Oxford Handbook of Critical Care (3 edn)
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Antimicrobials
Types
Penicillins, e.g. benzylpenicillin, flucloxacillin, piperacillin, ampicillin.
Cephalosporins, e.g. cefotaxime, ceftazidime, cefuroxime.
Carbapenems, e.g. imipenem, meropenem.
Aminoglycosides, e.g. gentamicin, amikacin, tobramycin.
Quinolones, e.g. ciprofloxacin.
Glycopeptides, e.g. teicoplanin, vancomycin.
Macrolides, e.g. erythromycin, clarithromycin.
Tetracyclines, e.g. tigecycline.
Other, e.g. clindamycin, metronidazole, linezolid, co‐trimoxazole, rifampicin.
Antifungals, e.g. amphotericin, fluconazole, caspofungin, voriconazole, itraconazole.
Antivirals, e.g. aciclovir, ganciclovir.
Uses
Treatment of infection.
Prophylaxis against infection, e.g. peri‐operatively.
Local choice of antimicrobial varies. As a guide, the following choices are common:
Pneumonia (hospital‐acquired Gram‐negative)—ceftazidime, ciprofloxacin, meropenem or piperacillin/tazobactam (piptazobactam).
Pneumonia (community acquired)—cefuroxime + clarithromycin.
Systemic sepsis—cefuroxime ± gentamicin (+ metronidazole if anaerobes likely).
Routes
Generally given IV in critically ill patients.
Side effects
Hypersensitivity reactions (all).
Seizures (high dose penicillins, high dose metronidazole, ciprofloxacin).
Gastrointestinal disturbance (cephalosporins, erythromycin, clindamycin, teicoplanin, vancomycin, co‐trimoxazole, rifampicin, metronidazole, ciprofloxacin, amphotericin, flucytosine).
Vestibular damage (aminoglycosides).
Renal failure (aminoglycosides, teicoplanin, vancomycin, ciprofloxacin, rifampicin, amphotericin, aciclovir).
Erythema multiforme (co‐trimoxazole).
Leucopaenia (co‐trimoxazole, metronidazole, teicoplanin, ciprofloxacin, flucytosine, aciclovir).
Thrombocytopaenia (linezolid).
Peripheral neuropathy (metronidazole).
Notes
Antimicrobials should be chosen according to microbial sensitivities, usually based on advice from the microbiology laboratory.
Appropriate empiric therapy for serious infections should be determined by likely organisms, taking into account known community and hospital infection, and resistance patterns.
Up to 10% of penicillin‐allergic patients are also cephalosporin‐allergic.
Optimal duration of therapy is unknown.
Drug dosages (intravenous)
Benzylpenicillin | 1.2g 6‐hourly (2‐hourly for pneumococcal pneumonia) |
Flucloxacillin | 500mg–2g 6‐hourly |
Ampicillin | 500mg–1g 6‐hourly |
Piptazobactam | 4.5g 6–8 hourly |
Ceftazidime | 2g 8‐hourly |
Ceftriaxone | 1–4g daily |
Cefuroxime | 750mg–1.5g 8‐hourly |
Gentamicin | 1.5mg/kg stat, then by levels (usually 80mg 8‐hourly) |
Amikacin | 7.5mg/kg stat, then by levels (usually 500mg 12‐hourly) |
Tobramycin | 5mg/kg stat, then by levels (usually 100mg 8‐hourly) |
Erythromycin | 500mg–1g 6–12hourly |
Metronidazole | 500mg 8‐hourly or 1g 12‐hourly PR |
Clindamycin | 300–600mg 6‐hourly |
Ciprofloxacin | 200–400mg 12‐hourly |
Co‐trimoxazole | 960mg 12‐hourly in Pneumocystis carinii pneumonia |
Tigecycline | 100mg initially, then 50mg 12‐hourly |
Imipenem | 1–2g 6–8 hourly |
Meropenem | 500mg–1g 8‐hourly |
Rifampicin | 600mg daily |
Teicoplanin | 400mg 12‐hourly for 3 doses, then 400mg daily |
Vancomycin | 500mg 6‐hourly (monitor levels) |
Linezolid | 600mg 12‐hourly |
Chloramphenicol | 1–2g 6‐hourly |
Amphotericin | 250mcg–1mg/kg daily |
Flucytosine | 25–50mg/kg 6‐hourly |
Fluconazole | 200–400mg daily |
Caspofungin | 70mg stat, then 50–70mg daily |
Voriconazole | 400mg 12‐hourly on first day, then 200–300mg 12‐hourly |
Itraconazole | 200mg 12‐hourly for 2 days, then 200mg daily |
Aciclovir | 10mg/kg 8‐hourly |
Ganciclovir | 5mg/kg 12‐hourly |
Benzylpenicillin | 1.2g 6‐hourly (2‐hourly for pneumococcal pneumonia) |
Flucloxacillin | 500mg–2g 6‐hourly |
Ampicillin | 500mg–1g 6‐hourly |
Piptazobactam | 4.5g 6–8 hourly |
Ceftazidime | 2g 8‐hourly |
Ceftriaxone | 1–4g daily |
Cefuroxime | 750mg–1.5g 8‐hourly |
Gentamicin | 1.5mg/kg stat, then by levels (usually 80mg 8‐hourly) |
Amikacin | 7.5mg/kg stat, then by levels (usually 500mg 12‐hourly) |
Tobramycin | 5mg/kg stat, then by levels (usually 100mg 8‐hourly) |
Erythromycin | 500mg–1g 6–12hourly |
Metronidazole | 500mg 8‐hourly or 1g 12‐hourly PR |
Clindamycin | 300–600mg 6‐hourly |
Ciprofloxacin | 200–400mg 12‐hourly |
Co‐trimoxazole | 960mg 12‐hourly in Pneumocystis carinii pneumonia |
Tigecycline | 100mg initially, then 50mg 12‐hourly |
Imipenem | 1–2g 6–8 hourly |
Meropenem | 500mg–1g 8‐hourly |
Rifampicin | 600mg daily |
Teicoplanin | 400mg 12‐hourly for 3 doses, then 400mg daily |
Vancomycin | 500mg 6‐hourly (monitor levels) |
Linezolid | 600mg 12‐hourly |
Chloramphenicol | 1–2g 6‐hourly |
Amphotericin | 250mcg–1mg/kg daily |
Flucytosine | 25–50mg/kg 6‐hourly |
Fluconazole | 200–400mg daily |
Caspofungin | 70mg stat, then 50–70mg daily |
Voriconazole | 400mg 12‐hourly on first day, then 200–300mg 12‐hourly |
Itraconazole | 200mg 12‐hourly for 2 days, then 200mg daily |
Aciclovir | 10mg/kg 8‐hourly |
Ganciclovir | 5mg/kg 12‐hourly |
Most antimicrobials need dose adjustment for renal or hepatic failure.
Common choices for specific organisms
S. aureus | Flucloxacillin |
MRSA | Teicoplanin, vancomycin, linezolid |
S. pneumoniae | Cefuroxime, benzylpenicillin |
N. meningitidis | Ceftriaxone, cefotaxime, benzylpenicillin |
H. influenzae | Cefuroxime, cefotaxime |
E. coli | Ampicillin, ceftazidime, ciprofloxacin, gentamicin, imipenem, meropenem |
Klebsiella spp. | Ceftazidime, ciprofloxacin, gentamicin, imipenem, meropenem |
P. aeruginosa | Ceftazidime, ciprofloxacin, gentamicin, imipenem, meropenem, piptazobactam |
S. aureus | Flucloxacillin |
MRSA | Teicoplanin, vancomycin, linezolid |
S. pneumoniae | Cefuroxime, benzylpenicillin |
N. meningitidis | Ceftriaxone, cefotaxime, benzylpenicillin |
H. influenzae | Cefuroxime, cefotaxime |
E. coli | Ampicillin, ceftazidime, ciprofloxacin, gentamicin, imipenem, meropenem |
Klebsiella spp. | Ceftazidime, ciprofloxacin, gentamicin, imipenem, meropenem |
P. aeruginosa | Ceftazidime, ciprofloxacin, gentamicin, imipenem, meropenem, piptazobactam |
See also:
Corticosteroids
Uses
Anti‐inflammatory—corticosteroids are often given in high dose for their anti‐inflammatory effect, e.g. asthma, allergic and anaphylactoid reactions, vasculitic disorders, rheumatoid arthritis, inflammatory bowel disease, neoplasm‐related cerebral oedema, ARDS, laryngeal oedema (e.g. after intubation), and after spinal cord injury. Benefit is unproven in cerebral oedema following head injury or cardiac arrest.
Infection—though their immunosuppressive actions may increase susceptibility to infection, corticosteroids are often used with antibiotics as first‐line therapy to reduce the inflammatory response of microbial killing, e.g. miliary TB, bacterial meningitis, pneumocystis pneumonia. Only in cerebral malaria has specific detriment been shown. In septic shock, high dose, short‐course corticosteroids were ineffective/detrimental. However, more recent trials found improved survival with ‘low dose’ hydrocortisone (50mg qds) ± fludrocortisone (50mcg), although only in the severe ‘vasopressor‐unresponsive’ subset. Pressor requirements fell faster with corticosteroid therapy. The short corticotropin (ACTH) test is not reliable in determining adrenal responders from non‐responders. Free cortisol levels should ideally be assayed, but this is not routinely offered by hospitals.
Replacement therapy—for patients with Addison's disease and post‐adrenalectomy or pituitary surgery. Fludrocortisone is also usually required long‐term for its mineralocorticoid Na+ retaining effect. Higher replacement doses are needed in chronic corticosteroid takers undergoing stress, e.g. surgery, infection.
Immunosuppressive—after organ transplantation.
Side effects/complications
Sodium and water retention (especially with mineralocorticoids).
Hypoadrenal crisis if stopped abruptly after prolonged treatment.
Immunosuppressive: increased infection risk.
Neutrophilia.
Impaired glucose tolerance/diabetes mellitus.
Hypokalaemic alkalosis.
Osteoporosis, proximal myopathy (long‐term use).
Increased susceptibility to peptic ulcer disease and GI bleeding.
Notes
Oral fungal infection is relatively common with inhaled corticosteroids, but systemic and pulmonary fungal infection is predominantly seen in the severely immunocompromised (e.g. AIDS, post‐chemotherapy) and not those taking high‐dose corticosteroids alone.
Choice of corticosteroid for short‐term anti‐inflammatory effect is probably irrelevant, provided the dose is sufficient. Chronic hydrocortisone should be avoided for anti‐inflammatory use because of its mineralocorticoid effect, but is appropriate for adrenal replacement.
Prednisone and cortisone are inactive until metabolised by the liver to prednisolone and hydrocortisone, respectively. Glucocorticoids antagonise the effects of anticholinesterase drugs.
Corticosteroids probably do not cause critical illness myopathy.
Relative potency and activity
| Drug | Glucocorticoid activity | Mineralocorticoid activity | Equivalent anti‐inflammatory dose (mg) |
|---|---|---|---|
Cortisone | ++ | ++ | 25 |
Dexamethasone | ++++ | − | 0.75 |
Hydrocortisone | ++ | ++ | 20 |
Methylprednisolone | +++ | + | 4 |
Prednisolone | +++ | + | 5 |
Prednisone | +++ | + | 5 |
Fludrocortisone | + | ++++ | − |
| Drug | Glucocorticoid activity | Mineralocorticoid activity | Equivalent anti‐inflammatory dose (mg) |
|---|---|---|---|
Cortisone | ++ | ++ | 25 |
Dexamethasone | ++++ | − | 0.75 |
Hydrocortisone | ++ | ++ | 20 |
Methylprednisolone | +++ | + | 4 |
Prednisolone | +++ | + | 5 |
Prednisone | +++ | + | 5 |
Fludrocortisone | + | ++++ | − |
Drug dosages
| Drug | Replacement dose | Anti‐inflammatory dose |
|---|---|---|
Dexamethasone | − | 4–20mg tds IV |
Hydrocortisone | 20–30mg daily | 100–200mg qds IV |
Methylprednisolone | − | 500mg–1g IV daily |
Prednisolone | 2.5–15mg mane | 40–60mg od PO |
Fludrocortisone | 0.05–0.3mg daily | − |
| Drug | Replacement dose | Anti‐inflammatory dose |
|---|---|---|
Dexamethasone | − | 4–20mg tds IV |
Hydrocortisone | 20–30mg daily | 100–200mg qds IV |
Methylprednisolone | − | 500mg–1g IV daily |
Prednisolone | 2.5–15mg mane | 40–60mg od PO |
Fludrocortisone | 0.05–0.3mg daily | − |
Weaning
Acute use (>3–4 days): | can stop immediately. |
Short‐term use (≥3–4 days): | wean over 2–5 days. |
Medium‐term use (weeks): | wean over 1–2 weeks. |
Long‐term use (months/years): | wean slowly (months to years). |
Acute use (>3–4 days): | can stop immediately. |
Short‐term use (≥3–4 days): | wean over 2–5 days. |
Medium‐term use (weeks): | wean over 1–2 weeks. |
Long‐term use (months/years): | wean slowly (months to years). |
Key papers
See also:
Electrolytes (Na+, K+, Cl−, HCO3 −), p212; Full blood count, p220; Immunomodulatory therapies in sepsis, p332; Airway obstruction, p348; Acute respiratory distress syndrome (2), p364; Asthma—general management, p364; Meningitis, p446; Raised intracranial pressure, p454; Myasthenia gravis, p458; Platelet disorders, p478; Hypercalcaemia, p494; Hypoadrenal crisis, p524; Sepsis and septic shock—treatment, p560; HIV related disease, p566; Rheumatic disorders, p572; Vasculitis, p574; Anaphylactoid reactions, p578; Spinal cord injury, p590.
Prostaglandins
Types
Epoprostenol (prostacyclin, PGI2).
Alprostadil (PGE1).
Modes of action
Stimulate adenyl cyclase, thus increasing platelet cAMP concentration; this inhibits phospholipase and cycloxygenase, and thus reduces platelet aggregation (epoprostenol is the most potent inhibitor known).
Reduces platelet procoagulant activity and release of heparin neutralising factor.
May have a fibrinolytic effect.
Pulmonary and systemic vasodilator by relaxation of vascular smooth muscle.
Uses
Anticoagulation, particularly for extracorporeal circuits, either as a substitute or in addition to heparin.
Pulmonary hypertension.
Microvascular hypoperfusion (including digital vasculitis).
Haemolytic uraemic syndrome.
Acute respiratory failure (by inhalation).
Side effect and complications
Hypotension.
Bleeding (particularly at cannula sites).
Flushing, headache.
Notes
Epoprostenol is active on both pulmonary and systemic circulations. Although alprostadil is claimed to be metabolised in the lung and have only pulmonary vasodilating effects, falls in systemic blood pressure are not uncommonly seen, especially if metabolism is incomplete.
Avoid extravasation into peripheral tissues as solution has high pH.
Effects last up to 30min following discontinuation of the drug.
Prostaglandins may potentiate the effect of heparin.
Recent studies have shown improvement in gas exchange by selective pulmonary vasodilatation following inhalation of epoprostenol at doses of 10–15ng/kg/min. The efficacy appears similar to that of nitric oxide inhalation, but is not as rapid.
Drug dosages
Epoprostenol | 2–20ng/kg/min |
Alprostadil | 2–20ng/kg/min |
Epoprostenol | 2–20ng/kg/min |
Alprostadil | 2–20ng/kg/min |
See also:
Immunomodulatory therapies in sepsis
Agents modulating different components of the inflammatory response have been studied. These target triggers (e.g. endotoxin), cytokines (e.g. tumour necrosis factor, interleukin‐1, and effector cells and their products (e.g. neutrophils, free oxygen radicals, NO)), aim to replace or boost often depleted endogenous anti‐inflammatory response systems, e.g. corticosteroids, activated protein C, antithrombin, immunoglobulin.
However, there is a variable degree of disruption and imbalance between pro‐ and anti‐inflammatory systems. Outside small research studies, current monitoring capability precludes the ability to determine which patient would benefit from either boosting or suppressing their inflammatory response, and to what degree, at a precise point of time. This issue has likely affected identification of subgroups who could have benefited from a large number of immunomodulatory drug trials that have failed to show outcome benefit. Only corticosteroids in severe septic shock, and activated protein C (also in a more severe subset) have demonstrated mortality reduction in reasonably sized multicentre trials. For the others, promising results from post hoc subgroup analysis and from tightly controlled small patient studies have not been reproduced.
Activated protein C
Drotrecogin alfa (activated) is a recombinant form of activated protein C and has anti‐inflammatory, anticoagulant and fibrinolytic properties. Its beneficial role in adult sepsis is most likely related to anti‐inflammatory effects. The pivotal PROWESS study demonstrated overall outcome benefit for patients with severe sepsis treated within 48h of presentation with a 96h infusion of 24mcg/kg/h. However, subset analysis showed benefit was restricted to those with a higher risk of death. Subsequent studies have failed to show benefit in lower risk adults (APACHE score <25) or in children. The major side effect is bleeding so caution should be exercised in those at high risk of potentially catastrophic bleeding, e.g. concurrent coagulopathy or a recent history of surgery, major trauma, head injury and/or peptic ulcer disease. Ongoing trials are attempting to reproduce the PROWESS findings and to use plasma protein C levels as a biomarker against which treatment will be titrated.
Corticosteroids
Hydrocortisone (50mg qds) ± fludrocortisone (50mcg) improves survival in severe ‘vasopressor‐unresponsive’ sepsis.
Immunoglobulin (IV Ig)
Intravenous immunoglobulin (IV Ig) has been studied in both general sepsis and in specific toxin‐related conditions. Meta‐analyses suggest benefit in general sepsis though no single large study has shown significant survival benefit. A single dose of 2g/kg should be given, and repeated only if the patient relapses after initial response. If an anaphylactoid reaction occurs, slow down/stop infusion and consider corticosteroids.
Uses
Severe invasive group A streptococcal disease (e.g. necrotising fasciitis).
Staphylococcal toxic shock syndrome or necrotising (Panton‐Valentine Leukocidin (PVL)‐associated) staphylococcal sepsis.
Severe or recurrent Clostridium difficile colitis.
Examples of drugs investigated in multi‐centre studies
Corticosteroids (methylprednisolone, hydrocortisone).
Immunoglobulin.
Anti‐endotoxin antibody (HA‐1A, E5).
Anti‐tumour necrosis factor antibody.
Tumour necrosis factor soluble receptor antibody.
Interleukin‐1 receptor antagonist.
Platelet activating factor antagonists, PAF‐ase.
Bradykinin antagonists.
Naloxone.
Ibuprofen.
N‐acetylcysteine, procysteine.
L‐N‐mono‐methyl‐arginine (L‐NMMA).
Antithrombin.
Tissue factor pathway inhibitor.
Activated protein C.
Key papers
See also:
Rituximab
This is an anti‐CD20 antibody directed against B lymphocytes that is finding increasing use in a variety of haematological, immune, and rheumatological conditions. Many of its uses are still off‐label, but it is increasingly popular.
Modes of action
Anti‐CD20 antibody directed against normal and malignant B cells.
Uses
Non‐Hodgkin's lymphoma.
Other haematological malignancies, including Burkitt's lymphoma, CLL, Waldenstrom's macroglobulinaemia.
Post‐transplant lymphoproliferative disorder (PTLD) without evidence of allograft rejection.
Acquired haemophilia.
Thrombotic thrombocytopaenic purpura.
Idiopathic thrombocytopaenic purpura.
Rheumatoid arthritis not responding to anti‐TNF therapy.
Other autoimmune conditions, including SLE.
Multifocal motor neuropathy.
Routes
IV infusion.
Adverse effects
Pulmonary events (hypoxaemia, pulmonary infiltrates, acute respiratory failure).
Hepatitis B reactivation.
Tumour lysis syndrome.
Severe mucocutaneous reactions (e.g. Stevens–Johnson syndrome).
Abdominal pain, bowel obstruction, and perforation.
Neutropaenia and thrombocytopaenia.
Reactivation of JC virus resulting in progressive multifocal leukoencephalopathy.
Arrhythmias.
Infusion‐related syndrome with hypotension, rigors, pyrexia, urticaria, angioedema, and bronchospasm.
