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Plasma lidocaine levels occurring with endotracheal administration during hemorrhagic shock
Resuscitution, 19 (1990) 291-301 Elsevier Scientific Publishers Ireland Ltd.
291
Plasma lidocaine levels occurring with endotracheal administration during hemorrhagic shock* Sharon E. Mace Department of Emergency Medicine and Division of Investigative Medicine, The Mt. Sinai Medical Center, One Mt. Sinai Drive, Cleveland, OH 44106 (U.S.A.) (Received May lst, 1989; revision received February 14th, 1990; accepted March lst, 1990)
During the many emergency situations in ivhich venous access is difficult or impossible, endotracheal drug administration is an effective alternative means of delivering life-saving medications. Shock is a commonly encountered emergency situation in which endotracheal drug therapy can and is often used. Yet whether a drug given endotracheally during shock can be absorbed from the lungs and pass into the bloodstream is not known. Forty-five sets of plasma lidocaine levels drawn at 5, 15, 30 and 60 min after the administration of endotracheal lidocaine at a dose of 2 or 4 mg/kg were obtained in dogs either in shock or in a normal control group: Group I = “Non-shock” or normal control, N = 27; Group II = “Shock”, N = 18. Significantly higher plasma lidocaine levels occurred in the shock group in all time periods and with either dose of lidocaine (P < 0.081). Mean plasma lidocaine levels @g/ml) at 5 min were: (at 2 mg/kg dose) Group I = 1.1, Group II = 2.0; and (at 4 mg/kg dose) Group I = 2.3, and Group II = 5.1. The dose of lidocaine, the technique of administration, and the time at which the plasma lidocaine level was drawn as well as whether shock vs. non-shock was present were all highly significant factors (P < 0.001) in determining plasma lidocaine levels. In summary: (1) endotracheal lidocaine is absorbed during shock and (2) higher plasma lidocaine levels occur during shock than during the non-shock control state. This suggests that the dosage of endotracheal medication may need to be adjusted for various clinical conditions such as shock. Absorption of endotracheal drugs - Absorption of endotracheai lidocaine - Blood lidocaine levels Endotracheal drug therapy - Endotracheal lidocaine - Hypovolemic shock - Plasma levels of endotracheal drugs - Plasma levels of endotracheal lidocaine - Plasma lidocaine levels - Shock
INTRODUCTION
The endotracheal administration of drugs can be used whenever it is difficult or impossible to quickly achieve an intravenous line needed for giving emergency lifeThere are many clinical conditions such as cardiovascusaving medications [l-4]. lar collapse or shock in which it is frequently impossible to rapidly gain venous access [4-81. Address all correspondence and reprint requests to: Sharon E. Mace, Department of Emergency Medicine, St. Mary’s Hospital, 89 Genesee Street, Rochester, NY 14611, U.S.A. *Supported by a grant from the American Heart Association, Northeast Ohio Chapter. Presented in part at the UAEM Meeting, May 15, 1986, Portland, Oregon. 0300-9572/90/$03.50 0 1990 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
292
There are also several types of patients in whom rapid intravenous access is often difficult [9-l 11. These patients, commonly encountered in emergency situations, include: infants, small children, dialysis patients, multiple trauma patients, burn victims, patients status post-multiple procedures, the markedly obese, and drug abusers [9-l 11. Unfortunately, there is relatively little knowledge abut the use of endotracheal medication in such emergency situations [ 1,12,13]. In this study, plasma lidocaine levels were measured following the endotracheal administration of lidocaine during shock and compared with the results obtained during normal or non-shock conditions in order to determine the effect of hemorrhagic shock on plasma lidocaine levels with endotracheal lidocaine administration. MATERIALS AND METHODS
Fourty-five sets of plasma lidocaine levels, drawn at 5, 15, 30 and 60 min after the administration of endotracheal lidocaine at a dose of 2 or 4 mg/kg, were obtained in 39 dogs either in shock or in a normal control group (Group I = “Non-shock” or normal control, N = 27; Group II = “Shock”, N = 18). Animal preparation Healthy adult mongrel dogs were anesthetized with sodium pentobarbital (30 mg/kg intravenously). Each animal was orally intubated and placed on a volume respirator set at a constant tidal volume of 10 cc/kg and respiratory rate of 20/ min. A femoral artery catheter was placed for continuous blood pressure monitoring and for obtaining arterial blood gas and plasma samples. The arterial blood pressure, electrocardiogram, and heart rate were continuously recorded on an eight-channel oscillograph. A femoral venous catheter was also placed. In Group II (“Shock”), phlebotomy was used to lower the blood pressure to a mean of 50 mmHg. The femoral venous line was connected to a reservoir. Blood was removed or added (via the femoral venous line) in order to maintain the mean arterial blood pressure (BP) at 50 mmHg in the shock group throughout the experiment . All Group II dogs were maintained on a respirator and in hypovolemic shock at a mean BP = 50 mmHg for 1 h before giving the endotracheal lidocaine and during the second hour when the plasma lidocaine samples were being obtained. Likewise, the control group with abnormal BP (Group I) was maintained on the respirator for 1 h before endotracheal lidocaine was given and during the second hour when plasma lidocaine samples were being collected. Laboratory measurements Plasma lidocaine levels. Each dog received a bolus of endotracheal lidocaine in a dose of 2 mg/kg or 4 mg/kg. Plasma lidocaine levels were drawn at 5, 15, 30 and 60 min after administration. Blood samples were obtained in the same manner from all the dogs at all four time periods. The same laboratory methods (using the Syra emit lidocaine assay procedure) [14-201 were routinely performed in the hospital clinical pathology laboratory.
293
Arterial blood gases. Three sets of arterial blood gases (ABGs) were drawn during each of the 45 experiments. ABG No. 1 was drawn at the onset of the experiment, before giving endotracheal lidocaine and before phlebotomy in the shock group. ABG No. 2 was drawn after 1 h of shock if in Group II (“Shock”) or after a l-h control period if in Group I (“Non-shock”). This was just prior to giving the endotracheal lidocaine. ABG No. 3 was drawn at the end of the experiment after obtaining the last plasma lidocaine sample or 60 min after giving the endotracheal lidocaine and 2 h after beginning the experiment. Endotracheai drug administration. In all the dogs, endotracheal lidocaine was given in an identical manner by one of the five techniques [21-231. The endotracheal lidocaine was always given as a rapid bolus injection immediately followed by five insufflations in 5 s with a manual bag ventilation device [24]. The technique of administration of endotracheal lidocaine followed that described previously [21-231. Lidocaine was injected: (1) from a syringe directly into the endotracheal tube (“syringe” technique); (2) from a syringe with a 13gauge spinal needle attached to the syringe (“needle” technique); (3) from a syringe (no needle attached) after mixing the lidocaine in a 1:l dilution with normal saline (“Dilution” Technique); (4) from a syringe into a long catheter placed inside and extending just beyond the end of the endotracheal tube (“Catheter” Technique); and (5) from a syringe immediately followed by an equal bolus of normal saline (NS) in a second syringe (“NS Follow-up” Technique). All the dogs received a lidocaine dose of 2 or 4 mg/kg. Twenty-one dogs received a 2 mg/kg dosage including 12 dogs in Group I (“Non-shock”) and nine dogs in Group II (“Shock”). In 24 dogs, a 4 mg/kg dose was used with 15 in the Non-shock Group and nine in the Shock Group. Serial studies. Serial studies were obtained in six dogs. Each dog was given a 4 mg/kg dose of lidocaine endotracheally while in a normal or non-shock condition. Then 1 week later the same dog was given an identical dose of endotracheal lidoCaine by the same technique, but now the dog was in hypovolemic shock. Pathology At the end of the experiment the thoracic cage was opened, gross pathology was done, then multiple histological sections were taken from all sections of all lobes of the lung. The dog lung has 12 lobules and multiple histology slides were made from each lobule of the lung to ensure adequate samples. Statistical analysis. Statistical analysis included Student’s r-test and analysis of variance [25-321. Multivariate analysis allowed us to determine the simultaneous effects of multiple variables including: clinical condition - e.g. shock vs. nonshock, lidocaine dose, time, technique, arterial blood gases (pH, PO,, HCO,, oxygen saturation), and plasma lidocaine levels [25-321. RESULTS
Piasma lidocaine levels The highest plasma lidocaine levels were obtained in the shock group at all four time periods (5, 15, 30 and 60 min) and with either dose of lidocaine (2 or 4 mg/
294 Table 1. Plasma lidocaine levels &g/ml} (mean -C S.E.M.) as a function of clinical condition (nonshock vs. shock and time).
Time (min)
1A. Dose = 2 mg/kg Non-shock (N = 12 dogs) Shock (N = 9 dogs) 1B. Dose = 4 mglkg Non-shock (N = 1.5dogs) Shock (N = 9 dogs)
5
15
30
60
1.12 (t0.5) 2.0 (zt 0.5)
0.90 ( & 0.03) 1.2 (S 0.4)
0.13 (*o.l) 0.62 (f 0.3)
0.11 (20.1) 0.31 (*0.1)
2.31 ( f 0.5)
1.03 (kO.3) 3.2 ( * 0.7)
0.46 (20.1) 1.8 ( -t 0.4)
0.18 (20.1) 0.86 (kO.2)
:: 1.1)
Plasma lidocaine levels @g/ml) (mean & S.E.M.) as a function of clinical condition (nonTable II. shock vs. shock), time and, technique of endotracheaf lidocaine administration. Time (min) 15
30
60
A. Endotracheal lidocaine dose = 2 mg/kg Non-shock (N = 12) Syringe (N = 5) 0.64 ( 2 0.3) Needle (iV = 4) 0.0 (&O.O) Dilution (N = 3) 3.4 (20.5)
0.5 (*0.2) 0.0 (*O*O) 0.9 (kO.3)
0 (.cO.O) 0.0 (iO.0)
0 (*O.O) 0.0 (1:O.O)
0.13(+o.l)
0.11 (zkO.1)
Shock (N = 9) Syringe(N = 4) Needle (N = 3) Dilution (N t 1) NS Flush (N = I)
2.2 (*O*S) 0.5 (20.4) 3.5 4.3
0.73 (+ 0.3) 0.37 ( f 0.2) 2.5 4.1
0.28 ( -c 0.2) 0 f&0.0) 2.0 2.5
0 (*0.0) 0.0 (kO.0) I.5 1.3
B. Endotracheal lidocaine dose = 4 mg/kg Non-shock (N = 15) 1.9 (k0.S) Syringe (N = 5) Needle (N = 3) 0.55 ( f 0.4) 6.15(*2.1) Dilution (N E 2) Tube (N = 4) 1.9 (kO.6) 1.85(*0.2) NS Flush (N = 2)
1.2 (kO.5) 0 (*o.o) 3.0 (kl.3) 0.25 (+ 0.2) 1.2 (kO.1)
0.68 ( f 0.4) 0 (*O*O) 1.2 (20.2) 0 (20.0) 0.50 ( f 0.3)
0.30 0.0 0.6 0 0
Shock (N = 9) Syringe (N = 4) Needle (N = 1) Dilution (N = 1) Tube (N = 2) NS Flush (N = 1)
2.4 (ir0.7) 4.9 8.2 1.7 (kO.4) 2.5
1.9 (* 1.2) 2.8 3.2 0.55 (1+.0.3) 1.3
1.1 (ztO.4) 1.4 1.6 0 (&O.O) 0
5
3.6 (+l.l) 6.2 12.4 2.7 (2 1.1) 7.7
N = Number of dogs in that group. NS = Normal saline.
( + 0.2) (rO.O) (kO.4) (*O.O) (kO.0)
295
Table III. Serial studies. Plasma lidocaine levels @/ml) following endotracheal lidocaine administration of 4 mg/kg in six dogs during non-shock and shock conditions. Each dog served as its own control. The technique of administration used in each individual dog is listed in parentheses.
Time (min)
Dog 1 (Syringe) Dog 2 (Needle) Dog 3 (Dilution) Dog 4 (Tube) Dog 5 (Tube) Dog 6 (NS Plush)
Non-shock Shock Non-shock Shock Non-shock Shock Non-shock Shock Non-shock Shock Non-shock Shock
Mean
Non-shock
( f S.E.M.)
(All 6 dogs)
Shock
5
15
30
60
1.1 5.9 1.1 6.2 3.1 12.4 1.1 1.4 1.0 4.3 2.2 7.1
1.4 2.1 1.0 4.9 1.2 8.2 0.0 1.0 1.0 2.3 1.1 2.5
0.0
0.0
2.0 0.0 3.2 1.0 2.8 0.0 0.0 0.0 1.1 0.0 1.3
1.0 0.0 1.6 0.0 1.4 0.0 0.0 0.0 0.0 0.0 0.0
0.95 (20.18)
0.17 (eo.1) 1.731 (+ 4.47)
0.0 (kO.0) 0.67* (kO.18)
(ki.32) 6.32’ (* 1.37)
*Significant at P< 0.05 by paired Student’s t-test.
kg) (Tables I-III, Figs. 1,2) and no matter what the technique of endotracheal administration was (Tables II and III). These results were all highly significant at P < 0.001 (Table V). Similarly, in the serial studies, all six dogs had significantly higher plasma lidoCaine levels (P < 0.05) at all four time periods when in shock than when in a normal “non-shock” condition (Table III, Fig. 2). Arterial blood gases For the non-shock group, there was no significant difference in arterial blood gases (ABG No. 1, ABG No. 2, ABG No. 3) at either the 2 or 4 mg/kg dose. For the shock group, there was a significant difference between ABG No. 1 and ABG No. 2 or ABG No. 3 in pH, PCO, and bicarbonate (P< 0.05) (Table IV). Pathology Pathology, both gross and microscopic, confirmed the presence of normal lungs in the Group I (Non-shock) dogs and abnormal “shock lung” in the Group II (Hemorrhagic Shock) dogs. DISCUSSION
The study indicates that an endotracheal drug can be absorbed during hemorrhagic shock. Even during hemorrhagic shock, lidocaine given endotracheally is absorbed, reached a detectable and even “therapeutic” level. This is true for either
@ Shock
. 1.5 =
.E P 2 2 ,_m=
A
a 0.5 E : iE
.
.
Dose Pmglkg
.
.. ‘9
x
f : ._ CQ ”
5
II Nonshock .
‘I
-. . -*.
\ \
‘.
\
.
.
\ \ -a. . . . ... \
.
’
. *
\
‘e
\
Time (mid
??Shock a Nonshock
.
Dose 4mglkg
.
“V
Time (mid Fig. 1. Mean plasma lidocaine level &/ml) as a function of time. 2A Endotracheal lidocaine dose t 2 mg/kg. 2B Endotracheal lidocaine dose = 4 m&kg.
297
DOG 6 ??=
10.
Shock O=No Shock
-\ I. . 30p 0515
-
\
\
_-T--
60
5 15
30
60
5 15
30
60
Time, Minutes Fig. 2. Serial studies. Mean plasma lidocaine levels over time for the six dogs. Each dog served as its own control: non-shock vs. shock. The technique of endotracheal administration is listed for each dog. Endotracheal lidocaine dose = 4 mg/kg for every dog and every experiment. Panel A = Dog 1 (Syringe), Panel B = Dog 2 (Needle), Panel 3 = Dog 3 (Dilution), Panel 4 = Dog 4 (Tube), Panel 5 = Dog 5 (Tube), Panel 6 = Dog 6 Normal Saline (Flush).
dose of lidocaine (2 or 4 mg/kg) and no matter what the technique of endotracheal administration is. Furthermore, higher plasma lidocaine levels following endotracheal lidocaine administration occur during shock than with the normal non-shock condition and may even reach “toxic” levels. Endotracheal drug therapy has been recommended as an alternative method of administering emergency drugs whenever venous access is difficult or impossible [l-4]. Shock is a common emergency situation in which endotracheal administration of drugs is likely to be used, yet the effects of endotracheal drug therapy during shock has not been fully investigated [12,13]. Our results agree with an earlier study using a different drug, Epinephrine, in anaphylactic shock which found that Epinephrine was effective even during anaphylactic shock [36]. The factor(s) responsible for the differences between the lidocaine levels in the two clinical conditions remains to be elucidated. However, many possibilities exist. These include: (1) -altered drug kinetics; (2) changes in alveolar capillary membranes and differences in absorption from the lungs; (3) variations in metabolism of lidocaine by the liver; (4) difference in binding of the drug to serum proteins; (5)
298 Table IV. Arterial blood gases (ABG) as a function of time and clinical state (e.g. shock vs. nonshock). Mean ( f S.E.M.) is listed.
Dose 2 mg/kg
ABG No. 1
ABG No.2
ABG No. 3
Non-shock PH PO, Pco, HCO, Oxygen saturation (%)
7.32 (+ 0.03) 91(25.1) 39.9 (f 2.5) 20.1 (+ 0.9) 96.0% (+ 2.1)
7.31 (kO.03) 97(zt5.4) 36.6(+3.0) 17.9(zbO.9) 98.8% (& 2.0)
7.31 (+ 0.03) 94 (+ 5.2) 38.3 (+ 2.7) 19 ( f 0.9) 97.2% (2 2.1)
Shock PH PO* Pco, HCO, Oxygen saturation (To)
7.26 ( f 0.04) 93.3 ( f 9.4) 46.3(*6.1) 19.4(& 1.1) 98.1%(+6.5)
7.22 (+ 0.03) 94.8 (+ 5.4) 36.2 (+ 2.5) 14.6 ( f 0.5) 97.0% (+ 2.8)
7.21 (+ 0.04) 93.6(+4.7) 3 1.4 ( f 4.7) 12 (f 0.6) 98.9% ( f 1.9)
PH PO, HCO, Oxygen saturation (W)
7.34 ( + 1.O) 93.4 (+ 4.0) 22.1 (+ 1.8) 95.4% (f 1.5)
7.38 (+ 0.01) 94.9 (f 2.4) 39.7 (+ 1.6) 97.4% (2 1.1)
7.36 ( f 0.06) 94.2(*3.1) 40.9 ( f 1.7) 96.9% ( f 1.3)
Shock PH PO* Pco, HCO, Oxygen saturation (o/o)
7.36(+0.02) 90(+4.0) 37.8(rt 1.9) 20.8 ( f 0.9) 93.0% (f 1.1)
7.30 (+ 0.16) 93.7 ( f 4.2) 25.9(* 1.6) 12.7(+ 1.1) 94.0% ( f 0.8)
7.24 (+ 0.04) 97.8 ( f 4.4) 23.8 ( + 1.9) 10.5 (f 1.3) 98.9% ( f 1.O)
Dose 4 mg/kg
changes in tissue extraction as well as other variables. The kinetics of an endotracheal drug may be altered during various clinical conditions such as shock. The absorption of drugs from the respiratory tract probably involves diffusion across a gradient from a higher concentration [37-401. Thus, movement of the drug molecules from the intra-alveolar space to the pulmonary capillaries could occur. It has been theorized that this process would be affected by pulmonary disease
Table V.
Analysis of variance of the plasma lidocaine levels.
Criteria
Mean square
F ratio
P-value
Shock Dose Technique Time Plasma lidocaine level
383 393 858 128,700 220
1,307 1,624 477 295 77
0.001* 0.001* 0.001+ 0.001* 0.0012
The degrees of freedom for all the criteria are 1174. *Significant at P< 0.001.
299
[13]. The alveolar capillary membrane is affected during shock (“shock lung”) [41 -431. During this condition of increased permeability with “shock lung”, it is possible that more of a drug given endotracheally could diffuse or move across the alveolar-capillary membrane than during the normal non-shock state. This would result in increased absorption of the endotracheal drug and higher plasma levels. Shock lung can occur with hemorrhagic shock and can occur early during the shock state [2]. In summary, this study suggests: (1) detectable plasma lidocaine levels occur following endotracheal administration of lidocaine even during the pathologic condition of hemorrhagic shock; (2) higher plasma lidocaine levels occur in the shock vs. non-shock state; and (3) this occurs no matter what the dose and/or the technique of endotracheal administration. ACKNOWLEDGEMENTS
We would like to thank Dr. Jerome Bernstein, Chairman, Pathology Department, which confirmed normal lungs in the Group I (Non-shock animals) and “Classic” shock lung in the Group II (Hypovolemic Shock) animals by both gross pathology and histology, and the Respiratory Therapy Department for their assistance in doing the arterial blood gases. REFERENCES 1
6 7 8 9 10 11 12 13 14
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291
Plasma lidocaine levels occurring with endotracheal administration during hemorrhagic shock* Sharon E. Mace Department of Emergency Medicine and Division of Investigative Medicine, The Mt. Sinai Medical Center, One Mt. Sinai Drive, Cleveland, OH 44106 (U.S.A.) (Received May lst, 1989; revision received February 14th, 1990; accepted March lst, 1990)
During the many emergency situations in ivhich venous access is difficult or impossible, endotracheal drug administration is an effective alternative means of delivering life-saving medications. Shock is a commonly encountered emergency situation in which endotracheal drug therapy can and is often used. Yet whether a drug given endotracheally during shock can be absorbed from the lungs and pass into the bloodstream is not known. Forty-five sets of plasma lidocaine levels drawn at 5, 15, 30 and 60 min after the administration of endotracheal lidocaine at a dose of 2 or 4 mg/kg were obtained in dogs either in shock or in a normal control group: Group I = “Non-shock” or normal control, N = 27; Group II = “Shock”, N = 18. Significantly higher plasma lidocaine levels occurred in the shock group in all time periods and with either dose of lidocaine (P < 0.081). Mean plasma lidocaine levels @g/ml) at 5 min were: (at 2 mg/kg dose) Group I = 1.1, Group II = 2.0; and (at 4 mg/kg dose) Group I = 2.3, and Group II = 5.1. The dose of lidocaine, the technique of administration, and the time at which the plasma lidocaine level was drawn as well as whether shock vs. non-shock was present were all highly significant factors (P < 0.001) in determining plasma lidocaine levels. In summary: (1) endotracheal lidocaine is absorbed during shock and (2) higher plasma lidocaine levels occur during shock than during the non-shock control state. This suggests that the dosage of endotracheal medication may need to be adjusted for various clinical conditions such as shock. Absorption of endotracheal drugs - Absorption of endotracheai lidocaine - Blood lidocaine levels Endotracheal drug therapy - Endotracheal lidocaine - Hypovolemic shock - Plasma levels of endotracheal drugs - Plasma levels of endotracheal lidocaine - Plasma lidocaine levels - Shock
INTRODUCTION
The endotracheal administration of drugs can be used whenever it is difficult or impossible to quickly achieve an intravenous line needed for giving emergency lifeThere are many clinical conditions such as cardiovascusaving medications [l-4]. lar collapse or shock in which it is frequently impossible to rapidly gain venous access [4-81. Address all correspondence and reprint requests to: Sharon E. Mace, Department of Emergency Medicine, St. Mary’s Hospital, 89 Genesee Street, Rochester, NY 14611, U.S.A. *Supported by a grant from the American Heart Association, Northeast Ohio Chapter. Presented in part at the UAEM Meeting, May 15, 1986, Portland, Oregon. 0300-9572/90/$03.50 0 1990 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
292
There are also several types of patients in whom rapid intravenous access is often difficult [9-l 11. These patients, commonly encountered in emergency situations, include: infants, small children, dialysis patients, multiple trauma patients, burn victims, patients status post-multiple procedures, the markedly obese, and drug abusers [9-l 11. Unfortunately, there is relatively little knowledge abut the use of endotracheal medication in such emergency situations [ 1,12,13]. In this study, plasma lidocaine levels were measured following the endotracheal administration of lidocaine during shock and compared with the results obtained during normal or non-shock conditions in order to determine the effect of hemorrhagic shock on plasma lidocaine levels with endotracheal lidocaine administration. MATERIALS AND METHODS
Fourty-five sets of plasma lidocaine levels, drawn at 5, 15, 30 and 60 min after the administration of endotracheal lidocaine at a dose of 2 or 4 mg/kg, were obtained in 39 dogs either in shock or in a normal control group (Group I = “Non-shock” or normal control, N = 27; Group II = “Shock”, N = 18). Animal preparation Healthy adult mongrel dogs were anesthetized with sodium pentobarbital (30 mg/kg intravenously). Each animal was orally intubated and placed on a volume respirator set at a constant tidal volume of 10 cc/kg and respiratory rate of 20/ min. A femoral artery catheter was placed for continuous blood pressure monitoring and for obtaining arterial blood gas and plasma samples. The arterial blood pressure, electrocardiogram, and heart rate were continuously recorded on an eight-channel oscillograph. A femoral venous catheter was also placed. In Group II (“Shock”), phlebotomy was used to lower the blood pressure to a mean of 50 mmHg. The femoral venous line was connected to a reservoir. Blood was removed or added (via the femoral venous line) in order to maintain the mean arterial blood pressure (BP) at 50 mmHg in the shock group throughout the experiment . All Group II dogs were maintained on a respirator and in hypovolemic shock at a mean BP = 50 mmHg for 1 h before giving the endotracheal lidocaine and during the second hour when the plasma lidocaine samples were being obtained. Likewise, the control group with abnormal BP (Group I) was maintained on the respirator for 1 h before endotracheal lidocaine was given and during the second hour when plasma lidocaine samples were being collected. Laboratory measurements Plasma lidocaine levels. Each dog received a bolus of endotracheal lidocaine in a dose of 2 mg/kg or 4 mg/kg. Plasma lidocaine levels were drawn at 5, 15, 30 and 60 min after administration. Blood samples were obtained in the same manner from all the dogs at all four time periods. The same laboratory methods (using the Syra emit lidocaine assay procedure) [14-201 were routinely performed in the hospital clinical pathology laboratory.
293
Arterial blood gases. Three sets of arterial blood gases (ABGs) were drawn during each of the 45 experiments. ABG No. 1 was drawn at the onset of the experiment, before giving endotracheal lidocaine and before phlebotomy in the shock group. ABG No. 2 was drawn after 1 h of shock if in Group II (“Shock”) or after a l-h control period if in Group I (“Non-shock”). This was just prior to giving the endotracheal lidocaine. ABG No. 3 was drawn at the end of the experiment after obtaining the last plasma lidocaine sample or 60 min after giving the endotracheal lidocaine and 2 h after beginning the experiment. Endotracheai drug administration. In all the dogs, endotracheal lidocaine was given in an identical manner by one of the five techniques [21-231. The endotracheal lidocaine was always given as a rapid bolus injection immediately followed by five insufflations in 5 s with a manual bag ventilation device [24]. The technique of administration of endotracheal lidocaine followed that described previously [21-231. Lidocaine was injected: (1) from a syringe directly into the endotracheal tube (“syringe” technique); (2) from a syringe with a 13gauge spinal needle attached to the syringe (“needle” technique); (3) from a syringe (no needle attached) after mixing the lidocaine in a 1:l dilution with normal saline (“Dilution” Technique); (4) from a syringe into a long catheter placed inside and extending just beyond the end of the endotracheal tube (“Catheter” Technique); and (5) from a syringe immediately followed by an equal bolus of normal saline (NS) in a second syringe (“NS Follow-up” Technique). All the dogs received a lidocaine dose of 2 or 4 mg/kg. Twenty-one dogs received a 2 mg/kg dosage including 12 dogs in Group I (“Non-shock”) and nine dogs in Group II (“Shock”). In 24 dogs, a 4 mg/kg dose was used with 15 in the Non-shock Group and nine in the Shock Group. Serial studies. Serial studies were obtained in six dogs. Each dog was given a 4 mg/kg dose of lidocaine endotracheally while in a normal or non-shock condition. Then 1 week later the same dog was given an identical dose of endotracheal lidoCaine by the same technique, but now the dog was in hypovolemic shock. Pathology At the end of the experiment the thoracic cage was opened, gross pathology was done, then multiple histological sections were taken from all sections of all lobes of the lung. The dog lung has 12 lobules and multiple histology slides were made from each lobule of the lung to ensure adequate samples. Statistical analysis. Statistical analysis included Student’s r-test and analysis of variance [25-321. Multivariate analysis allowed us to determine the simultaneous effects of multiple variables including: clinical condition - e.g. shock vs. nonshock, lidocaine dose, time, technique, arterial blood gases (pH, PO,, HCO,, oxygen saturation), and plasma lidocaine levels [25-321. RESULTS
Piasma lidocaine levels The highest plasma lidocaine levels were obtained in the shock group at all four time periods (5, 15, 30 and 60 min) and with either dose of lidocaine (2 or 4 mg/
294 Table 1. Plasma lidocaine levels &g/ml} (mean -C S.E.M.) as a function of clinical condition (nonshock vs. shock and time).
Time (min)
1A. Dose = 2 mg/kg Non-shock (N = 12 dogs) Shock (N = 9 dogs) 1B. Dose = 4 mglkg Non-shock (N = 1.5dogs) Shock (N = 9 dogs)
5
15
30
60
1.12 (t0.5) 2.0 (zt 0.5)
0.90 ( & 0.03) 1.2 (S 0.4)
0.13 (*o.l) 0.62 (f 0.3)
0.11 (20.1) 0.31 (*0.1)
2.31 ( f 0.5)
1.03 (kO.3) 3.2 ( * 0.7)
0.46 (20.1) 1.8 ( -t 0.4)
0.18 (20.1) 0.86 (kO.2)
:: 1.1)
Plasma lidocaine levels @g/ml) (mean & S.E.M.) as a function of clinical condition (nonTable II. shock vs. shock), time and, technique of endotracheaf lidocaine administration. Time (min) 15
30
60
A. Endotracheal lidocaine dose = 2 mg/kg Non-shock (N = 12) Syringe (N = 5) 0.64 ( 2 0.3) Needle (iV = 4) 0.0 (&O.O) Dilution (N = 3) 3.4 (20.5)
0.5 (*0.2) 0.0 (*O*O) 0.9 (kO.3)
0 (.cO.O) 0.0 (iO.0)
0 (*O.O) 0.0 (1:O.O)
0.13(+o.l)
0.11 (zkO.1)
Shock (N = 9) Syringe(N = 4) Needle (N = 3) Dilution (N t 1) NS Flush (N = I)
2.2 (*O*S) 0.5 (20.4) 3.5 4.3
0.73 (+ 0.3) 0.37 ( f 0.2) 2.5 4.1
0.28 ( -c 0.2) 0 f&0.0) 2.0 2.5
0 (*0.0) 0.0 (kO.0) I.5 1.3
B. Endotracheal lidocaine dose = 4 mg/kg Non-shock (N = 15) 1.9 (k0.S) Syringe (N = 5) Needle (N = 3) 0.55 ( f 0.4) 6.15(*2.1) Dilution (N E 2) Tube (N = 4) 1.9 (kO.6) 1.85(*0.2) NS Flush (N = 2)
1.2 (kO.5) 0 (*o.o) 3.0 (kl.3) 0.25 (+ 0.2) 1.2 (kO.1)
0.68 ( f 0.4) 0 (*O*O) 1.2 (20.2) 0 (20.0) 0.50 ( f 0.3)
0.30 0.0 0.6 0 0
Shock (N = 9) Syringe (N = 4) Needle (N = 1) Dilution (N = 1) Tube (N = 2) NS Flush (N = 1)
2.4 (ir0.7) 4.9 8.2 1.7 (kO.4) 2.5
1.9 (* 1.2) 2.8 3.2 0.55 (1+.0.3) 1.3
1.1 (ztO.4) 1.4 1.6 0 (&O.O) 0
5
3.6 (+l.l) 6.2 12.4 2.7 (2 1.1) 7.7
N = Number of dogs in that group. NS = Normal saline.
( + 0.2) (rO.O) (kO.4) (*O.O) (kO.0)
295
Table III. Serial studies. Plasma lidocaine levels @/ml) following endotracheal lidocaine administration of 4 mg/kg in six dogs during non-shock and shock conditions. Each dog served as its own control. The technique of administration used in each individual dog is listed in parentheses.
Time (min)
Dog 1 (Syringe) Dog 2 (Needle) Dog 3 (Dilution) Dog 4 (Tube) Dog 5 (Tube) Dog 6 (NS Plush)
Non-shock Shock Non-shock Shock Non-shock Shock Non-shock Shock Non-shock Shock Non-shock Shock
Mean
Non-shock
( f S.E.M.)
(All 6 dogs)
Shock
5
15
30
60
1.1 5.9 1.1 6.2 3.1 12.4 1.1 1.4 1.0 4.3 2.2 7.1
1.4 2.1 1.0 4.9 1.2 8.2 0.0 1.0 1.0 2.3 1.1 2.5
0.0
0.0
2.0 0.0 3.2 1.0 2.8 0.0 0.0 0.0 1.1 0.0 1.3
1.0 0.0 1.6 0.0 1.4 0.0 0.0 0.0 0.0 0.0 0.0
0.95 (20.18)
0.17 (eo.1) 1.731 (+ 4.47)
0.0 (kO.0) 0.67* (kO.18)
(ki.32) 6.32’ (* 1.37)
*Significant at P< 0.05 by paired Student’s t-test.
kg) (Tables I-III, Figs. 1,2) and no matter what the technique of endotracheal administration was (Tables II and III). These results were all highly significant at P < 0.001 (Table V). Similarly, in the serial studies, all six dogs had significantly higher plasma lidoCaine levels (P < 0.05) at all four time periods when in shock than when in a normal “non-shock” condition (Table III, Fig. 2). Arterial blood gases For the non-shock group, there was no significant difference in arterial blood gases (ABG No. 1, ABG No. 2, ABG No. 3) at either the 2 or 4 mg/kg dose. For the shock group, there was a significant difference between ABG No. 1 and ABG No. 2 or ABG No. 3 in pH, PCO, and bicarbonate (P< 0.05) (Table IV). Pathology Pathology, both gross and microscopic, confirmed the presence of normal lungs in the Group I (Non-shock) dogs and abnormal “shock lung” in the Group II (Hemorrhagic Shock) dogs. DISCUSSION
The study indicates that an endotracheal drug can be absorbed during hemorrhagic shock. Even during hemorrhagic shock, lidocaine given endotracheally is absorbed, reached a detectable and even “therapeutic” level. This is true for either
@ Shock
. 1.5 =
.E P 2 2 ,_m=
A
a 0.5 E : iE
.
.
Dose Pmglkg
.
.. ‘9
x
f : ._ CQ ”
5
II Nonshock .
‘I
-. . -*.
\ \
‘.
\
.
.
\ \ -a. . . . ... \
.
’
. *
\
‘e
\
Time (mid
??Shock a Nonshock
.
Dose 4mglkg
.
“V
Time (mid Fig. 1. Mean plasma lidocaine level &/ml) as a function of time. 2A Endotracheal lidocaine dose t 2 mg/kg. 2B Endotracheal lidocaine dose = 4 m&kg.
297
DOG 6 ??=
10.
Shock O=No Shock
-\ I. . 30p 0515
-
\
\
_-T--
60
5 15
30
60
5 15
30
60
Time, Minutes Fig. 2. Serial studies. Mean plasma lidocaine levels over time for the six dogs. Each dog served as its own control: non-shock vs. shock. The technique of endotracheal administration is listed for each dog. Endotracheal lidocaine dose = 4 mg/kg for every dog and every experiment. Panel A = Dog 1 (Syringe), Panel B = Dog 2 (Needle), Panel 3 = Dog 3 (Dilution), Panel 4 = Dog 4 (Tube), Panel 5 = Dog 5 (Tube), Panel 6 = Dog 6 Normal Saline (Flush).
dose of lidocaine (2 or 4 mg/kg) and no matter what the technique of endotracheal administration is. Furthermore, higher plasma lidocaine levels following endotracheal lidocaine administration occur during shock than with the normal non-shock condition and may even reach “toxic” levels. Endotracheal drug therapy has been recommended as an alternative method of administering emergency drugs whenever venous access is difficult or impossible [l-4]. Shock is a common emergency situation in which endotracheal administration of drugs is likely to be used, yet the effects of endotracheal drug therapy during shock has not been fully investigated [12,13]. Our results agree with an earlier study using a different drug, Epinephrine, in anaphylactic shock which found that Epinephrine was effective even during anaphylactic shock [36]. The factor(s) responsible for the differences between the lidocaine levels in the two clinical conditions remains to be elucidated. However, many possibilities exist. These include: (1) -altered drug kinetics; (2) changes in alveolar capillary membranes and differences in absorption from the lungs; (3) variations in metabolism of lidocaine by the liver; (4) difference in binding of the drug to serum proteins; (5)
298 Table IV. Arterial blood gases (ABG) as a function of time and clinical state (e.g. shock vs. nonshock). Mean ( f S.E.M.) is listed.
Dose 2 mg/kg
ABG No. 1
ABG No.2
ABG No. 3
Non-shock PH PO, Pco, HCO, Oxygen saturation (%)
7.32 (+ 0.03) 91(25.1) 39.9 (f 2.5) 20.1 (+ 0.9) 96.0% (+ 2.1)
7.31 (kO.03) 97(zt5.4) 36.6(+3.0) 17.9(zbO.9) 98.8% (& 2.0)
7.31 (+ 0.03) 94 (+ 5.2) 38.3 (+ 2.7) 19 ( f 0.9) 97.2% (2 2.1)
Shock PH PO* Pco, HCO, Oxygen saturation (To)
7.26 ( f 0.04) 93.3 ( f 9.4) 46.3(*6.1) 19.4(& 1.1) 98.1%(+6.5)
7.22 (+ 0.03) 94.8 (+ 5.4) 36.2 (+ 2.5) 14.6 ( f 0.5) 97.0% (+ 2.8)
7.21 (+ 0.04) 93.6(+4.7) 3 1.4 ( f 4.7) 12 (f 0.6) 98.9% ( f 1.9)
PH PO, HCO, Oxygen saturation (W)
7.34 ( + 1.O) 93.4 (+ 4.0) 22.1 (+ 1.8) 95.4% (f 1.5)
7.38 (+ 0.01) 94.9 (f 2.4) 39.7 (+ 1.6) 97.4% (2 1.1)
7.36 ( f 0.06) 94.2(*3.1) 40.9 ( f 1.7) 96.9% ( f 1.3)
Shock PH PO* Pco, HCO, Oxygen saturation (o/o)
7.36(+0.02) 90(+4.0) 37.8(rt 1.9) 20.8 ( f 0.9) 93.0% (f 1.1)
7.30 (+ 0.16) 93.7 ( f 4.2) 25.9(* 1.6) 12.7(+ 1.1) 94.0% ( f 0.8)
7.24 (+ 0.04) 97.8 ( f 4.4) 23.8 ( + 1.9) 10.5 (f 1.3) 98.9% ( f 1.O)
Dose 4 mg/kg
changes in tissue extraction as well as other variables. The kinetics of an endotracheal drug may be altered during various clinical conditions such as shock. The absorption of drugs from the respiratory tract probably involves diffusion across a gradient from a higher concentration [37-401. Thus, movement of the drug molecules from the intra-alveolar space to the pulmonary capillaries could occur. It has been theorized that this process would be affected by pulmonary disease
Table V.
Analysis of variance of the plasma lidocaine levels.
Criteria
Mean square
F ratio
P-value
Shock Dose Technique Time Plasma lidocaine level
383 393 858 128,700 220
1,307 1,624 477 295 77
0.001* 0.001* 0.001+ 0.001* 0.0012
The degrees of freedom for all the criteria are 1174. *Significant at P< 0.001.
299
[13]. The alveolar capillary membrane is affected during shock (“shock lung”) [41 -431. During this condition of increased permeability with “shock lung”, it is possible that more of a drug given endotracheally could diffuse or move across the alveolar-capillary membrane than during the normal non-shock state. This would result in increased absorption of the endotracheal drug and higher plasma levels. Shock lung can occur with hemorrhagic shock and can occur early during the shock state [2]. In summary, this study suggests: (1) detectable plasma lidocaine levels occur following endotracheal administration of lidocaine even during the pathologic condition of hemorrhagic shock; (2) higher plasma lidocaine levels occur in the shock vs. non-shock state; and (3) this occurs no matter what the dose and/or the technique of endotracheal administration. ACKNOWLEDGEMENTS
We would like to thank Dr. Jerome Bernstein, Chairman, Pathology Department, which confirmed normal lungs in the Group I (Non-shock animals) and “Classic” shock lung in the Group II (Hypovolemic Shock) animals by both gross pathology and histology, and the Respiratory Therapy Department for their assistance in doing the arterial blood gases. REFERENCES 1
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