- Email: [email protected]
Verifying dose response
CORRESPONDENCE
lobar pneumonia, rhabdomyolysis, and renal insufficiency, but he was discharged 17 days after admission with no neurologic deficits. There were no complications attributed directly to the pleural lavage. It should be emphasized that spontaneous resolution of our patient's ventricular fibrillation occurred well before a significant rise in general core t e m p e r a t u r e , s u p p o r t i n g the concept that direct warming of the heart is advantageous in the resuscitation of the severely hypothermic patient with life-threatening dysrhythmias refractory to conventional treatment. In situations in w h i c h partial c a r d i o p u l m o n a r y bypass is not available, closed thoracic cavity lavage presents an effective alternative method of active core rewarming. In addition to its ease of application, o u r method of active core rewarming using a single chest tube with bolus pleural lavage has the theoretical advantage of maximum heat exchange per liter of solution because the full liter is placed in the hemithorax, maximizing surface area exposure (in particular, cardiac surface area exposure) prior to evacuation. We continue to use this technique in the t r e a t m e n t of the sev e r e l y h y p o t h e r m i c p a t i e n t . We believe its near universal availability, ease of application, and excellent ability to rapidly rewarm the heart warrants its consideration as a treatment of severe hypothermia in selected patients when cardiopulmonary bypass is not available.
David T Walters, MD Department of Emergency Medicine Kern Medical Center Bakersfield, California
Verifying Dose Response To the Editor: Defining the vasopressor response to different doses of epinephrine is an i m p o r t a n t step in d e t e r m i n i n g whether "high-dose" epinephrine is of benefit during CPR. The methodology used by Gonzalez and colleagues in their paper, "Dose-Dependent Vasopressor Response to Epi20:4 April 1991
n e p h r i n e D u r i n g CPR in H u m a n Beings" [September 1989;18:920-926] involved the administration of repeated, increasing doses of epinephrine. This study design should be used cautiously in clinical trials so that results are not misinterpreted. Selection of the appropriate time interval between doses is critical in ensuring that effects seen are due to the last dose, rather than secondary to the cumulative effect of all doses given. 1,2 The magnitude and duration of a drug's effect with repeated administration is determined by the agent's p h a r m a c o k i n e t i c profile; the relationship between drug dose, plasma concentration and pharmacologic effect; and the time interval between doses. When a second, equal dose is administered subsequent to the complete elimination of the first dose, the effect seen is greater than that of the first dose. ~ As Levy succinctly discusses, this appears to be more significant with drugs that have a large volume of distribution. The effect can increase with each of the first four equal doses. A drug with a small volume of distribution may reach p h a r m a e o k i n e t i c and pharmacologic equilibrium after the second dose. 1 The five-minute dosing interval selected by Gonzalez et al was based on current advanced cardiac life support recommendations and epinephrine's short half-life in normal perfusion states. Information concerning e p i n e p h r i n e ' s e l i m i n a t i o n during CPR w o u l d be more appropriate; however, it is unavailable. Baseline plasma epinephrine concentrations are elevated after cardiac arrest. 3 In patients undergoing CPR, plasma epinephrine concentrations remain elevated five minutes after epinephrine administration. 4 When the substance of interest is both administered as a drug and produced endogenously, extreme difficulty arises in determining the most appropriate interval between doses. The most valid method of verifying the dose response described by Gonzalez et al would be to randomize the order that the different epinephrine doses are administered. A Annals of Emergency Medicine
review of epinephrine use in CPR did not find studies that randomized the order of different IV e p i n e p h r i n e doses. The a d m i n i s t r a t i o n of one dose level to each subject or prolonging the time interval between doses to 30 minutes, designs used in animal models,5, 6 are probably not reasonable in human studies. Investigators and readers of clinical trials should be aware of the phen o m e n o n of increasing drug effect with repeated dose drug administration. Study designs should be assessed to determine whether the information required to accurately select the time interval between doses has been considered. When the duration of pharmacologic effect does not allow for a prolonged period between d i f f e r e n t size d o s e s in c l i n i c a l studies, randomization of dosing order is necessary.
William A Watson, PharmD Janet Jordan, MD Department of Emergency Health Services School of Medicine University of Missouri-Kansas City Truman Medical Center 1. Levy G: Kinetics of pharmacologic effects. Clin PharmacoI Therap 1966;7:362-372. 2. Husain PJ, Watson WA, Runegin L, et al: A new model for evaluating lidocaine induced seizure activity (abstract). Anesthesiology 1984;6hA212. 3. Foley PF, Tacker WA, Wortsman J, et ah Plasma cateeholamine and serum cortiso] responses to experimental cardiac arrest in dogs. Am J PhysioI 1987;253: E283-289. 4. Quinton DN, O'Byrne G, Aitkenhead AR: Comparison of endotracheal and peripheral intravenous adrenaline in cardiac arrest. Lancet 1987~1:828-829. 5. Kosnik JW, Jackson RE, Keats S, et ah Dose-related response of centrally administered epinephrine on the change in aortic diastolic pressure during closed-chest massage in dogs. Ann Emerg Med 1985;14:204-208. 6. Ralston SH, Tacker WA, Showen L, et ah Endotracheai versus intravenous epinephrine during electromechanical dissociation with CPR in dogs. Ann Emerg Med 1985;14:1044-1048.
In Reply: We agree that randomization of the dosing order is scientifically appropriate when the pharmacological effect does not allow for a prolonged period b e t w e e n doses in clinical studies. However, early investigation of a promising new treatment often requires c o m p r o m i s e b e t w e e n the 440/159
lobar pneumonia, rhabdomyolysis, and renal insufficiency, but he was discharged 17 days after admission with no neurologic deficits. There were no complications attributed directly to the pleural lavage. It should be emphasized that spontaneous resolution of our patient's ventricular fibrillation occurred well before a significant rise in general core t e m p e r a t u r e , s u p p o r t i n g the concept that direct warming of the heart is advantageous in the resuscitation of the severely hypothermic patient with life-threatening dysrhythmias refractory to conventional treatment. In situations in w h i c h partial c a r d i o p u l m o n a r y bypass is not available, closed thoracic cavity lavage presents an effective alternative method of active core rewarming. In addition to its ease of application, o u r method of active core rewarming using a single chest tube with bolus pleural lavage has the theoretical advantage of maximum heat exchange per liter of solution because the full liter is placed in the hemithorax, maximizing surface area exposure (in particular, cardiac surface area exposure) prior to evacuation. We continue to use this technique in the t r e a t m e n t of the sev e r e l y h y p o t h e r m i c p a t i e n t . We believe its near universal availability, ease of application, and excellent ability to rapidly rewarm the heart warrants its consideration as a treatment of severe hypothermia in selected patients when cardiopulmonary bypass is not available.
David T Walters, MD Department of Emergency Medicine Kern Medical Center Bakersfield, California
Verifying Dose Response To the Editor: Defining the vasopressor response to different doses of epinephrine is an i m p o r t a n t step in d e t e r m i n i n g whether "high-dose" epinephrine is of benefit during CPR. The methodology used by Gonzalez and colleagues in their paper, "Dose-Dependent Vasopressor Response to Epi20:4 April 1991
n e p h r i n e D u r i n g CPR in H u m a n Beings" [September 1989;18:920-926] involved the administration of repeated, increasing doses of epinephrine. This study design should be used cautiously in clinical trials so that results are not misinterpreted. Selection of the appropriate time interval between doses is critical in ensuring that effects seen are due to the last dose, rather than secondary to the cumulative effect of all doses given. 1,2 The magnitude and duration of a drug's effect with repeated administration is determined by the agent's p h a r m a c o k i n e t i c profile; the relationship between drug dose, plasma concentration and pharmacologic effect; and the time interval between doses. When a second, equal dose is administered subsequent to the complete elimination of the first dose, the effect seen is greater than that of the first dose. ~ As Levy succinctly discusses, this appears to be more significant with drugs that have a large volume of distribution. The effect can increase with each of the first four equal doses. A drug with a small volume of distribution may reach p h a r m a e o k i n e t i c and pharmacologic equilibrium after the second dose. 1 The five-minute dosing interval selected by Gonzalez et al was based on current advanced cardiac life support recommendations and epinephrine's short half-life in normal perfusion states. Information concerning e p i n e p h r i n e ' s e l i m i n a t i o n during CPR w o u l d be more appropriate; however, it is unavailable. Baseline plasma epinephrine concentrations are elevated after cardiac arrest. 3 In patients undergoing CPR, plasma epinephrine concentrations remain elevated five minutes after epinephrine administration. 4 When the substance of interest is both administered as a drug and produced endogenously, extreme difficulty arises in determining the most appropriate interval between doses. The most valid method of verifying the dose response described by Gonzalez et al would be to randomize the order that the different epinephrine doses are administered. A Annals of Emergency Medicine
review of epinephrine use in CPR did not find studies that randomized the order of different IV e p i n e p h r i n e doses. The a d m i n i s t r a t i o n of one dose level to each subject or prolonging the time interval between doses to 30 minutes, designs used in animal models,5, 6 are probably not reasonable in human studies. Investigators and readers of clinical trials should be aware of the phen o m e n o n of increasing drug effect with repeated dose drug administration. Study designs should be assessed to determine whether the information required to accurately select the time interval between doses has been considered. When the duration of pharmacologic effect does not allow for a prolonged period between d i f f e r e n t size d o s e s in c l i n i c a l studies, randomization of dosing order is necessary.
William A Watson, PharmD Janet Jordan, MD Department of Emergency Health Services School of Medicine University of Missouri-Kansas City Truman Medical Center 1. Levy G: Kinetics of pharmacologic effects. Clin PharmacoI Therap 1966;7:362-372. 2. Husain PJ, Watson WA, Runegin L, et al: A new model for evaluating lidocaine induced seizure activity (abstract). Anesthesiology 1984;6hA212. 3. Foley PF, Tacker WA, Wortsman J, et ah Plasma cateeholamine and serum cortiso] responses to experimental cardiac arrest in dogs. Am J PhysioI 1987;253: E283-289. 4. Quinton DN, O'Byrne G, Aitkenhead AR: Comparison of endotracheal and peripheral intravenous adrenaline in cardiac arrest. Lancet 1987~1:828-829. 5. Kosnik JW, Jackson RE, Keats S, et ah Dose-related response of centrally administered epinephrine on the change in aortic diastolic pressure during closed-chest massage in dogs. Ann Emerg Med 1985;14:204-208. 6. Ralston SH, Tacker WA, Showen L, et ah Endotracheai versus intravenous epinephrine during electromechanical dissociation with CPR in dogs. Ann Emerg Med 1985;14:1044-1048.
In Reply: We agree that randomization of the dosing order is scientifically appropriate when the pharmacological effect does not allow for a prolonged period b e t w e e n doses in clinical studies. However, early investigation of a promising new treatment often requires c o m p r o m i s e b e t w e e n the 440/159