symptoms with increased sweating, salivation and bradycardia (intermediate syndrome). Despite amelioration of the decrement test in 2 cases, toxogonin was given for another 24 hours. On the 4th day of intoxication both clinical deterioration as well as mild increase in decremental response to (30 Hz) RNS were observed (Fig. 4 a, b, c, and d). Therapy with toxogonin was subsequently discontinued.

-        Type 2 response: (Initial improvement and subsequent normalization of neuromuscular transmission) was observed in 23 patients. Initial RNS test revealed characteristic abnormalities in the form of decrement responses first at 30 followed by 20 then 3 HZ, improved after toxogonin therapy. Toxogonin in these cases was continued for another 24-48 hrs and RNS tests continued to improve (Fig. 5 a, b, c, and d). No further doses of toxogonin were given. None of these patients had severe toxicity or required mechanical ventilation. There was good clinical –neurophysiologic concordance. In these cases; fasciculations, muscular weakness and other symptoms which were noted upon clinical examination, disappeared after the initial dose of toxogonin.

-        Type 3 response: (lack of improvement after the first dose) was observed in 4 cases. Initial dose of toxogonin on day 2 and 4 (due to delayed presentation of the patient) failed to produce neurophysiologic amelioration in these cases. The repetitive response persisted and 30 Hz RNS produced mildly worse decrement after therapy. Follow up of these cases revealed delayed polyneuropathy 2-4 weeks later (OPIDN).

 

Assessment of Severity:

Decrement response (decrease in amplitude of the fifth response to the first CMAP during RNS) occurred at the period of severest weakness in each case. In severe cases it was marked at 30 Hz stimulation only with decrement more than 50%. In moderate cases the decrement was marked at the height of their weakness at 3 and 30 Hz stimulation, with decrement (30–50 %). In mild cases no or only slight decremental response (10-30%) was evident at 30 Hz and also at 3 HZ stimulation (Table 3).

The decremental response of the PMAP in moderate cases evolved a consistent fashion during the course of intoxication i.e. the degree of decrement increased or decreased with the respective worsening and improvement of weakness. All the patients reached the maximum decrement 8 – 45 hours after intoxication. At this time the CMAP was abolished after a few stimuli with high frequency stimulation (30 Hz) while at low stimulation (3HZ) only a decline in PMAP occurred. Slow recovery had occurred 24-36 hours later (first low and later high frequencies of stimulation).  It was also noted that the posterior tibial and median nerves showed more mean values of percentage of decremental response than the common peroneal and ulnar nerves (Table 3).

Statistically significant decrease in the percentage of decrement test was noticed 30 minutes after toxogonin treatment, especially in the posterior tibial, median and common peroneal nerves at 30, 20 and 3 Hz stimulation as shown in  table (4).

There was also statistically significant decrease in decrement test 2days and 4 days after toxogonin therapy in the posterior tibial, median and common peroneal nerves at 30,20and 3 Hz stimulation as shown in tables (5) and (6).

Statistical analysis using "Friedman test" to compare the percentage of decrement at 30 Hz before toxogonin, 30 min, day 2 and day 4 after toxogonin in the mild, moderate and severe groups revealed significant improvement in the percentage of decrement test after toxogonin treatment especially in the posterior tibial followed by the median then the ulnar and lastly the common peroneal nerves in the moderate and sever groups (Table 7).

Statistical analysis using "Friedman test" to compare the percentage of decrement at 3 Hz before toxogonin, 30 min, day 2 and day 4 after toxogonin revealed statistically significant improvement in the percentage of decrement test after toxogonin only in the moderate group in (the median, ulnar, common peroneal and posterior tibial nerves). While statistically non significant improvement was observed in the percentage of decrement test after toxogonin in the mild and severe groups at low (3 Hz) stimulation (Table 8).


 

Table 1. Autonomic changes in patients.

 

Clinical manifestation

Mild group

(n=6)

Moderate group (n=20)

Severe group

(n=6)

Total

(n=32)

No.

%

No.

%

No.

%

No.

%

Hypothermia

2

33

10

50

5

83

17

53.1

Hypotension

0

0

8

40

6

100

14

44

Hypertension

0

0

2

10

0

0

2

6

Bradycardia

2

33

12

60

6

100

20

62.5

Tachycardia

0

0

2

10

0

0

2

6

Tachypnea

1

17

8

40

5

83

14

44

Bradypnea

1

17

7

35

1

17

9

28

Bronchorrhea

0

0

7

35

5

83

12

37.5

Miosis

3

50

19

95

6

100

28

87.5

Skin Pallor

1

17

10

50

4

67

15

47

Sweating

1

17

11

55

4

67

16

50

 

Table 2. Neurological and gastrointestinal manifestations among the studied patients.

 

Clinical manifestation

Mild group

(n=6)

Moderate group

(n=20)

Severe group

(n=6)

Total

(n=32)

No.

%

No.

%

No.

%

No.

%

Neurological manifestation

Easy fatigue

6

100

20

100

6

100

32

100

Weakness

0

0

20

100

6

100

26

81

Hypotonia

0

0

20

100

6

100

26

81

Fasciculation

1

17

20

100

6

100

27

84

Coma

0

0

0

0

3

50

3

9

Delayed neuropathy

0

0

2

10

2

33

4

12.5

GIT

Nausea and vomiting

6

100

20

100

6

100

32

100

Abdominal colic

4

66

20

100

6

100

30

94

diarrhea

6

100

20

100

6

100

32

100

Intermediate syndrome

0

0

2

10

3

50

5

16

Table 3. Percentage of decremental response before treatment.

Nerve examined

Frequency of stimulation

Mild group n=6

Moderate group n=20

Severe group n=6

Total

n=32

Mean±SD

Mean±SD

Mean±SD

Mean±SD

Median

3

11.5±0.7

12.3±2.08

29.66±18.5

21.63±16.03

20

29.8±12.27

40.5±4.8

57.75±4.7

41.41±28.85

30

31.5±3.14

48.5±13.9

52.75±2.83

47.90±27.31

Ulnar

3

8±2.30

10±1.41

12 ±2.25

10±1.56

20

15±3.10

25.125±4.729

52±1.4

32.36±24.86

30

24.66±19.73

34.6±12.4

54.33± 4.1

36.43±7.87

Com. per.

3

10±2.80

28.5±20.35

11±1.31

26.44±20.013

20

14.8±3.12

34±1.4

59±4.24

25.5±18.25

30

23±2.8

37.83±11.63

56.5±2.12

32.6±15.46

Post. tib.

3

26.31±11.5

42.42±6.7

69.46±3.9

48.8±32.69

20

27.81±2.59

43.25±3.7

70.33±9.8

45.27±30.62

30

29.25±4.22

45±3.5

79.81±21.75

53.19±34.17

com. per. = common peroneal post. tib. = posterior tibial

 

Table 4. Decrement test before and 30 min. after toxogonin treatment in all cases.

Nerve examined

Frequency of stimulation

Total n=32

T  value

P  value

Before treatment

30 min. after treatment

Median

3

21.63±16.03

19.09±14.83

4.504

0.001

20

41.41±28.85

28.411±17.78

4.055

0.001

30

47.90±27.31

38.09±24.37

9.315

0.000

Ulnar

3

10±1.56

7±1.4

3

0.205

20

32.36±24.86

26.54±23.29

6.375

0.000

30

36.43±7.87

28.56±22.46

3.918

0.001

Com. per.

3

26.44±20.013

21.33±17.44

5.08

0.001

20

25.5±18.25

19.1±14.96

5.358

0.000

30

32.6±15.46

26.6±14.99

4.992

0.001

Post. tib.

3

48.8±32.69

34.75±33.27

2.45

0.032

20

45.27±30.62

36.44±29.8

6.327

0.000

30

53.19±34.17

40.85±30.14

4.236

0.000

P< 0.05 =significant, com. per.=common peroneal post. tib.=posterior tibial

 

Table 5. Decrement test before and 2 days after toxogonin treatment in all cases.

Nerve examined

Frequency of stimulation

Total n=32

T  value

P  value

Before treatment

2 days after treatment

Median

3

21.63±16.03

11.27±8.8

4.504

0.001

20

41.41±28.85

18.11±10.56

3.693

0.002

30

47.90±27.31

29.77±20.9

11.241

0.000

Ulnar

3

10±1.56

5.5±3.5

1.8

0.323

20

32.36±24.86

20.63±19.61

6.243

0.000

30

36.43±7.87

19.75±16.23

4.635

0.000

Com. per.

3

26.44±20.013

16.44±15.82

6.29

0.001

20

25.5±18.25

17.4±19.37

7.727

0.000

30

32.6±15.46

17.6±8.099

6.17

0.000

Post. tib

3

48.8±32.69

24.58±25.67

3.963

0.002

20

45.27±30.62

25.27±19.22

5.572

0.000

30

53.19±34.17

31.38±23.95

5.695

0.000

P< 0.05 =significant, com. per.=common peroneal post. tib.=posterior tibial

 

Table 6. Decrement test before and 4 days after toxogonin treatment in all cases.

 

Nerve examined

Frequency of stimulation

Total n=32

T  value

P  value

Before treatment

4 days  after treatment

Median

3

21.63±16.03

7.36±2.5

3.292

0.008

20

41.41±28.85

12.76±6.4

4.502

0.000

30

47.90±27.31

20.95±13.7

8.808

0.000

Ulnar

3

10±1.56

5.5±0.707

1.9

0.070

20

32.36±24.86

14.9±14.31

5.144

0.0001

30

36.43±7.87

14.31±12.59

4.86

0.0003

Com. per.

3

26.44±20.013

12.44±10.32

6.29

0.000

20

25.5±18.25

10.9±7.6

4.042

0.003

30

32.6±15.46

13.1±7.34

7.187

0.000

Post. tib

3

48.8±32.69

16.66±16.8

4.717

0.001