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Grande half-sweet caffeine for

post-dural headaches

Iona Berger

January 31, 2017

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Objectives

o Describe the pathophysiology and signs and

symptoms of post-dural headaches

o Explain the proposed mechanism of action of

caffeine

o Summarize the evidence of caffeine in post-dural

headaches

Meet our Patient

ID TR- 17 y/o ♂ 49.8 kg

CC Headaches lasting > 3 hours post-LP

HPI Burkitt’s leukemia diagnosed Dec 2016 treated with

ANHL01P1 group C

Received intrathecal (IT) therapy as part of chemotherapy – on

Jan 13, developed a headache that persisted >3 h

Had similar headaches during PICU stay in December

(=hypotension, fever, hematemesis)

Allergies NKDA

Immunization UTD

Birth Hx Unremarkable

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Meet our Patient

PMHx Previously healthy

MPTA None

Social

history

No drinking/smoking

Some recreational marijuana use

Not sexually active.

Lives at home with 3 siblings and parents

Family

history

Maternal great aunt X 2: breast cancer

Maternal great uncle: liver and prostate cancer (associated

with alcohol abuse)

Maternal great uncle: leukemia

Maternal great grandfather: liver cancer

Paternal grandmother: adrenal and lung cancer

Paternal great uncle: liver and lung cancer (was a ppd smoker)

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Review of Systems Vitals T:36.7oC(PO), HR: 59supine-110standing, BP: 112/67, RR: 18,

O2 sat: 98% on RA

CNS Headache:

• P: provoked by standing, alleviated when supine

• Q: frontal/occiptal distribution associated with marked

orthostatic tachycardia

• R: radiating from base of neck, bilateral

• S: pain score 4/10

• T: occurring ~ 3hrs post-LP/IT therapy, occurred when

hypotensive during PICU stay

HEENT Ulcers in oral cavity (=mucositis)

7 dental caries

CVS Unremarkable

RESP Unremarkable

GI Unremarkable

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Review of Systems GU/renal Urea: 4.8, Cr: 60

MTX level: 2.04

Liver Alb: 33

Lytes/Fluids Na: 144, K: 3.5, Ca: 2.07, Mg: 0.82, PO4: 1.05

Heme WBC: 4.7, Neuts: 2,71, Hgb: 88, Plt: 547

CSF analysis: 0.5mL, clear, colourless, nucleated cells <1,

RBC <1, lymph: 53, monomacrophages: 23, cells counted: 76,

glucose = 4.9, protein: 0.37

Endocrine Unremarkable

MSK Unremarkable

Derm Scrotal erythema

Satellite lesions on thighs

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Medical Problem List

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Medical Problems Medications

Burkitt’s leukemia ANHL01P1 protocol:

COMRAP 1 regimen (Day -2 = Dec 17)

- Rituximab (day -2, 0)

- Vincristine (day 0)

- Prednisone (day 0-7)

- Methotrexate (day 0)

- Leucovorin (day 1-3)

- Cyclophosphomide (day 1-3)

- Doxorubicin (day 1)

- IT MTX + hydrocortisone + cytarabine (day 0, 2, 4)

- G-CSF (days 6-20)

COMRAP 2 regimen (Day -2 = Jan 10)

Same as above except:

- IT MTX + hydrocortisone + cytarabine (day 1, 4, 6)

Medical Problem List

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Medical Problems Medications

Post-LP headache

Chemotherapy-induced

mucositis

Glutamine powder 10g PO once daily (=0.2g/kg/day)

Hydromorphone 1mg PO Q4H PRN (=0.02mg/kg/dose)

Seattle mouthwash (AlOH+MgOH) 10mL swish and

spit TID

PJP prophylaxis TMP/SMX: 2 tabs AM and 1 tab PM PO every Saturday

& Sunday (=5mg/kg/day)

GERD Ranitidine 50mg IV Q6H (=4.16 mg/kg/day)

Chemotherapy-induced

nausea and vomiting

Ondansetron 8mg IV Q8H (=0.16 mg/kg/dose)

Dimenhydrinate 50mg IV Q4H PRN (=1.04mg/kg/dose)

Scrotal erythema and

satellite lesions

Triple cream (desitin, nystatin and polysporin) apply to

affected area BID PRN

DTPs

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• TR is experiencing post-dural (post-LP)

headaches and requires reassessment of drug

therapy

• TR is experiencing mucositis and requires

reassessment of glutamine dosing

• TR is at risk of tooth pain and infections due to

having untreated dental caries and requires

reassessment

DTPs

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• TR is experiencing post-dural (post-LP)

headaches and requires reassessment of drug

therapy

• TR is experiencing mucositis and requires

reassessment of glutamine dosing

• TR is at risk of tooth pain and infections due to

having untreated dental caries and requires

reassessment

LPs

• Performed to obtain CSF from

subarachnoid space

• Typically midline between:

o L3&L4 or L4&L5

o Inferior to spinal cord

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Pathophysiology post-LP

headaches • Lumbar puncture can cause excessive

CSF volume leakage:

• May cause downward pull and

stretching of pain-sensitive intracranial

structures esp. when upright

• May cause an increase in blood flow

resulting in arterial and venous

venodilation intracranial hypotension

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S/Sx of post-LP headache

• Postural nature of the headache is the

hallmark

– ↑ in severity of the headache when standing

is essential for diagnosis

• Throbbing pain in frontal or occipital areas

• 90% of post-LP Has occur w/in 3 days of

LP and 66% start in the first 48 hours

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Goals of Therapy

1. Prevent morbidity (=ongoing headache, inability

to participate in physiotherapy)

2. Alleviate signs and symptoms (=headache, pain)

3. Minimize adverse drug reactions

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Alternatives Prevention: Needle size, shape & orientation

Patient positioning

Hydration

Analgesics (acetaminophen, ibuprofen)

Opioids (morphine, hydromorphone)

Caffeine

Epidural blood patch

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J Pediatr Oncol Nurs 2007;24(4):200–7

Alternatives Prevention: Needle size, shape & orientation

Patient positioning

Hydration

Analgesics (acetaminophen, ibuprofen)

Opioids (morphine, hydromorphone)

Caffeine

Epidural blood patch

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J Pediatr Oncol Nurs 2007;24(4):200–7

Proposed Mechanism of

Action of Caffeine

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• Caffeine readily crosses the blood-brain

barrier and is a nonselective competitive

antagonist of adenosine receptors

• Caffeine inhibits adenosine which ↓ resting

cerebral blood flow vasoconstriction of

dilated cerebral vessels

Clinical Question

Patient Post-dural headaches

Intervention Caffeine

Comparison Placebo or conventional therapy (hydration, postural

positioning)

Outcome Efficacy: relief of headache symptoms, prevention of

recurrence of headache

Safety: adverse events of caffeine

Search Strategy Databases Medline/PubMed, Ovid/Embase, Google Scholar

Search Terms 1. Post-dural or post lumbar puncture

2. Headache

3. Caffeine

4. Treatment

Limitations Excluded trials about: prophylaxis

Limited to: English language

Results 2 RCTs

1 case report

Ford, et al. 1988

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A Simple Treatment of Post-Lumbar Puncture

Headache P 34 y/o woman with severe headache (had myelogram of the lumbar

region 3 days prior to onset of headache)

I Caffeine sodium benzoate 500mg IV (infused over 1.5 hours)

O Efficacy: Headache resolution

F/up @ 72 hours: no headache recurrence

Safety: No adverse events reported

The use of intravenous caffeine sodium

benzoate should be considered for patients

presenting to the ED with post-lumbar

puncture headache

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Conclusion

Limitations

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Evidence Quality • Case report

• Minimal details regarding clinical outcomes and safety

outcomes reported

• No placebo control

Generalizability • Pediatric oncology implications

• N=1

• Short follow up (72 hours)

• No description of other agents that may have been

used (? confounders)

Camann, et al. 1990

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Effects of Oral Caffeine on Postdural Puncture

Headache: A Double-Blind Placebo-Controlled Trial D Randomized double-blind placebo-control trial

P 40 postpartum patients with a postdural puncture headache

Exclusion: Hypertension, pre-eclampsia, seizure disorder, intolerance to

caffeine or consumed beverages containing caffeine within the previous

4 hours

I Caffeine 300 mg capsule

C Placebo capsule (lactose powder)

O 1. Number of participants with EBP performed

2. Change in pain severity VAS score after 4 and 24 hours

3. Number of participants showing improvements in pain severity VAS

score at 4 hours

4. Adverse events

Results

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Outcome Caffeine

(n= 20)

Placebo

(n=20)

P-value

DVAS (from baseline) at 4h 36.1 + 5.5 10.9 + 6.7 0.014

Number of patients with improved

VAS scores at 4h

18/20 12/20 0.06

DVAS (from baseline) at 24h 28 + 5 16 + 4

Require epidural blood patch 35% 55%

ADRs reported N=1

(transient

flushing and

jitteriness)

N=1

(transient

flushing and

jitteriness)

A single dose of oral caffeine (300 mg) is

effective and safe and merits consideration

in the early treatment of PDPH.

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Conclusion

Limitations

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Selection bias • No information provided. Reported as randomized

• Baseline characteristics mostly balanced

• VAS scores higher in caffeine group at baseline (69

vs. 60)

Performance and

detection bias

• Low risk – capsules were prepared to appear

identical

Reporting bias • Does not report statistical p value of effect at VAS

reduction at 24 hours

Generalizability • Present study conducted in postpartum patients –

different elimination than non-pregnant patients

• Short follow up (only 24 hours) – post lumbar

puncture headache can last ~ 7 days

Sechzer and Abel. 1978

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Post-spinal anesthesia headache treated with

caffeine. Evaluation with demand method. Part 1

D Randomized, double-blind, parallel placebo-controlled, single-center

P 41 pts post-spinal anaesthesia, with “usual symptomatic treatment”

unsatisfactory and headache through a 2- to 4-day course

I Intravenous caffeine sodium benzoate 500 mg iv q8h

* Supplementary caffeine (500 mg) was administered if H/A persisted

after 1 to 2 hours

C Intravenous physiologic saline solution

O PDPH relieved (of any severity) at 1 to 2 hours

Results

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Outcome Caffeine

(n=20)

Placebo

(n=20)

RR

(95% CI)

Primary outcome:

“Do you want another injection of

caffeine sodium benzoate?”/Lack of

headache relief

5/20 18/21 0.29

[0.13-0.64]

ARR: 61%

NNT: 1.6

Caffeine sodium benzoate (1-2 doses of 500

mg IV) was effective at alleviating post-dural

headaches after 1-2 hours.

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Conclusion

Limitations

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Selection bias • Randomized – but poorly described

• No baseline characteristics described

Performance and

detection bias

• Syringes were coded so that observers were not

aware of the contents

Reporting bias • No adverse events reported

Generalizability • Subjective assessment of primary outcome

• Questionable methodology

• Placebo arm of the study crosses over into

treatment arm

Conclusion of the evidence

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Article Efficacy Safety

Ford, et al. 1988 Headache resolved with

caffeine sodium benzoate

500 mg IV

Not described

Camann, et al. 1990 Headache severity

decreased by 36 pts at

4h, 28 pts at 24h from

baseline respectively

# of pts with improved

VAS scores at 4h:

RR = 150% (p =0.06)

Transient flushing

and jitteriness

(N=2)

(1caffeine ;1placebo)

Sechzer and Abel.

1978

ARR: 61% of caffeine to

reduce H/A at 1-2 hours

Not described

Relating it to TR

• Recommendations:

– Non-pharm: Hydration/fluids, to remain supine

post-LP

– Caffeine 300mg PO as a single dose

– Glutamine 13g PO BID *mix w/ liquid or soft

food*

– Book dentistry appointment before next round

of chemo (Feb 3)

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Monitoring Plan

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Expected change Frequency of

monitoring

Vitals BP: 110-131/64-83 mmHg (change between

standing and supine BP < 20/10 mmHg), HR:

57-97, RR: 15-20, T <37.3oC(ax)

Q4H (BP/HR)

Qshift (RR, temp)

CNS Pain score = 0-1/10 (even when not supine)

Absence of dizziness, insomnia, irritability,

restlessness, facial edema

Q4H

HEENT Resolution of ulcers in oral cavity Daily

CVS Absence of flushing

GI/Liver Absence of abdominal pain, nausea, gastritis Daily

Lytes Fluid balance ~ 0 mL/day Daily

HEME ANC > 0.5 Twice weekly

Follow up

• Team accepted recommendations and recommended a

smaller gauge needle for future LP/IT

• TR found caffeine effective at aborting headache

however time of administration was 16:00 resulting in

insomnia (did not sleep until 06:00 next day)

• Subsequent post-LP headache was treated with caffeine

300mg x 1 dose. Headache persisted and also had

insomnia secondary to caffeine. Headache aborted with

PRBC transfusion (patient was found to be anemic at

later date) and adequate hydration.

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References

1. Lee LC-Y, Sennett M, Erickson JM. Prevention and management of post-lumbar puncture

headache in pediatric oncology patients. J Pediatr Oncol Nurs [Internet]. 2007;24(4):200–7.

Available from: http://www.ncbi.nlm.nih.gov/pubmed/17588892

2. Ona X, Osorio D, Cosp X. Drug therapy for treating post-dural puncture headache.

Cochrane Database Syst Rev [Internet]. 2015;(7): 1-49. Available from:

http://search.ebscohost.com/login.aspx?direct=true&db=rzh&AN=108247857&site=ehost-

live

3. Janssens E, Aerssens P, Alliët P, Gillis P, Raes M. Post-dural puncture headaches in

children. A literature review. Eur J Pediatr [Internet]. 2003;162(3):117–21. Available from:

http://www.ncbi.nlm.nih.gov/pubmed/12655411

4. Ford CD, Ford DC, Koenigsberg MD. A simple treatment of post-lumbar-puncture

headache. J Emerg Med. 1989;7(1):29–31.

5. Camann WR, Murray RS, Mushlin PS, Lambert DH. Effects of oral caffeine on postdural

puncture headache. A double-blind, placebo-controlled trial. Anesth Analg [Internet].

1990;70(2):181–4. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2405733

6. Sechzer PH, Abel L. Post-spinal anesthesia headache treated with caffeine. Evaluation

with demand method. Part I. Current Therapeutic Research Clinical and Experimental

1978;24(3):307–12.

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Questions?