Intravenous Fluid Therapy for the Treatment of Emergency Department Patients With Migraine Headache: a Pilot Randomized Controlled Trial
Phase: PHASE2
Conditions: Migraine Headache
Sponsor: The Cooper Health System

Principal	  Investigator/Program	  Director	  (Last,	  first,	  middle):	  Jones,	  Christopher,	  Warren	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  1	  
Feb	  8,	  2016	  
Intravenous	  fluid	  therapy	  for	  the	  treatment	  of	  emergency	  department	  patients	  with	  migraine	  
headache:	  a	  pilot	  randomized	  controlled	  trial	  
	  
	  
Abstract:	  
	  
Headache	  is	  one	  of	  the	  most	  common	  reasons	  patients	  visit	  the	  emergency	  department	  (ED),	  
with	  migraines	  accounting	  for	  over	  one	  million	  annual	  US	  ED	  visits.	  While	  intravenous	  fluid	  (IVF)	  
has	  not	  been	  prospectively	  studied	  in	  migraine	  patients,	  there	  is	  evidence	  that	  intravascular	  
volume	  status	  affects	  central	  pain	  processing,	  and	  dehydration	  can	  trigger	  migraines.	  We	  
propose	  a	  pilot,	  randomized	  controlled	  trial	  assessing	  the	  impact	  of	  an	  IVF	  bolus	  on	  patients	  
with	  migraine	  headache.	  We	  hypothesize	  that	  patients	  who	  receive	  IVF	  will	  experience	  greater	  
improvement	  in	  pain	  one	  hour	  after	  treatment	  as	  compared	  to	  controls.	  Adults	  treated	  in	  the	  
Cooper	  ED	  with	  migraine	  headache	  will	  be	  randomized	  to	  receive	  normal	  saline	  at	  either	  1000	  
ml/hr	  (treatment)	  or	  10	  ml/hr	  (control)	  for	  one	  hour,	  with	  a	  comparison	  in	  pain	  scores	  before	  
and	  after	  treatment.	  Our	  first	  specific	  aim	  will	  establish	  the	  feasibility	  of	  successfully	  enrolling	  
patients	  with	  migraine	  in	  the	  study	  and	  adhering	  to	  the	  study	  protocol.	  Our	  second	  specific	  aim	  
will	  examine	  the	  efficacy	  of	  a	  normal	  saline	  bolus	  for	  relieving	  pain	  among	  patients	  with	  
migraine	  headache.	  The	  data	  collected	  during	  this	  pilot	  study	  will	  support	  a	  competitive,	  larger-­‐
scale	  external	  grant	  application	  further	  investigating	  the	  efficacy	  of	  IVF	  for	  migraine.	  	  
	  
	  
	  
	  
	  
	  

Principal	  Investigator/Program	  Director	  (Last,	  first,	  middle):	  Jones,	  Christopher,	  Warren	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  2	  
Feb	  8,	  2016	  
Research	  plan	  
	  
I.	  Project	  statement	  
	  
Patients	  commonly	  present	  to	  the	  emergency	  department	  due	  to	  migraine	  headache.	  While	  some	  
patients	  receive	  intravenous	  fluids	  as	  a	  method	  of	  controlling	  pain,	  the	  effectiveness	  of	  this	  intervention	  
has	  not	  been	  prospectively	  studied.	  Our	  long-­‐term	  objective	  is	  to	  determine	  the	  effect	  of	  an	  intravenous	  
fluid	  bolus	  on	  pain	  among	  patients	  treated	  in	  the	  emergency	  department	  for	  migraine	  headache.	  The	  
purpose	  of	  this	  pilot	  study	  is	  to	  obtain	  feasibility	  and	  preliminary	  outcome	  data	  in	  support	  of	  a	  future	  
trial.	  	  	  	  	  	  	  
	  
	  
	  

Principal	  Investigator/Program	  Director	  (Last,	  first,	  middle):	  Jones,	  Christopher,	  Warren	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  3	  
Feb	  8,	  2016	  
II.	  Specific	  aims	  
	  
Migraine	   headache	   exacerbation	   is	   one	   of	   the	   most	   common	   reasons	   that	   people	   seek	   emergency	  
department	   (ED)	   care.1	   Common	   treatments	   in	   the	   emergency	   department	   include	   phenothiazines,2	  
serotonin	   receptor	   agonists,3	   and	   corticosteroids.4	   Because	   severe	   headache	   exacerbation	   is	   often	  
refractory	  to	  these	  interventions,	  approximately	  50%	  also	  end	  up	  receiving	  opioids,5,	  6	  despite	  the	  fact	  
that	  these	  medications	  are	  contraindicated	  in	  migraine	  headache,	  can	  cause	  headache	  recurrence,	  and	  
can	  contribute	  to	  drug	  abuse	  and	  addiction.7-­‐11	  
	  
One	  commonly	  used	  but	  little-­‐studied	  treatment	  for	  migraine	  headache	  is	  IV	  fluid	  (IVF).	  Using	  a	  
nationally	  representative	  staged	  probability	  sampling	  survey	  we	  recently	  found	  that	  approximately	  40%	  
of	  patients	  treated	  in	  US	  EDs	  for	  headache	  received	  IV	  fluid	  therapy.12	  Theoretical	  reasons	  to	  suggest	  
that	  IVF	  may	  be	  useful	  in	  painful	  conditions	  such	  as	  migraine	  headache	  include	  data	  from	  healthy	  
volunteers	  suggesting	  that	  IV	  fluid	  administration	  may	  reduce	  headache	  pain	  by	  correcting	  
dehydration,13-­‐15	  and	  by	  reducing	  pain-­‐related	  brain	  activity	  in	  the	  anterior	  cingulate	  cortex,	  insula,	  and	  
thalamus.16-­‐18	  	  However,	  despite	  its	  common	  use,	  no	  prospective	  studies	  have	  been	  performed	  
evaluating	  the	  efficacy	  of	  IVF	  in	  acute	  migraine	  headache	  exacerbation.	  Consistent	  with	  contemporary	  
uncertainty	  regarding	  efficacy,	  our	  national	  survey	  data	  indicate	  that	  the	  use	  of	  IVF	  is	  highly	  variable	  
across	  institutions.12	  If	  IVF	  is	  efficacious,	  then	  currently	  it	  is	  a	  highly	  underutilized	  opioid-­‐sparing	  
intervention.	  In	  contrast,	  if	  IVF	  is	  not	  efficacious,	  then	  IVF	  treatment	  currently	  adds	  unnecessary	  cost,	  
resource	  utilization,	  and	  time	  to	  contemporary	  ED	  care.	  
	  
Our	  study	  coordinator	  and	  network	  of	  ED-­‐based	  research	  associates	  currently	  screen	  and	  enroll	  patients	  
for	  research	  studies	  in	  the	  Cooper	  Hospital	  ED	  14	  hours	  per	  day,	  7	  days	  per	  week.	  We	  will	  use	  this	  
research	  infrastructure	  to	  recruit	  patients	  (n	  =	  50)	  presenting	  to	  the	  ED	  with	  a	  chief	  complaint	  of	  
headache	  or	  migraine	  who	  meet	  International	  Classification	  of	  Headache	  Disorders-­‐3	  (ICHD-­‐3)	  diagnostic	  
criteria	  for	  migraine.19	  As	  described	  below,	  individuals	  with	  extensive	  vomiting	  or	  other	  definitive	  IVF	  
requirement	  will	  be	  excluded.	  Patients	  will	  be	  randomized	  to	  receive	  a	  1000	  ml	  bolus	  of	  normal	  saline	  
over	  one	  hour	  vs.	  normal	  saline	  at	  10	  ml/hr	  for	  one	  hour,	  and	  pain,	  functional	  status,	  and	  side	  effects	  
will	  be	  assessed	  at	  time	  zero,	  one	  hour,	  two	  hours	  and	  48	  hours.	  
	  
Hypothesis	  1:	  The	  proposed	  RCT	  protocol	  is	  feasible.	  
Specific	  Aims	  	  
1a.	  To	  determine	  whether	  the	  proposed	  study	  protocol	  can	  successfully	  recruit	  at	  least	  75%	  of	  eligible	  
patients.	  
1b.	  To	  assess	  the	  ability	  of	  the	  proposed	  protocol	  to	  successfully	  blind	  participants	  to	  their	  intervention	  
group,	  such	  that	  fewer	  than	  half	  of	  participants	  correctly	  identify	  their	  treatment	  arm.	  
1c.	  To	  test	  the	  ability	  of	  the	  proposed	  protocol	  to	  successfully	  obtain	  patient	  follow-­‐up	  at	  one	  hour,	  two	  
hours,	  and	  48	  hours	  in	  at	  least	  85%	  of	  participants.	  
	  
Hypothesis	  2:	  IVF	  administration	  will	  result	  in	  reduced	  pain	  scores	  in	  the	  ED	  and	  at	  follow-­‐up.	  
Specific	  Aims	  	  
1a.	  To	  test	  the	  efficacy	  of	  IVF	  in	  achieving	  an	  improvement	  in	  reported	  pain	  (0-­‐10	  scale)	  of	  at	  least	  1.3	  
(minimally	  significant	  pain	  difference)	  as	  compared	  to	  controls	  between	  time	  0	  and	  one	  hour.	  	  
	  
The	  proposed	  study	  constitutes	  a	  critical	  first	  step	  in	  demonstrating	  the	  potential	  feasibility	  and	  value	  of	  
performing	  a	  large-­‐scale	  RCT	  evaluating	  the	  potential	  efficacy	  of	  IVF	  administration	  for	  individuals	  
presenting	  to	  the	  ED	  with	  migraine	  headache.	  This	  study	  will	  collect	  the	  necessary	  data	  to	  advance	  to	  
initial	  stage	  NIH	  (R03,	  R21,	  R34)	  or	  PCORI	  funding.	  
	  
	  

Principal	  Investigator/Program	  Director	  (Last,	  first,	  middle):	  Jones,	  Christopher,	  Warren	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  4	  
Feb	  8,	  2016	  
	  
III.	  Research	  strategy	  
	  
A)	  Significance	  
Headache	  is	  a	  substantial	  global	  public	  health	  problem,20	  and	  the	  fourth	  most	  common	  reason	  that	  
patients	  visit	  an	  emergency	  department	  (ED)	  in	  the	  United	  States	  (US).1	  	  Migraine	  headache	  accounts	  for	  
over	  one	  million	  patients	  encounters	  in	  US	  EDs	  each	  year,	  and	  many	  more	  patients	  seek	  care	  for	  
migraine-­‐like	  headaches.5	  While	  multiple	  drugs	  are	  currently	  used	  in	  the	  management	  of	  migraine	  
exacerbations,	  including	  non-­‐steroidal	  anti-­‐inflammatories,5	  phenothiazines,2	  serotonin	  receptor	  
agonists,3	  and	  corticosteroids,4	  severe	  headaches	  are	  often	  refractory	  to	  these	  interventions.	  As	  a	  result,	  
approximately	  50%	  of	  ED	  patients	  with	  migraine	  headache	  receive	  opioids.5,	  6	  Furthermore,	  ED	  opioid	  
use	  for	  headache	  has	  increased	  over	  time.21	  This	  is	  despite	  known	  risks	  of	  opioid	  use	  in	  patients	  with	  
migraine	  headache,	  including	  the	  development	  of	  transformed	  migraine,	  in	  which	  patients	  with	  
infrequent	  migraine	  symptoms	  develop	  increasingly	  chronic,	  frequent,	  and	  disabling	  headaches,7,	  11	  as	  
well	  as	  opioid-­‐related	  antagonism	  of	  other	  analgesic	  medications	  such	  as	  COX1/COX2	  inhibitors.9	  
Additionally,	  chronic	  opioid	  use	  and	  abuse	  is	  an	  enormous	  public	  health	  problem	  in	  the	  United	  States,22	  
with	  opioid-­‐related	  overdose	  deaths	  increasing	  200%	  since	  2000.10	  Importantly,	  initiation	  of	  opioid	  
medications	  for	  acute	  pain	  in	  the	  ED	  among	  opioid-­‐naïve	  patients	  is	  associated	  with	  increased	  risk	  of	  
ongoing	  use	  one	  year	  later.8	  The	  high	  rate	  of	  opioid	  utilization	  for	  migraine	  headache	  despite	  these	  
known	  risks	  indicates	  the	  need	  to	  development	  effective,	  opioid-­‐sparing	  interventions.	  	  	  
	  	  
Data	  from	  both	  healthy	  volunteers	  and	  from	  other	  painful	  conditions	  suggest	  that	  fluid	  administration	  
may	  provide	  effective	  analgesia	  for	  patients	  with	  migraine.	  Even	  mild	  dehydration	  lowers	  pain	  
thresholds,	  and	  increases	  central	  pain-­‐related	  activity	  in	  the	  anterior	  cingulate	  cortex,	  insula,	  and	  
thalamus.16-­‐18	  Consistent	  with	  this	  hypothesis,	  headache	  is	  commonly	  reported	  by	  patients	  undergoing	  
dialysis,23	  and	  recent	  research	  has	  identified	  dehydration	  as	  a	  trigger	  for	  migraine	  headache.13-­‐15	  	  	  
	  
Despite	  these	  theoretical	  benefits,	  IVF	  has	  not	  been	  prospectively	  studied	  in	  patients	  with	  migraine	  and	  
its	  efficacy	  is	  unknown.	  One	  recent	  secondary	  analysis	  of	  data	  from	  four	  ED-­‐based	  migraine	  headache	  
trials	  evaluating	  the	  use	  of	  metoclopramide	  demonstrated	  no	  association	  between	  IVF	  administration	  
and	  improved	  pain	  outcomes,	  though	  the	  observational	  nature	  of	  these	  data	  are	  subject	  to	  substantial	  
confounding.	  Despite	  this	  lack	  of	  existing	  clinical	  evidence,	  experts	  often	  recommend	  IVF	  for	  patients	  
requiring	  ED	  treatment	  for	  migraine,25,	  26	  and	  approximately	  40%	  of	  patients	  visiting	  US	  EDs	  for	  
headache	  receive	  treatment	  with	  IVF.12	  If	  IVF	  is	  beneficial,	  then	  this	  represents	  a	  substantial	  opportunity	  
to	  improve	  the	  care	  of	  patients	  with	  this	  common,	  painful	  condition	  through	  increased	  use	  of	  this	  
potentially	  opioid-­‐sparing	  intervention.	  If,	  however,	  IVF	  does	  not	  benefit	  individuals	  with	  migraine,	  then	  
these	  patients	  are	  burdened	  by	  unnecessary	  costs.	  In	  addition,	  while	  generally	  safe,	  risks	  associated	  with	  
IV	  placement	  and/or	  fluid	  administration	  include	  pain	  with	  insertion,27	  infection,28	  and	  
thrombophlebitis.29	  While	  these	  outcomes	  are	  rare,	  the	  use	  of	  IVF	  in	  millions	  of	  headache	  patients	  each	  
year	  makes	  them	  relevant	  to	  risk/benefit	  calculations.	  If	  found	  to	  be	  ineffective,	  IVF	  may	  also	  contribute	  
to	  ED	  crowding	  by	  unnecessarily	  prolonging	  ED	  length	  of	  stay,	  and	  by	  occupying	  staff	  time	  when	  this	  
time	  is	  often	  critical	  to	  ensuring	  patient	  safety.	  

Principal	  Investigator/Program	  Director	  (Last,	  first,	  middle):	  Jones,	  Christopher,	  Warren	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  5	  
Feb	  8,	  2016	  
	  
B)	  Innovation	  
The	  proposed	  study	  will	  be	  the	  first	  randomized	  trial	  assessing	  the	  efficacy	  of	  IVF	  in	  migraine	  headache,	  
thereby	  addressing	  a	  significant	  knowledge	  gap	  in	  the	  treatment	  of	  this	  common	  disorder.	  Additionally,	  
we	  plan	  to	  assess	  the	  success	  of	  our	  blinding	  strategy.	  Several	  prior	  studies	  assessing	  the	  effectiveness	  
of	  IVF	  for	  the	  treatment	  of	  other	  painful	  conditions	  have	  attempted	  to	  achieve	  blinding	  by	  placing	  
opaque	  covers	  over	  the	  IV	  bag	  and	  IV	  pump.30,	  31	  However,	  these	  studies	  have	  not	  assessed	  the	  success	  
of	  this	  blinding	  method.	  Validation	  of	  this	  technique	  has	  the	  potential	  to	  inform	  the	  design	  of	  future	  
studies	  of	  IVF	  across	  a	  broad	  spectrum	  of	  clinical	  conditions.	  	  
	  
C.	  Approach	  
We	  intend	  to	  perform	  a	  small-­‐scale	  pilot	  study	  assessing	  the	  effectiveness	  of	  IVF	  therapy	  for	  patients	  
presenting	  to	  the	  ED	  with	  migraine	  headache.	  	  	  
	  
1.   Study	  participants	  
Participants	  will	  be	  English-­‐speaking	  patients	  aged	  18	  or	  older,	  treated	  in	  the	  Cooper	  Hospital	  ED	  
with	  a	  headache	  meeting	  ICHD-­‐3	  criteria	  for	  migraine.19	  Patients	  will	  be	  excluded	  if	  in	  the	  opinion	  of	  
the	  treating	  physician	  IVF	  administration	  is	  definitively	  indicated	  (ie.	  intractable	  vomiting,	  severe	  
dehydration)	  or	  contraindicated	  (e.g.	  exacerbation	  of	  congestive	  heart	  failure).	  	  	  
Research	  assistants	  who	  are	  trained	  to	  identify	  potential	  clinical	  study	  participants	  and	  assess	  their	  
eligibility	  for	  study	  enrollment	  are	  available	  in	  the	  ED	  from	  8:30	  am	  until	  10:30	  pm,	  7	  days	  per	  week	  
to	  screen	  patients	  for	  inclusion.	  	  
	  	  
2.   Interventions	  
No	  previous	  trials	  have	  prospectively	  studied	  an	  IVF	  bolus	  for	  adults	  with	  migraine,	  limiting	  data	  on	  
which	  to	  make	  dosing	  decisions.	  However,	  several	  trials	  have	  assessed	  the	  impact	  of	  IVF	  on	  post-­‐
operative	  nausea	  and	  vomiting	  and	  post-­‐operative	  opioid	  requirements.	  One	  compared	  15	  ml/kg	  
(mean	  total	  intervention	  dose	  of	  1215	  ml)	  with	  2	  ml/kg	  (mean	  dose	  226	  ml)	  of	  crystalloid	  solution	  
before	  induction	  of	  anesthesia	  for	  minor	  surgery,	  finding	  a	  substantial	  reduction	  in	  post-­‐operative	  
nausea	  and	  vomiting,	  along	  with	  trends	  toward	  lower	  post-­‐operative	  opioid	  requirements.32	  Two	  
additional	  small	  trials	  showed	  that	  for	  patients	  undergoing	  gynecologic	  procedures	  a	  1000	  ml	  
crystalloid	  bolus	  resulted	  in	  improved	  post-­‐operative	  nausea	  and	  vomiting	  compared	  with	  
controls.33,	  34	  Finally,	  another	  trial	  comparing	  a	  control	  group	  of	  2	  ml/kg	  crystalloid	  to	  12	  ml/kg	  
crystalloid	  solution	  or	  12	  ml/kg	  colloid	  solution	  showed	  improved	  post-­‐operative	  nausea	  and	  
vomiting	  among	  the	  two	  experimental	  arms.35	  In	  addition	  to	  these	  results	  showing	  efficacy	  with	  
doses	  of	  approximately	  1000	  ml,	  clinical	  experience	  suggests	  that	  a	  dose	  of	  1000	  ml	  is	  commonly	  
selected	  by	  ED	  physicians	  when	  treating	  patients	  with	  migraine,	  making	  this	  dose	  relevant	  to	  current	  
clinical	  practice.	  Finally,	  a	  dose	  of	  1000	  ml	  limits	  opportunities	  for	  unblinding	  by	  avoiding	  
administration	  of	  more	  than	  one	  bag	  of	  IVF.	  Based	  on	  these	  considerations,	  we	  plan	  to	  study	  the	  
efficacy	  of	  a	  1000	  ml	  normal	  saline	  bolus	  versus	  control.	  In	  order	  to	  maximize	  the	  generalizability	  of	  
our	  results,	  we	  will	  not	  restrict	  the	  use	  of	  additional	  interventions	  by	  ED	  providers.	  	  
	  

Principal	  Investigator/Program	  Director	  (Last,	  first,	  middle):	  Jones,	  Christopher,	  Warren	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  6	  
Feb	  8,	  2016	  
	  Patients	  will	  be	  randomly	  allocated	  between	  two	  arms:	  	  	  
	  
Patients	  in	  the	  intervention	  arm	  (“IVF	  group”)	  will	  have	  a	  peripheral	  IV	  line	  placed	  by	  ED	  staff,	  
and	  will	  receive	  1000	  ml	  of	  0.9%	  normal	  saline	  bolus	  over	  one	  hour.	  	  
	  
Patients	  in	  the	  control	  arm	  (“control	  group”)	  will	  have	  a	  peripheral	  IV	  line	  placed	  by	  ED	  staff,	  and	  
will	  have	  a	  1000	  ml	  bag	  of	  0.9%	  normal	  saline	  attached	  to	  the	  IV	  line,	  but	  the	  IV	  pump	  will	  be	  
programmed	  to	  infuse	  10	  ml	  of	  fluid	  over	  one	  hour.	  	  
	  
3.   Allocation	  and	  blinding	  
We	  will	  randomize	  patients	  in	  permuted	  blocks	  of	  4	  or	  6.	  	  Study	  assignments	  will	  be	  made	  through	  
the	  use	  of	  sequentially	  numbered,	  opaque,	  sealed	  envelopes.	  Following	  enrollment,	  the	  nurse	  -­‐-­‐	  
who	  will	  remain	  un-­‐blinded	  -­‐-­‐	  will	  open	  the	  envelope	  and	  initiate	  the	  assigned	  intervention.	  An	  
opaque	  cover	  will	  be	  placed	  over	  the	  IV	  pump,	  fluid	  bag,	  and	  drip	  chamber	  to	  maintain	  blinding	  of	  
the	  patient,	  treating	  physician,	  and	  outcome	  assessor.	  Following	  completion	  of	  the	  intervention,	  in	  
order	  to	  evaluate	  the	  success	  of	  blinding,	  patients	  and	  outcome	  assessors	  will	  be	  asked	  which	  
treatment	  group	  they	  think	  was	  assigned.	  	  
	  
4.   Data	  collection	  
Research	  assistants	  will	  collect	  demographic	  information	  from	  patients,	  including	  age,	  sex,	  race,	  
ethnicity,	  pre-­‐existing	  comorbid	  conditions,	  and	  headache	  history.	  	  
	  
We	  will	  assess	  pain	  at	  time	  0	  (start	  of	  the	  intervention),	  one	  hour	  (end	  of	  the	  intervention),	  and	  two	  
hours	  using	  both	  a	  categorical	  scale	  (none,	  mild,	  moderate,	  or	  severe)	  and	  an	  11	  point	  verbal	  pain	  
scale	  ranging	  from	  0	  (no	  pain)	  to	  10	  (worst	  pain	  imaginable),	  which	  has	  been	  validated	  for	  use	  in	  the	  
ED	  setting.36	  	  
	  
Functional	  disability	  will	  be	  assessed	  before	  treatment,	  at	  one	  hour,	  and	  two	  hours.	  As	  
recommended	  by	  the	  International	  Headache	  Society,37	  patients	  will	  describe	  their	  functional	  
disability	  due	  to	  headache	  as	  none,	  mild	  (able	  to	  perform	  all	  activities	  of	  daily	  living,	  but	  with	  some	  
difficulty),	  moderate	  (unable	  to	  perform	  some	  activities	  of	  daily	  living),	  and	  severe	  (unable	  to	  
perform	  most	  activities	  or	  requiring	  bed	  rest).	  	  
	  
We	  will	  measure	  adverse	  effects	  of	  treatment,	  including	  pain	  at	  the	  IV	  site	  by	  asking	  participants	  to	  
rate	  the	  pain	  associated	  with	  IV	  insertion,	  as	  well	  as	  IV	  site	  pain	  at	  one	  and	  two	  hours.	  	  
	  
Research	  assistants	  will	  record	  visit	  characteristics,	  including	  the	  timing	  of	  medications	  
administered,	  need	  for	  rescue	  medication,	  opioid	  use,	  length	  of	  stay	  in	  the	  ED,	  and	  ED	  disposition	  
(discharged,	  observation,	  admission).	  	  
	  
Research	  assistants	  will	  contact	  participants	  48	  hours	  after	  they	  leave	  the	  ED.	  It	  is	  anticipated	  that	  
the	  substantial	  majority	  of	  patients	  will	  have	  been	  discharged	  from	  the	  hospital,	  in	  which	  case	  

Principal	  Investigator/Program	  Director	  (Last,	  first,	  middle):	  Jones,	  Christopher,	  Warren	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  7	  
Feb	  8,	  2016	  
follow-­‐up	  will	  occur	  over	  the	  telephone.	  During	  this	  follow	  up	  assessment	  we	  will	  ask	  participants	  
about	  their	  current	  pain,	  any	  recurrence	  of	  pain	  since	  leaving	  the	  hospital,	  current	  functional	  status,	  
ability	  to	  tolerate	  oral	  intake,	  and	  adverse	  effects	  potentially	  related	  to	  the	  study	  intervention,	  
including	  pain	  at	  the	  IV	  site,	  symptoms	  of	  thrombophlebitis,	  or	  peripheral	  edema.	  Global	  assessment	  
of	  treatment	  is	  a	  function	  of	  both	  efficacy	  and	  tolerability,	  and	  will	  also	  be	  assessed	  by	  asking	  
patients	  “The	  next	  time	  you	  visit	  the	  ED	  with	  a	  headache,	  would	  you	  wish	  to	  receive	  the	  same	  IV	  
fluid	  treatment	  again?”	  
	  
5.   Outcomes	  
The	  primary	  outcome	  will	  be	  the	  difference	  in	  pain	  rating	  (0-­‐10)	  between	  the	  start	  of	  the	  study	  
intervention	  and	  one	  hour	  later,	  at	  completion	  of	  the	  intervention.	  	  The	  minimum	  clinically	  
significant	  difference	  between	  treatment	  groups	  on	  the	  0-­‐10	  verbal	  scale	  is	  1.3.36,	  38,	  39	  	  	  
	  
Secondary	  outcomes	  will	  include:	  
Percentage	  of	  patients	  in	  each	  group	  who	  are	  pain-­‐free	  two	  hours	  after	  initiation	  of	  the	  study	  
intervention.	  This	  outcome	  is	  recommended	  for	  study	  by	  the	  International	  Headache	  Society.37	  	  
	  
Difference	  in	  verbal	  pain	  scale	  between	  start	  and	  two	  hours.	  
	  
Global	  assessment	  of	  treatment,	  as	  described	  above.	  
	  
Functional	  disability	  at	  one	  and	  two	  hours	  as	  compared	  to	  the	  start	  of	  treatment.	  	  
	  
6.   Analysis	  
We	  performed	  our	  sample	  size	  calculation	  with	  the	  understanding	  that	  the	  primary	  goal	  of	  this	  pilot	  
study	  is	  to	  demonstrate	  the	  feasibility	  of	  the	  study	  protocol	  so	  as	  to	  inform	  a	  subsequent	  larger-­‐
scale	  trial.40	  The	  sample	  size	  calculation	  assumes	  a	  normal	  distribution.	  A	  sample	  size	  of	  50	  patients	  
will	  provide	  the	  ability	  to	  detect	  a	  protocol	  adherence	  rate	  of	  85%	  (+/-­‐	  10%)	  at	  a	  confidence	  level	  of	  
95%.	  In	  2015,	  the	  Cooper	  ED	  treated	  over	  300	  patients	  who	  were	  diagnosed	  with	  migraine	  
headache,	  suggesting	  that	  a	  goal	  of	  50	  participants	  over	  the	  10	  month	  active-­‐enrollment	  period	  is	  
attainable.	  	  
	  
Using	  an	  intention-­‐to-­‐treat	  analysis,	  the	  primary	  outcome	  will	  be	  analyzed	  by	  calculating	  the	  mean	  
change	  in	  pain	  scale	  within	  each	  study	  group,	  as	  well	  as	  95%	  confidence	  intervals	  surrounding	  these	  
point	  estimates.	  	  
IV.	  Expected	  outcome	  
	  
We	  anticipate	  that	  the	  results	  from	  this	  study	  will	  demonstrate	  the	  feasibility	  of	  identifying	  and	  enrolling	  
ED	  patients	  with	  migraine	  headache,	  completing	  the	  study	  protocol,	  and	  obtaining	  outcome	  data	  
including	  post-­‐discharge	  follow-­‐up	  assessments.	  We	  will	  determine	  the	  success	  of	  blinding	  both	  
participants	  and	  outcome	  assessors	  to	  the	  study	  intervention.	  This	  study	  will	  also	  provide	  preliminary	  

Principal	  Investigator/Program	  Director	  (Last,	  first,	  middle):	  Jones,	  Christopher,	  Warren	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  8	  
Feb	  8,	  2016	  
outcome	  data	  regarding	  the	  use	  of	  an	  IVF	  bolus	  for	  the	  treatment	  of	  migraine	  headache.	  These	  pilot	  
data	  will	  be	  used	  to	  support	  a	  future	  grant	  application	  for	  a	  larger	  study	  which	  will	  be	  appropriately	  
powered	  to	  determine	  the	  efficacy	  of	  this	  intervention.	  	  
	  
	  
	  
	  

Principal	  Investigator/Program	  Director	  (Last,	  first,	  middle):	  Jones,	  Christopher,	  Warren	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  9	  
Feb	  8,	  2016	  
References	  
	  
1.	  
Burch	  RC,	  Loder	  S,	  Loder	  E	  and	  Smitherman	  TA.	  The	  prevalence	  and	  burden	  of	  migraine	  
and	  severe	  headache	  in	  the	  United	  States:	  updated	  statistics	  from	  government	  health	  
surveillance	  studies.	  Headache.	  2015;	  55:	  21-­‐34.	  
2.	  
Friedman	  BW,	  Esses	  D,	  Solorzano	  C,	  et	  al.	  A	  randomized	  controlled	  trial	  of	  
prochlorperazine	  versus	  metoclopramide	  for	  treatment	  of	  acute	  migraine.	  Ann	  Emerg	  Med.	  
2008;	  52:	  399-­‐406.	  
3.	  
Bird	  S,	  Derry	  S	  and	  Moore	  RA.	  Zolmitriptan	  for	  acute	  migraine	  attacks	  in	  adults.	  
Cochrane	  Database	  Syst	  Rev.	  2014;	  5:	  CD008616.	  
4.	  
Singh	  A,	  Alter	  HJ	  and	  Zaia	  B.	  Does	  the	  addition	  of	  dexamethasone	  to	  standard	  therapy	  
for	  acute	  migraine	  headache	  decrease	  the	  incidence	  of	  recurrent	  headache	  for	  patients	  treated	  
in	  the	  emergency	  department?	  A	  meta-­‐analysis	  and	  systematic	  review	  of	  the	  literature.	  Acad	  
Emerg	  Med.	  2008;	  15:	  1223-­‐33.	  
5.	  
Friedman	  BW,	  West	  J,	  Vinson	  DR,	  Minen	  MT,	  Restivo	  A	  and	  Gallagher	  EJ.	  Current	  
management	  of	  migraine	  in	  US	  emergency	  departments:	  an	  analysis	  of	  the	  National	  Hospital	  
Ambulatory	  Medical	  Care	  Survey.	  Cephalalgia.	  2015;	  35:	  301-­‐9.	  
6.	  
Vinson	  DR,	  Hurtado	  TR,	  Vandenberg	  JT	  and	  Banwart	  L.	  Variations	  among	  emergency	  
departments	  in	  the	  treatment	  of	  benign	  headache.	  Ann	  Emerg	  Med.	  2003;	  41:	  90-­‐7.	  
7.	  
Bigal	  ME,	  Serrano	  D,	  Buse	  D,	  Scher	  A,	  Stewart	  WF	  and	  Lipton	  RB.	  Acute	  migraine	  
medications	  and	  evolution	  from	  episodic	  to	  chronic	  migraine:	  a	  longitudinal	  population-­‐based	  
study.	  Headache.	  2008;	  48:	  1157-­‐68.	  
8.	  
Hoppe	  JA,	  Kim	  H	  and	  Heard	  K.	  Association	  of	  emergency	  department	  opioid	  initiation	  
with	  recurrent	  opioid	  use.	  Ann	  Emerg	  Med.	  2015;	  65:	  493-­‐9	  e4.	  
9.	  
Jakubowski	  M,	  Levy	  D,	  Goor-­‐Aryeh	  I,	  Collins	  B,	  Bajwa	  Z	  and	  Burstein	  R.	  Terminating	  
migraine	  with	  allodynia	  and	  ongoing	  central	  sensitization	  using	  parenteral	  administration	  of	  
COX1/COX2	  inhibitors.	  Headache.	  2005;	  45:	  850-­‐61.	  
10.	  
Rudd	  RA,	  Aleshire	  N,	  Zibbell	  JE	  and	  Gladden	  RM.	  Increases	  in	  Drug	  and	  Opioid	  Overdose	  
Deaths	  -­‐	  United	  States,	  2000-­‐2014.	  MMWR	  Morb	  Mortal	  Wkly	  Rep.	  2016;	  64:	  1378-­‐82.	  
11.	  
Scher	  AI,	  Lipton	  RB,	  Stewart	  WF	  and	  Bigal	  M.	  Patterns	  of	  medication	  use	  by	  chronic	  and	  
episodic	  headache	  sufferers	  in	  the	  general	  population:	  results	  from	  the	  frequent	  headache	  
epidemiology	  study.	  Cephalalgia.	  2010;	  30:	  321-­‐8.	  
12.	  
Jones	  CW,	  Gaughan	  JP	  and	  McLean	  SA.	  Epidemiology	  of	  Intravenous	  Fluid	  Use	  for	  
Treatment	  of	  Headache	  in	  the	  Emergency	  Department:	  Findings	  from	  the	  National	  Hospital	  
Ambulatory	  Medical	  Care	  Survey.	  Manuscript	  under	  consideration,	  available	  on	  request.	  
13.	  
Blau	  JN.	  Water	  deprivation:	  a	  new	  migraine	  precipitant.	  Headache.	  2005;	  45:	  757-­‐9.	  
14.	  
Bhatia	  MS,	  Gupta	  R	  and	  Srivastava	  S.	  Migraine	  associated	  with	  water	  deprivation	  and	  
progressive	  myopia.	  Cephalalgia.	  2006;	  26:	  758-­‐60.	  
15.	  
Blau	  JN,	  Kell	  CA	  and	  Sperling	  JM.	  Water-­‐deprivation	  headache:	  a	  new	  headache	  with	  
two	  variants.	  Headache.	  2004;	  44:	  79-­‐83.	  
16.	  
Ogino	  Y,	  Kakeda	  T,	  Nakamura	  K	  and	  Saito	  S.	  Dehydration	  enhances	  pain-­‐evoked	  
activation	  in	  the	  human	  brain	  compared	  with	  rehydration.	  Anesth	  Analg.	  2014;	  118:	  1317-­‐25.	  
17.	  
Perry	  BG,	  Bear	  TL,	  Lucas	  SJ	  and	  Mundel	  T.	  Mild	  dehydration	  modifies	  the	  
cerebrovascular	  response	  to	  the	  cold	  pressor	  test.	  Exp	  Physiol.	  2015.	  

Principal	  Investigator/Program	  Director	  (Last,	  first,	  middle):	  Jones,	  Christopher,	  Warren	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
10	  
Feb	  8,	  2016	  
18.	  
Sedan	  O,	  Sprecher	  E	  and	  Yarnitsky	  D.	  Vagal	  stomach	  afferents	  inhibit	  somatic	  pain	  
perception.	  Pain.	  2005;	  113:	  354-­‐9.	  
19.	  
Headache	  Classification	  Committee	  of	  the	  International	  Headache	  S.	  The	  International	  
Classification	  of	  Headache	  Disorders,	  3rd	  edition	  (beta	  version).	  Cephalalgia.	  2013;	  33:	  629-­‐808.	  
20.	  
Stovner	  L,	  Hagen	  K,	  Jensen	  R,	  et	  al.	  The	  global	  burden	  of	  headache:	  a	  documentation	  of	  
headache	  prevalence	  and	  disability	  worldwide.	  Cephalalgia.	  2007;	  27:	  193-­‐210.	  
21.	  
Mazer-­‐Amirshahi	  M,	  Dewey	  K,	  Mullins	  PM,	  et	  al.	  Trends	  in	  opioid	  analgesic	  use	  for	  
headaches	  in	  US	  emergency	  departments.	  Am	  J	  Emerg	  Med.	  2014;	  32:	  1068-­‐73.	  
22.	  
Dart	  RC,	  Surratt	  HL,	  Cicero	  TJ,	  et	  al.	  Trends	  in	  opioid	  analgesic	  abuse	  and	  mortality	  in	  the	  
United	  States.	  N	  Engl	  J	  Med.	  2015;	  372:	  241-­‐8.	  
23.	  
Milinkovic	  M,	  Zidverc-­‐Trajkovic	  J,	  Sternic	  N,	  et	  al.	  Hemodialysis	  headache.	  Clin	  Nephrol.	  
2009;	  71:	  158-­‐63.	  
24.	  
Balbin	  JE,	  Nerenberg	  R,	  Baratloo	  A	  and	  Friedman	  BW.	  Intravenous	  fluids	  for	  migraine:	  A	  
post-­‐hoc	  analysis	  of	  clinical	  trial	  data.	  AJEM.	  2015;	  doi:	  10.1016/j.ajem.2015.12.080.	  
25.	  
Denny	  CJ	  and	  Schull	  MJ.	  In:	  Tintinalli	  JE,	  Stapczynski	  JS,	  Ma	  OJ,	  Cline	  DM,	  Cydulka	  RK,	  
Meckler	  GD,	  eds.	  Emergency	  Medicine:	  A	  Comprehensive	  Study	  Guide.	  7	  ed.	  New	  York,	  NY:	  
McGraw-­‐Hill,	  2011.	  
26.	  
Robertson	  CE,	  Black	  DF	  and	  Swanson	  JW.	  Management	  of	  migraine	  headache	  in	  the	  
emergency	  department.	  Semin	  Neurol.	  2010;	  30:	  201-­‐11.	  
27.	  
Hijazi	  R,	  Taylor	  D	  and	  Richardson	  J.	  Effect	  of	  topical	  alkane	  vapocoolant	  spray	  on	  pain	  
with	  intravenous	  cannulation	  in	  patients	  in	  emergency	  departments:	  randomised	  double	  blind	  
placebo	  controlled	  trial.	  BMJ.	  2009;	  338:	  b215.	  
28.	  
Lee	  WL,	  Liao	  SF,	  Lee	  WC,	  Huang	  CH	  and	  Fang	  CT.	  Soft	  tissue	  infections	  related	  to	  
peripheral	  intravenous	  catheters	  in	  hospitalised	  patients:	  a	  case-­‐control	  study.	  J	  Hosp	  Infect.	  
2010;	  76:	  124-­‐9.	  
29.	  
Tagalakis	  V,	  Kahn	  SR,	  Libman	  M	  and	  Blostein	  M.	  The	  epidemiology	  of	  peripheral	  vein	  
infusion	  thrombophlebitis:	  a	  critical	  review.	  Am	  J	  Med.	  2002;	  113:	  146-­‐51.	  
30.	  
Holte	  K,	  Klarskov	  B,	  Christensen	  DS,	  et	  al.	  Liberal	  versus	  restrictive	  fluid	  administration	  
to	  improve	  recovery	  after	  laparoscopic	  cholecystectomy:	  a	  randomized,	  double-­‐blind	  study.	  
Annals	  of	  Surgery.	  2004;	  240:	  892-­‐9.	  
31.	  
Springhart	  WP,	  Marguet	  CG,	  Sur	  RL,	  et	  al.	  Forced	  versus	  minimal	  intravenous	  hydration	  
in	  the	  management	  of	  acute	  renal	  colic:	  a	  randomized	  trial.	  J	  Endourol.	  2006;	  20:	  713-­‐6.	  
32.	  
Ali	  SZ,	  Taguchi	  A,	  Holtmann	  B	  and	  Kurz	  A.	  Effect	  of	  supplemental	  pre-­‐operative	  fluid	  on	  
postoperative	  nausea	  and	  vomiting.	  Anaesthesia.	  2003;	  58:	  780-­‐4.	  
33.	  
Elhakim	  M,	  el-­‐Sebiae	  S,	  Kaschef	  N	  and	  Essawi	  GH.	  Intravenous	  fluid	  and	  postoperative	  
nausea	  and	  vomiting	  after	  day-­‐case	  termination	  of	  pregnancy.	  Acta	  Anaesthesiol	  Scand.	  1998;	  
42:	  216-­‐9.	  
34.	  
Lambert	  KG,	  Wakim	  JH	  and	  Lambert	  NE.	  Preoperative	  fluid	  bolus	  and	  reduction	  of	  
postoperative	  nausea	  and	  vomiting	  in	  patients	  undergoing	  laparoscopic	  gynecologic	  surgery.	  
AANA	  J.	  2009;	  77:	  110-­‐4.	  
35.	  
Chaudhary	  S,	  Sethi	  AK,	  Motiani	  P	  and	  Adatia	  C.	  Pre-­‐operative	  intravenous	  fluid	  therapy	  
with	  crystalloids	  or	  colloids	  on	  post-­‐operative	  nausea	  &	  vomiting.	  Indian	  J	  Med	  Res.	  2008;	  127:	  
577-­‐81.	  

Principal	  Investigator/Program	  Director	  (Last,	  first,	  middle):	  Jones,	  Christopher,	  Warren	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
11	  
Feb	  8,	  2016	  
36.	  
Bijur	  PE,	  Latimer	  CT	  and	  Gallagher	  EJ.	  Validation	  of	  a	  verbally	  administered	  numerical	  
rating	  scale	  of	  acute	  pain	  for	  use	  in	  the	  emergency	  department.	  Acad	  Emerg	  Med.	  2003;	  10:	  
390-­‐2.	  
37.	  
Tfelt-­‐Hansen	  P,	  Pascual	  J,	  Ramadan	  N,	  et	  al.	  Guidelines	  for	  controlled	  trials	  of	  drugs	  in	  
migraine:	  third	  edition.	  A	  guide	  for	  investigators.	  Cephalalgia.	  2012;	  32:	  6-­‐38.	  
38.	  
Gallagher	  EJ,	  Liebman	  M	  and	  Bijur	  PE.	  Prospective	  validation	  of	  clinically	  important	  
changes	  in	  pain	  severity	  measured	  on	  a	  visual	  analog	  scale.	  Ann	  Emerg	  Med.	  2001;	  38:	  633-­‐8.	  
39.	  
Todd	  KH,	  Funk	  KG,	  Funk	  JP	  and	  Bonacci	  R.	  Clinical	  significance	  of	  reported	  changes	  in	  
pain	  severity.	  Ann	  Emerg	  Med.	  1996;	  27:	  485-­‐9.	  
40.	  
Arnold	  DM,	  Burns	  KE,	  Adhikari	  NK,	  et	  al.	  The	  design	  and	  interpretation	  of	  pilot	  trials	  in	  
clinical	  research	  in	  critical	  care.	  Crit	  Care	  Med.	  2009;	  37:	  S69-­‐74.