Oxford Handbook of Critical Care - part 5 pps

Frequent, objective reassessment of sedati on depth with corresponding adjustment of i nfusi on doses i s necessary to avoid severe cardi ovascular and respiratory depression.. Plasma co

Note that the above doses are a guide only and may need to be altered widely according to individual circumstances The correct dose of an opiate analgesic is generally enough to ablate pain.

Uses

Pain associated with i nflammatory condi tions (aspirin, indomethaci n, di clofenac)Post-operative pain and musculoskeletal pai n (aspiri n, indomethaci n, diclofenac, paracetamol, ketami ne, ni trousoxide, li docaine, bupivacai ne)

Opi ate spari ng effect (aspi rin, i ndomethacin, di cl ofenac used with strong anal gesics)Antipyretic (aspirin, paracetamol)

Routes

IV (ketami ne)

IM (diclofenac)

PO (aspirin, indomethaci n, diclofenac, paracetamol)

PR (aspiri n, di clofenac, paracetamol)Local /regional (l idocai ne, bupivacaine)Inhaled (nitrous oxide)

Side-effects

Gastrointestinal bleedi ng (aspirin, indomethaci n, diclofenac)Renal dysfunction (indomethacin, dicl ofenac if any hypovol aemi a)Reduced pl atelet aggregation (aspi ri n, indomethacin, dicl ofenac)Reduced prothrombin formation (aspiri n, indomethaci n, diclofenac)Myocardial depression (l idocai ne, bupivacaine)

Hypertension and tachycardi a (ketamine)Sei zures (li docaine, bupivacai ne)

Paracetamol overdose can cause severe hepatic fai lure due to the effects of alkylating metaboli tes Though normal ly

removed by conjugation wi th gl utathi one, stores are rapidly depleted in overdose

Non-steroidal anti -i nfl ammatory agents should be generall y avoi ded in patients wi th renal dysfuncti on, GI bl eeding or

coagul opathy

Ketami ne is a deri vative of phencycl idi ne used as an i ntravenous anaestheti c agent In subanaestheti c doses it is a

powerful analgesic It has several advantages over opi ates i n that it is associated with good ai rway maintenance,

all ows spontaneous respi ration and provides cardiovascul ar sti mulation It i s also a bronchodi lator

Nitrous oxi de i s a powerful , short acting analgesi c used to cover short, painful procedures It may be useful when

del ivered vi a an i ntermi ttent positive pressure breathi ng system as an adjunct to chest physiotherapy Nitrous oxide

should not be used in cases of undrained pneumothorax since i t may diffuse i nto the pneumothorax resulting i n

tensi on

Drug dosages

Opi oi d anal gesics, p234; Sal icylate poi soning, p454; Rheumatic di sorders, p492; Pyrexi a (1), p518; Pyrexi a (2),

p520; Pai n, p532; Post-operative i ntensi ve care, p534

Sedatives

Types

Benzodiazepi nes: e.g di azepam, mi dazolam, lorazepamMajor tranqui ll isers: e.g chl orpromazine, haloperidolAnaesthetic agents: e.g propofol, isofl urane

α2 agonists e.g cl onidi ne, dexmedetomidine

Uses

Sedati on and anxiol ysi s

Routes

IV (di azepam, mi dazolam, lorazepam, chlorpromazi ne, hal operi dol , propofol, clonidine, dexmedetomi di ne)

IM (diazepam, chlorpromazine, haloperidol)

PO (diazepam, lorazepam, chl orpromazi ne, haloperi dol , clonidine)Inhaled (i soflurane)

Notes

Sedati on is necessary for most ICU pati ents Whi le the appropriate use of sedative drugs can provide comfort, most

have cardiovascular and respi ratory si de-effects Objective assessment of the depth of sedati on i s necessary to

ensure that comfort does not give way to excessively and dangerousl y deep levels of sedation All sedatives are

potential ly cumul ati ve so doses must be kept to a mi ni mum

Benzodiazepi nes have the advantage of being amnesic Di azepam is mainl y admi nistered as an emulsi on in intralipid

as organi c sol vents are extremely irri tant to veins Midazolam is shorter acting than di azepam although 10% of

patients are sl ow metabolisers All benzodiazepines accumul ate i n renal fail ure; care must be taken to avoi d

excessive dosage by regular reassessment of need Some patients suffer unpredictable severe respiratory depression

with hypotension

Propofol used i n subanaestheti c doses i s short-acting though effects are cumul ati ve when i nfusions are prolonged or

with coexisting hepatic or renal failure It is gi ven as an emulsion in 10% i ntral ipi d so l arge volumes may contribute

si gni ficantly to cal ori e i ntake

As chlorpromazine and haloperidol antagonise catechol ami nes, they may cause vasodilatation and hypotension

Dystonic reactions and arrhythmi as are al so occasi onall y seen

α2 antagonists also provide analgesi a and are synergisti c with opiates Dexmedetomidine causes minimal respiratory

depressi on and the patient is easil y rousabl e Bradycardia and hypotension may occur, especi all y with the l oading

dose

Isoflurane i s largel y exhal ed unchanged and i s therefore short acting Cumulative effects have been recorded with

prolonged use, carryi ng the theoretical risk of fl uoride toxicity Exhaled i sofl urane shoul d be scavenged

Frequent, objective reassessment of sedati on depth with corresponding adjustment of i nfusi on doses i s necessary to

avoid severe cardi ovascular and respiratory depression Simpl e sedation scores are avail abl e to ai d assessment

UCL Hospitals Sedation Score

Roused by painful or noxious stimuli -2

Sedati on doses are adjusted to achieve a score as cl ose as possi bl e to 0 Positive scores require i ncreased sedati on

doses and negative scores require reduced sedati on doses

See also:

IPPV—fail ure to tolerate venti lation, p12; Opi oi d anal gesics, p234; Agitation/confusi on, p370; Sedati ve poi soning,

p458; Post-operati ve i ntensive care, p534

Prol onged effects are seen where there i s congeni tal or acqui red pseudocholi nesterase deficiency

Non-depolarising muscle rel axants prevent acetyl choline from depol ari si ng the post-synapti c membrane of theneuromuscular junction by competi tive blockade Reversal of paralysis is achieved by antichol inesterase drugssuch as neostigmine They have a slower onset and longer duration of action than the depolarisi ng agents

Uses

To faci li tate endotracheal intubation

To faci li tate mechani cal venti lation where optimal sedati on does not prevent pati ent interference with thefuncti on of the ventil ator

Modern intensi ve care practice and developments in ventil ator technology have rendered the use of muscl e rel axants

less common Furthermore, i t i s rarely necessary to full y paralyse muscles to facil itate mechanical ventil ati on

Requirement for muscl e relaxants should be reassessed frequentl y Ideall y, rel axants shoul d be stopped

intermittently to al low depth of sedati on to be assessed If mechanical ventil ati on proceeds smoothly when relaxants

have been stopped they probably shoul d not be restarted

Suxamethonium i s contrai ndicated in spinal neurol ogi cal di sease, hepatic disease and for 5–50 days after burns

Atracuri um is non-cumul ati ve and popul ar for infusion Non-enzymatic (Hoffman) degradati on al lows clearance

independent of renal or hepati c function, although effects are prolonged in hypothermia

Uses

Control of status epil epticusIntermittent seizure controlMyoclonic seizures (clonazepam, sodi um val proate)

Routes

IV (lorazepam, diazepam, clonazepam, phenytoin, sodi um val proate, magnesi um sul phate, thiopental)

PO (diazepam, cl onazepam, phenytoi n, carbamazapine, sodi um val proate)

PR (diazepam)

Side-effects

Sedati on (benzodiazepi nes, thi opentone)Respiratory depression (benzodi azepi nes, thiopentone)

Common insul ts causing sei zures include cerebral ischaemic damage, space occupyi ng lesions, drugs or drug/alcohol

withdrawal, metabolic encephal o-pathy (i ncluding hypoglycaemia), and neurosurgery Anti convul sants provi de control

of sei zures but do not repl ace removal of the cause where thi s i s possible

Onset of sei zure control may be delayed by up to 24h wi th phenytoin but a loadi ng dose i s usually gi ven during the

acute phase of sei zures

Magnesium sulphate is especial ly useful i n eclamptic sei zures (and i n thei r prevention)

Phenytoin has a narrow therapeuti c range and a non-l inear rel ationshi p between dose and plasma level s It is

therefore essential to moni tor pl asma l evels frequentl y Enteral feeding shoul d be stopped temporaril y whil e oral

phenytoin is administered Intravenous use should onl y occur i f the ECG is monitored continuously

Carbamazepine has a wi der therapeuti c range than phenytoin and there i s a li near rel ati onship between dose and

plasma level s It is not, therefore, critical to moni tor pl asma l evels frequentl y

Plasma concentrati ons of sodium valproate are not related to effects so moni toring of pl asma l evels is not useful

Intravenous drug dosages

Steroi ds: e.g dexamethasoneCalcium antagoni sts: e.g ni modipi neBarbiturates: e.g thiopental

Cerebral protecti on requires generalised sedati on and aboli ti on of seizures to reduce cerebral metaboli c rate, cerebral

oedema and neuronal damage duri ng ischaemia and reperfusion

Mannitol reduces cerebral intersti tial water by the osmoti c l oad The effect is transient and at i ts best where the

blood–brain barri er is intact Intersti tial water i s mainly reduced i n normal areas of brain and this may accentuate

cerebral shift Repeated doses accumulate in the interstiti um and may eventual ly increase oedema formation;

mannitol shoul d only be given 4–5 ti mes in 48h In additi on to its osmotic effect, there i s some evidence of cerebral

vasoconstri cti on due to a reduction in bl ood vi scosity and free radi cal scavengi ng

The loop diuretic effect of furosemi de encourages salt and water l oss There may also be a reduction of CSF chloride

transport reducing the formation of CSF

Dexamethasone reduces oedema around space occupyi ng lesions such as tumours Steroids are not currentl y

consi dered useful in head i njury or after a cerebrovascul ar accident but benefit has been shown if given early after

spi nal i njury Steroids encourage salt and water retenti on and must be withdrawn sl owl y to avoid rebound oedema

Nimodi pi ne i s used to prevent cerebral vasospasm duri ng recovery from cerebrovascul ar insults As a cal cium channel

blocker i t also prevents calcium ingress during neuronal i njury This cal ci um ingress i s associ ated wi th cel l death It

is commonly used i n the management of subarachnoi d haemorrhage for 5–14 days

Thi opental reduces cerebral metabol ism thus prolonging the ti me that the brai n may sustai n an i schaemic insul t

However, it also reduces cerebral bl ood fl ow, al though bl ood fl ow i s redistri buted preferential ly to ischaemic areas

Thi opental acutel y reduces intracranial pressure and this is probably the main cerebroprotective effect Seizure

control is a further benefi t Despi te these effects, barbiturate coma has not been shown to i mprove outcome i n

cerebral insul ts of various causes

Bracken MB, et al Admi nistrati on of methylprednisol one for 24 or 48 hours or ti ri lazad mesylate for 48 hours in the

treatment of acute spinal cord injury Results of the Thi rd National Acute Spinal Cord Injury Randomi zed Controll ed

Tri al Nati onal Acute Spi nal Cord Injury Study JAMA 1997; 277:1597–604

See also:

Intracranial pressure moni toring, p134; Jugular venous bul b saturation, p136; EEG/CFM moni toring, p138; Other

neurol ogi cal moni toring, p140; Basic resusci tation, p270; Generalised sei zures, p372; Intracranial haemorrhage,

p376; Subarachnoid haemorrhage, p378; Rai sed i ntracrani al pressure, p382; Head i njury (1), p504; Head injury (2),

p506

Ovid: Oxford Handbook of Critical Care

Editors: Singer, Mervyn; Webb, Andrew R.

Title: Oxford Handbook of Critical Care, 2nd Edition

Copyri ght ©1997,2005 M Si nger and A R Webb, 1997, 2005 Publ ished in the United States by Oxford Universi tyPress Inc

> Table of Co ntents > Haemato logical Dru gs

Haematological Drugs

Anticoagulants

Types

Hepari nLow mol ecular weight (LMW) heparin: e.g dal teparin, enoxi parinAnticoagulant prostanoids: e.g epoprostenol, al prostadi l

Sodium ci trateWarfarin

Activated Protein C

Modes of action

Hepari n potenti ates natural ly occurring AT-III, reduces the adhesionof platel ets to injured arteri al wal ls, binds to

platel ets and promotes in vitro aggregation.

LMW hepari n appears to speci fi cal ly influence factor Xa acti vi ty; its simpler pharmacokineti cs al low for a smaller(two thirds) dose to be admi nistered to the same effect

The effects of the prostanoi ds depend on the balance betweenTXA2 and PGI2.Sodium ci trate chelates ionised cal cium

Warfarin produces a control led deficiency of vitami n K dependent coagulation factors (II, VII, IX and X)

Activated Protein C i s the activated form of the endogenous anti coagul ant, Protein C

Uses

Maintenance of an extracorporeal circul ati onPrevention or treatment of thromboemboli smSevere sepsi s (activated Protei n C)

Notes

Al prostadil has simi lar effects to epoprostani l but is less potent As i t i s metabol ised i n the lungs, systemi c

vasodi latati on effects are usuall y mini mal Thi s may be an i mportant advantage in the shocked patient Major uses i n

P.250

intensive care are for anti coagul ation of fil ter circui ts, di gital vascul itis/ischaemi a and pulmonary hypertension

For extracorporeal use citrate has advantages over hepari n i n that it has no known antiplatel et activi ty, is readi ly

fil tered by a haemofi lter (reduci ng systemic anticoagulation), and i s overwhel med and neutral ised when returned to

central venous blood

Warfarin is gi ven orall y and needs 48–72h to develop i ts effect It can be reversed by fresh frozen plasma or low

doses (1mg) of vitamin K

Activated Protein C has anti-i nfl ammatory and pro-fibrinolytic properti es in addition to its anti coagul ant actions

Drug dosages

Heparin

Dose requirement i s variable to produce an APTT of 1.5–3 times control Thi s usuall y requires 500–2000IU/h with an

ini ti al loading dose of 3000–5000IU

Low molecular weight heparin

For deep vei n thrombosis prophylaxis gi ve 2500IU SC 12-hrly For anti coagul ati on of an extracorporeal circui t a bolus

of 35IU/kg i s given IV foll owed by an infusion of 13IU/kg The dose is adjusted to mai ntain anti-factor Xa activi ty at

0.5–1IU/ml (or 0.2–0.4IU/ml if there is a high risk of haemorrhage)

For pulmonary embol ism give 200IU/kg SC dai ly (or 100IU/kg bd if at ri sk of bleeding)

Start at 10mg/day orally for 2 days then 1–6mg/day accordi ng to INR For DVT prophylaxis, pulmonary embolus,

mitral stenosi s, atrial fi brill ation and tissue val ve replacements the INR should be mai ntained between2 and 3 For

recurrent DVT or pul monary embol us and mechanical val ve repl acements the INR should be kept between 3 and 4.5

Activated Protein C (Drotrecogin α activated)

For sepsi s, an infusi on of 24 µg/kg/h is gi ven for 96h

See also:

Extracorporeal respi ratory support, p34; Haemo(di a)fi ltration (2), p64; Plasma exchange, p68; Coagulation

monitori ng, p156; Thrombolytics, p250; Pulmonary embolus, p308; Acute coronary syndrome (1), p320; Acute

coronary syndrome (2), p322; Cl otting disorders, p398; Hyperosmolar di abetic emergencies, p444; Sepsi s and septi c

shock—treatment, p248; Post-operative i ntensi ve care, p534

Thrombolytics

Types

Altepl ase (rt-PA)Streptoki naseUrokinase

To unbl ock indwell ing vascular access catheters

Routes

Contraindications (relative)

Systol ic BP >200mmHgAortic di ssection

Prol iferative diabeti c reti nopathy

Notes

In acute myocardial i nfarction they are of most val ue when used within 12h of the onset They may require adjuvant

therapy (e.g aspi rin wi th streptoki nase or hepari n wi th rt-PA) to maximise the effect in acute myocardial i nfarction

rt-PA is said to be clot selecti ve and is therefore useful where a need for invasive procedures has been i denti fied

Anaphylactoi d reacti ons to streptokinase are not uncommon, particularl y i n those who have had streptococcal

infections, and pati ents should not be exposed twice between 5 days and 1 year of receivi ng the last dose

Drug dosages

Alteplase (rt-PA) The dose schedule for acute myocardial infarction is 10mgin 1–2min, 50mg in 1h and 40mg over 2h intravenously.

Streptokinase In acute myocardial infarction (1.5mu over 60min).In severe venous thrombosis

(250,000U over 30min followed by 100,000U/h for 24–72h).

For thromboembolic disease 4400IU/kg is given over 10min followed by 4400IU/kg/h for 12–24h.

IV

Notes

A uni t (150ml) of fresh frozen pl asma i s usually collected from one donor and contai ns all coagulation factors

including 200 uni ts factor VIII, 200 uni ts factor IX and 400mg fibrinogen Fresh frozen plasma is stored at -30°C and

should be infused within 2h once defrosted

Platel et concentrates are viable for 3 days when stored at room temperature If they are refri gerated viabil ity

decreases They must be infused quickly vi a a short gi ving set with no filter Indi cations for platel et concentrates

include platel et count <10 × 109, or <50 × 109 with spontaneous bleeding, or to cover i nvasi ve procedures and

spontaneous bleedi ng with platelet dysfuncti on They are less useful in condi tions associ ated with immune platelet

destruction (e.g ITP)

A 15ml vi al of cryopreci pi tate contains 100 uni ts factor VIII, 250mg fi brinogen, factor XIII and von Wi llebrand factor

and is stored at -30° In haemophili a, cryopreci pi tate i s given to achi eve a factor VIII level >30% of normal

Factor VIII concentrate contains 300 units factor VIII per vi al In severe haemorrhage due to haemophi li a 10–15

uni ts/kg are gi ven 12-hrly

Factor IX compl ex is ri ch in factors II, IX and X It i s formed from pooled plasma so fresh frozen pl asma i s preferred

See also:

Coagul ati on monitoring, p156; Blood transfusi on, p182; Anticoagulants, p248; Bl eeding di sorders, p396; Clotting

disorders, p398; Post-operative i ntensi ve care, p534; Post-partum haemorrhage, p542

Coagulants and antifibrinolytics

Types

Vitami n KProtami neTranexamic acidActivated factor VII (F VIIa)

Bleedi ng from major trauma or haemophili a (F VIIa)

Routes

IV (vi tami n K, protami ne, tranexamic aci d, F VIIa)

PO (vitami n K, tranexamic acid)

Notes

The effects of vitami n K are prolonged so i t should be avoided where patients are dependent on oral anti coagul ant

therapy A dose of 10mg i s given oral ly or by sl ow i ntravenous i njection daily In l ife threatening haemorrhage

P.256

P.257

5–10mg is gi ven by sl ow intravenous injection wi th other coagul ati on factor concentrates If INR >7 or in less severe

haemorrhage 0.5–2mg may be given by slow intravenous injection wi th mi nimum lasting effect on oral anti coagul ant

therapy

Protamine has an anti coagul ant effect of its own in high doses Protamine 1mg neutral ises 100IU unfractionated

hepari n i f given within 15min Less is requi red i f gi ven later since heparin is excreted rapidly Protamine should be

given by slow i ntravenous i njecti on according to the APTT Total dose shoul d not exceed 50mg Protamine injecti on

may cause severe hypotension

Tranexami c acid has an anti fibri nol yti c effect by antagonising pl asminogen The usual dose i s 1–1.5g 6–12-hrly orall y

or by slow i ntravenous i njecti on

Recombinant factor VIIa is li censed for use i n haemophil ia but a number of case seri es in major trauma, orthopaedi c

and cardi ac surgery report benefi t in severe, i ntractabl e bleeding that had not responded to standard measures The

dose i s 4500IU/kg over 2–5mi n, fol lowed by 3000–6000IU/kg dependi ng on the severity of bl eeding

See also:

Coagul ati on monitoring, p156; Anticoagulants, p248; Thrombolytics, p250; Aproti ni n, p256; Bl eeding di sorders, p396;

Clotti ng di sorders, p398; Post-operative intensi ve care, p534;Post-partum haemorrhage, p542

Aprotinin

The role of serine protease inhibitors in coagulation and anti coagul ati on is compl icated due to thei r effects at various

poi nts i n the coagul ati on pathway Aproti nin is a naturally occurri ng, non-specifi c seri ne protease inhibitor with an

eli mi nation half-l ife of about 2h Prevention of systemic bl eeding wi th aproti nin does not promote coagul ati on within

the extracorporeal ci rculati on and may even contri bute to the maintenance of extracorporeal anti coagul ati on

Modes of action

The effects of aproti nin on the coagulation cascade are dependent on the circul ating pl asma concentrations

(expressed as kall ikrein i nactivati on uni ts—kIU/ml ) since the affi ni ty of aproti nin for plasmin is si gnifi cantly greater

than that for plasma kal likrei n At a plasma level of 125kIU/ml aprotini n i nhi bi ts fibri nol ysi s and complement

activati on Inhibiti on of plasma kal li krein requi res hi gher doses to provide pl asma l evels of 250–500kIU/ml

Plasma kal li krein inhibi ti on—reduces blood coagulation medi ated via contact wi th anionic surfaces and, i n thecri tical ly ill pati ent, i mproves circulatory stabil ity vi a reduced ki nin acti vati on

Prevention of inappropri ate pl atelet activati on—neutrophi l activation (complement or kall ikrein mediated) causes

a secondary acti vation of pl atelets Important i n this pl atelet–neutrophil interaction i s the rel ease of Cathepsi n

G by neutrophil degranul ati on It has been demonstrated recentl y that aprotini n can signi ficantly inhibi t theplatel et activation due to purifi ed Cathepsin G, this mechanism formi ng a direct inhibiti on of inappropriateneutrophi l medi ated platelet acti vation

Uses

The mai n role of aprotini n i n the management of the extracorporeal circul ati on has been to prevent bleedingassoci ated wi th heparini sation High dose aproti ni n given duri ng cardiopul monary bypass procedures has beenshown to reduce post-operati ve blood loss dramati cal ly

Editors: Singer, Mervyn; Webb, Andrew R.

Title: Oxford Handbook of Critical Care, 2nd Edition

Copyri ght ©1997,2005 M Si nger and A R Webb, 1997, 2005 Publ ished in the United States by Oxford Universi tyPress Inc

> Table of Co ntents > Misc ellaneous Dr ugs

Glycopeptides: e.g teicopl ani n, vancomyci nMacrol ides: e.g erythromyci n, cl ari thromyci nOther antibacterials: e.g cl indamyci n, metronidazol e, linezoli d, co-tri moxazol e, ri fampicinAntifungals: e.g amphoteri cin, flucytosine, fluconazole, caspofungin, vori conazole, i traconazoleAntivi ral s: e.g aciclovir, gancicl ovi r

Vestibular damage (ami noglycosides)Renal fail ure (aminogl ycosides, teicopl ani n, vancomyci n, ciprofloxaci n, ri fampicin, amphoterici n, aci cl ovi r)Erythema multiforme (co-trimoxazol e)

Leucopeni a (co-tri moxazol e, metronidazol e, tei coplanin, ciprofl oxacin, flucytosi ne, aci cl ovi r)Thrombocytopenia (l inezol id)

Peri pheral neuropathy (metroni dazole)

Notes

Antimicrobi al s should be chosen according to mi crobi al sensi tiviti es, usual ly based on advice from the mi crobiology

laboratory

Appropri ate empiric therapy for serious i nfections should be determined by l ikely organi sms, taki ng into account

known communi ty and hospi tal i nfecti on and resistance patterns

Up to 10% of penici ll in-all ergic patients are also cephalosporin-all ergic