112  Standardization  of  Preparations.      { AmMarch,f908.rm' 
The  third  stage  is  the  stage  in  which  the  toxic  action  of  the  drug 
is  the  most  marked.  In  this  stage  the  rhythm  of  the  heart  is 
markedly  increased,  sometimes  the  pulse  is  very  much  faster  than 
normal,  but  the  most  characteristic  feature  of  this  stage  is  the 
extreme  irregularity  of  the  contraction  of  the  ventricle.  If  we 
examine  this  by,  means  of  a  tracing,  we  get  a  curve  which  is  char- 
acterized by  the  extreme  irregularity  of  the  up-stroke,  which  repre- 
sents the  contraction  of  the  ventricle.  During  this  stage  the  effect 
of  digitalis  on  the  central  nervous  system  is  quite  marked.  Vom- 
iting and  convulsions  are  prominent  symptoms.  Death  rapidly 
follows  and  is  immediately  preceded  by  an  extreme  irregularity  and 
rapidity  of  the  beat,  the  so-called  "  delirium  cordis."  On  autopsy, 
the  heart  in  mammals  is  found  to  be  dilated  and  full  of  blood. 
The  first  or  therapeutic  stage  is  the  important  one  to  consider  in 
the  administration  of  digitalis  as  a  medicine.  It  has  little,  if  any, 
relation  to  the  second  or  third  stage,  and  in  fact  any  of  the  symp- 
toms of  the  second  and  third  stage  are  danger  signals  to  be  heeded, 
and  call  for  the  immediate  withdrawal  of  the  drug. 
The  question  of  physiological  standardization  of  digitalis  has 
resolved  itself  into  the  specific  action  of  the  drug  on  the  heart 
of  the  frog.  Frogs  were  treated  with  digitalis  in  varying  quantities, 
and  that  amount  of  digitalis  which  would  kill  a,  frog  of  definite 
weight,  and  which  on  autopsy  showed  its  heart  to  be  in  systole 
was  considered  to  be  an  index  of  the  physiological  activity  of  the 
preparation. 
While  no  objections  can  be  offered  against  this  method  as  showing 
one  of  the  actions  of  digitalis  on  the  heart,  we  do  not  think  that  it 
is  an  absolute  or  even  a  safe  method  for  the  standardization  of  this 
drug.  It  is,  after  all,  only  a  toxic  effect,  and  the  fact  that  the  frog 
dies  with  its  heart  in  systole  is  not  any  more  characteristic  than  the 
mammalian  heart  in  diastole.  In  either  case  the  animal  dies,  and  the 
cause  of  its  death  is  the  action  of  digitalis  on  the  heart,  and  this 
method  of  the  physiological  standardization  of  digitalis  is  nothing 
more  than  a  determination  of  the  lethal  dose. 
Recognizing  the  great  irregularity  of  the  frog  in  its  response  to 
digitalis,  in  which  the  season  of  the  year  plays  a  very  important 
role,  the  difference  with  which  different  species  of  frogs  respond  to 
digitalis,  and  the  necessity  of  carrying  out  tests  on  frogs  of  equal 
weight,  it  was  deemed  advisable  to  standardize  digitalis  by  using  a 
