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Cefalosporins

Cefalosporins have a broader activity than penicillins, esp 3rd generation eg cefotaxime, ceftriaxone which are effective against most gram positives and gram negatives.

Good for meningitis (penetrate inflamed meninges at high dose) but not effective against pseudomonas, enterococcus, listeria, MRSA, and not that great against normal staphs so beware if possible line infection or neonatal meningitis. Some pneumococci can be resistant (1st line meningitis treatment in US is cef with vanc).

Ceftriaxone is drug of choice for Lyme with complications; it is not recommended for immediate treatment of meningococcal disease as any subsequent calcium containing infusions will reduce its plasma levels.

Ceftriaxone also eradicates meningococcal colonization – since cefotaxime is essentially equivalent, no reason to switch just for this indication.

Contraindications to ceftriaxone:

  • Concomitant treatment with intravenous calcium (including total parenteral nutrition) in premature and full-term neonates—risk of precipitation in urine and lungs (fatal reactions) ;
  • full-term neonates with jaundice, hypoalbuminaemia, acidosis, unconjugated hyperbilirubinaemia, or impaired bilirubin binding—risk of developing bilirubin encephalopathy;
  • premature neonates less than 41 weeks corrected gestational age

Paediatric Sepsis 6

Consider sepsis or septic shock if a child has a suspected or proven infection and has at least 2 of the following:

  • Core temperature <36°C or >38.5°C
  • Inappropriate tachycardia (according to local criteria or advanced paediatric life support guidance)
  • Altered mental state (e.g., sleepiness, irritability, lethargy, floppiness, decreased conscious level)
  • Reduced peripheral perfusion or prolonged capillary refill.

If in doubt, seek an experienced opinion!

Within 1 hour of presentation, sepsis should be treated with:

  • Supplemental oxygen
  • IV (or IO) access – within 5 minutes of presentation – and blood tests including blood cultures, blood glucose,  and blood gas.
    • FBC, serum lactate, and CRP should also be ordered for baseline assessment.
    • Low blood glucose should be treated
  • IV or IO antibiotics should be given with broad-spectrum cover as per local policies.
  • Fluid resuscitation should be considered – aim to restore normal circulating volume and physiological parameters. Isotonic fluid (20 mL/kg) should be titrated over 5 minutes and repeated as necessary.
    • Beware fluid overload – look for crepitations and hepatomegaly.
  • Experienced senior clinicians or specialists should be involved and consulted early.
  • Inotropes should be considered early if normal physiological parameters are not restored after giving ≥40 mL/kg of fluids. It is important to note that adrenaline (epinephrine) or dopamine may be given via peripheral IV or IO access.

UK Sepsis Trust have Red Flag screening & action tool –

Start Sepsis6 pathway if ONE red flag:

  • objective change in behaviour or mental state
  • Unrousable or won’t stay awake
  • Looks very ill to HCP
  • Sats under 90% or new need for oxygen
  • Severe tachypnoea
  • Severe tachycardia
  • Bradycardia
  • Not passed urine in last 18h
  • Mottled, ashen or blue skin, lips or tongue
  • Non-blanching rash

Otherwise, any amber flags:

  • Behaving abnormally, not wanting to play
  • Significantly decreased activity/parental concern
  • Sats under 90^% or moderate tachypnoea
  • Moderate tachycardia
  • CRT >=3secs
  • Reduced urine output
  • leg pain
  • Cold feet/hands
  • Immunocompromise

If 2 then do bloods, consider if just 1.  Review by ST4 within 1 hour.

If lactate >2 then start Sepsis6

Antenatal corticosteroids

Proven to reduce the incidence of respiratory distress syndrome (RDS) due to surfactant deficiency.

Meta-analysis shows benefit even for babies near term ie 34-39/40!  Risk ratio 0.74.

Not much data on long term outcomes, of course, but RDS rates high even at 38 weeks so LSCS should not be planned until 39 weeks.

Repeat courses of antenatal steroids (due to threatened delivery) associated with lower birth weight, so should ideally be limited to 3. [https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002771]

The GINI study

German study from 1998.

Some potential benefit from using hydrolyzed formula in terms of preventing allergy.  The relative risk for the cumulative incidence of any allergic disease in the intention-to-treat analysis (n = 2252) was:

  • 0.87 (95% CI, 0.77-0.99) for partially hydrolysed whey-based formula (pHF-W),
  • 0.94 (95% CI, 0.83-1.07) for extensively hydrolysed whey-based formula (eHF-W) eg Pepti, and
  • 0.83 (95% CI, 0.72-0.95) for extensively hydrolysed casein-based formula (eHF-C) eg Nutramigen compared with standard cow’s milk formula.

The corresponding figures for atopic eczema/dermatits (AD) were 0.82 (95% CI, 0.68-1.00), 0.91 (95% CI, 0.76-1.10), and 0.72 (95% CI, 0.58-0.88), respectively.

In the per-protocol analysis (ie where patients stuck to protocol) effects were stronger (0.49 for eczema at 1yr). The period prevalence of AD at 7 to 10 years was significantly reduced with eHF-C in this analysis, but there was no preventive effect on asthma or allergic rhinitis.

[J Allergy Clin Immunol. 2013 Jun;131(6):1565-73. doi: 10.1016/j.jaci.2013.01.006. ]

Cochrane review 2009 biased towards GINI data.  Since then big Melbourne study (MACS) not in favour; per protocol analysis for eczema at age 1 yr did not show any benefit (0.55-1.93).

Even with GINI, NNT could be as high as 80!

[http://onlinelibrary.wiley.com/doi/10.1111/pai.12138/full]

15 yr follow up of GINI study – between 11 and 15 years,

  • prevalence of asthma was reduced in the eHF‐C group compared to CMF (OR 0.49, 95% CI 0.26–0.89)
  • cumulative incidence of atopic rhinitis was lower in eHF‐C (risk ratio (RR) 0.77, 95% CI 0.59–0.99]) and the AR prevalence lower in pHF‐W (OR 0.67, 95% CI 0.47–0.95) and eHF‐C (OR 0.59, 95% CI 0.41–0.84).
  • cumulative incidence of eczema was reduced in pHF‐W (RR 0.75, 95% CI 0.59–0.96) and eHF‐C (RR 0.60, 95% CI 0.46–0.77), as was the eczema prevalence between 11 and 15 years in eHF‐C (OR 0.42, 95% CI0.23–0.79).
  • No significant effects were found in the eHF‐W group on any manifestation,nor was there an effect on sensitization with any formula.

[Allergy 2016; 71: 210–219. http://onlinelibrary.wiley.com/doi/10.1111/all.12790/abstract]

The EAT study

2016 study of early introduction of six common food allergens into the diet of 1303 breastfed 3 month old infants recruited from a general (not high risk) population.

Randomized.  Breast feeding needed to be maintained until at least 5 months, at least 5 weeks of at least 75% of recommended dose (ie 3g of protein per week) between 3 and 6 months.

2g protein twice weekly was recommended – 2g is roughly:

  • 2 teaspoons peanut butter or 21 Bamba pieces
  • 1 small pot yogurt
  • 1/2 small egg
  • 10g fish
  • 1tsp tahini

In an intention to treat analysis, 7.1% of the standard introduction group (at parental discretion) and 5.6% of the early introduction group developed food allergy to one or more of the six intervention foods (peanuts, egg, cow’s milk, sesame, white fish and wheat) up to 3 years of age (p=0.32, ie no difference).

However, when the analysis was adjusted for adherence to early introduction, there was a statistically significant 67% lower rate of food allergy in the early introduction group (2.4% vs 6.4%; p=0.03), with no cases of peanut allergy (rate was 2.5% in control group) and 75% less egg allergy (1.4% vs 5.5%).  Rate of skin prick test positivity significantly lower for peanut, egg, milk, sesame.

Cooked egg works! Increasing dose, increasing effect.  Modelling suggests 2g protein weekly effective.

Safe!

However, poor adherence to the study protocol (only 32% managed to follow early introduction fully) highlights the challenges around introducing solids.

[Michael Perkins, DOI: 10.1056/NEJMoa1514210]

Cluster headache

Very rare – unilateral, orbital, supraorbital and/or temporal. Pain lasts 15-180mins but attacks occur multiple times a day (or at least on alternate days). Associated with autonomic features eg ipsilateral conjunctival injection, nasal congestion, forehead sweating, miosis, ptosis, agitation. Peak incidence in 20s, males predominate.

Can be episodic (bouts lasting 6-12 weeks every 1-2years) or else chronic.

Treat with high flow O2! Sumatriptan SC better than nasal, Zolmitriptan nasal preferred to oral or sumatriptan. Safe, licensed for kids.

Prophylaxis in adults is with verapamil!

Tension headache

Tension headache

  • Mild to moderate rather than severe,
  • pressing or tightening rather than pulsatile,
  • Bilateral,
  • Not aggravated by routine physical activity.

Can be continuous. Phonophobia, photophobia, nausea are possible, but if more than one present, and particularly if vomiting or severe nausea, then migraine would be preferred diagnosis.

Often spreads into or arises from neck.

Chronic tension-type headache – as above but on >/15 days/month for at least 3 months. But gets messy – it is possible that a patient can have both this and Chronic migraine, viz only two of the four pain characteristics are present and associated with mild nausea. In all these cases consider Medication-overuse headache.

Idiopathic intracranial hypertension

Previously “Benign” Intracranial Hypertension but not entirely benign…

Intracranial hypertension but with normal CSF, and no ventriculomegaly. Presents with usual symptoms of early morning headache, effortless vomiting. VI nerve palsy may be seen, rarely II/IV. Papilloedema is often the first clue.

No sex differential prepubertally, not associated with obesity (contrary to popular belief).

Normal CSF opening pressure is 7.5cm of water <2yr, 13.5 <5yr, 20 over 5yr. Lumbar puncture is therapeutic; 2 step tap procedure is usually used if opening pressure is over 30cm. NB General anaesthetic can give false pos result! Secondary causes include drugs, endocrine conditions.

Since repeated LP is unpleasant, medical therapy can be considered. Topiramate is probably equivalent to the more usual acetazolamide (a diuretic). Steroids should be used for malignant hypertension (ie where there is rapid progression). Any of these treatments may result in a low pressure headache.

Surgical options include Optic nerve sheath fenestration, lumbar-peritoneal shunt.

Headache

Common problem in children, as well as adults!

Distinguish primary from secondary.

Most headaches get worse with exertion so that’s not a discriminating feature.  Headaches that get worse on standing suggest a CSF leak; worse on lying down suggests a tumour.  See NICE CKS.

Primary

Secondary

Migraine

International Headache Society 2004 Migraine without aura def:

  • A – at least 5 attacks fulfilling B-D
  • B – lasting 1-72hr
  • C – at least 2 of:
    • unilateral, may be bilateral frontotemporal but not occipital;
    • pulsing;
    • moderate or worse pain;
    • aggravation by routine physical activity eg walking, stairs
  • D – during headache at least 1 of: nausea +/or vomiting, photophobia and phonophobia (which may be inferred from behaviour)
  • E – not attributed to other disorder

Aura – Hemianopia or spreading scintillating scotoma. Note that migraine with aura is a contraindication to treatment with combined oral contraceptives.

Some specific types:

  • Hemiplegic – can be familial or sporadic.  Can be confusion.  Rare to not have headache with it (but then diagnosis perhaps not recognised!?).  Triptans were initially thought to be risky, but more recently good evidence of usefulness and no longer contraindicated in BNFc.
  • Ocular/retinal – blindness or flashing lights, may not be headache.  NOT aura, which is prodromal.  Horner’s syndrome seen.
  • Basilar (also called Bickerstaff’s – but better termed migraine with brainstem aura) – transient dysarthria, vertigo, tinnitus, hearing impairment, diplopia, ataxia, confusion, bilateral paresthesia,
  • Confusional

Pathology

Neuronovascular condition – baseline hyperexcitability in cortex.

Double the risk if you had infant colic, which is not true for tension headache!  Sleep disruption as common factor? [JAMA 2013;309:1607-12]

Several genetic links found eg C677T mutation of the methylenetetrahydrofolate reductase gene (MTHFR), EAAT2. [J Headache Pain. Jan 2012; 13(1): 1–9.  doi:  10.1007/s10194-011-0399-0]

Investigations

Beware Occipital epilepsy!

American Academy of Neurology recommendations are that neuroimaging should be considered in:

  • recent onset of severe headache;
  • change in type of headache;
  • or neurological dysfunction;
  • seizures

Factors

  • Biofeedback and relaxation/stress management are as effective as beta blockers. Indian trial of yoga for migraine showed substantial improvement at 3 months [neurology 2020]
  • Sleep disturbance is associated but not necessarily causal – so recommend good sleep hygiene.
  • Exercise is beneficial.
  • Obesity – clusters with diet, exercise, sleep issues of course.
  • Missing breakfast is a common precipitant.
  • Episodic migraine (without aura) can become chronic (ie 15 days per month or more), but in this case you would always want to exclude medication overuse.
  • Caffeine is linked to headache and also sleep/mood disorder which exacerbates. Withdrawal headache can last as long as a week.
  • Wine is well recognised trigger in adults!
  • Often linked to menstrual cycle.
  • Screen time (>2hrs per day) linked to migraine but not non-migraine headache in French and Sri Lankan students.  Doesn’t necessarily mean reducing screen time helps, of course.  But note eye strain, posture relevant too.  And possibly differences between TV/PC use and mobile devices.
  • Some evidence for magnesium and zinc supplementation

[CurrOpPeds Dec 2004]

Diet

Although popular perception is that migraine is caused or at least triggered by dietary factors, there is a wide variation in reporting of dietary triggers. Certainly migraine is associated with obesity, and dietary habits seem to be as important as specific foods, and there is probably a cycle of inconsistent nutrition and poor control of migraine.

My colleagues talk about 4Cs (chocolate, cheese, coffee, citrus) but I have found no evidence for this.  Awareness of possibility of dietary triggers actually has greater influence on perception of personal triggers than personal experience!  See below.

Some evidence for lipid intake esp PUFA (decreased ingestion of lipids was associated with a decrease in the frequency, intensity, and duration of migraines and a decrease in the use of medication) but confounded by obesity, weight reduction, and changes in nutrient intake.  Another study found reduced migraine spells among children subjected to a diet rich in fibre. Not much evidence for cheese at all! [Nutrition Reviews. 70(6):337-56, 2012 Jun.  UI: 22646127]

Trial of cyanocobalamin, folate, and pyridoxine (2 mg of folic acid, 25 mg vitamin B6, and 400 microg of vitamin B12) in patients with MTHFR gene defects found a reduction of homocysteine levels and improvement of migraines. [Pharmacogenetics and Genomics. 22(10):741-749, October 2012]

Medication

Paracetamol, ibuprofen, and nasal-spray sumatriptan are all effective symptomatic treatments for episodes of migraine (peds sys rv 2005). Migraleve is paracetamol, codeine (8mg), buclizine – for 10yr plus. Paramax, with metoclopramide, for 12 yr plus.  Anti-emetic improves pain killer absorption so potential benefit even if no nausea!

Sumatriptan was previously contraindicated for hemiplegic migraine, but this was probably a theoretical concern, and there is evidence that it works. No caution or contraindication mentioned in BNF now.

Mefenamic acid for menstrual, esp with dysmenorrhea.

CGRP receptor antagonists – olcegepant, telcagepant [not in BNF].  Now erenumab [monthly subcut injections, BNF says specialist use only, minimum 4 migraines per month – SMC approved with restrictions], eptinezumab etc vs same calcitonin gene-related peptide receptor.  Significant improvement in headaches in 40%, about 3 less headache days per month.

For prophylaxis, Pizotifen does not work (grade I evidence, plus makes you fat), flunarizine (CCB) is the most effective (not in BNF), also amitriptyline (dangerous in overdose), propanolol (dizziness, sleep disturbance, depression etc, also dangerous in overdose). Encouraging data (grade IV) for anti-epileptic mediations topiramate, valproate, levetiracetam, zonisamide. Cyproheptadine? Candesartan (anti-hypertensive, in BNF for migraine prevention)?

Always increase preventer dose to maximum before giving up, note that often symptoms worsen after initial benefit.

Current evidence on the efficacy of percutaneous closure of patent foramen ovale (PFO) for recurrent migraine is inadequate in quality and quantity. The evidence on safety shows a small incidence of well-recognised but sometimes serious adverse events, including device embolisation and device prolapse (each reported in less than 1% of patients). Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research. [NICE]

Contraception

Combined oral contraceptives are contraindicated in migraine with aura.  But may be useful if menstrual pattern to headaches if no aura.

Prognosis

50% migraine in childhood remits at puberty. Onset in adolescence associated with persistence.

Support

Patient support at Migraine Trust.