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					     16.6 Other medical issues on the ICU

          Procedures                                                                (1) Acute respiratory distress syndrome (ARDS)—paralysis allows the
Surgery                Inflammation                                                     patient to tolerate unusual ventilatory modes, e.g. reverse ratio venti-
                                                                                    (2) raised intracranial pressure—paralysis prevents coughing and strain-
          Analgesia                   Amnesia              Catecholamines
                                                                                        ing; and
                                                                                    (3) status asthmaticus—paralysis can reduce risks of barotrauma to
             Anxiety           PATIENT DISCOMFORT                  Personality          lungs.
                                                                                        The intravenous route is used almost exclusively for the administration
                                                                                    of analgesia and sedation in the critically ill, as it is faster and more reliable
                      Discomfort      Sleep          Mechanical           Culture   than other routes. Drugs can be given either as repeated bolus doses, or as a
                                                     ventilation                    continuous infusion. Although a continuous infusion has the advantage of
                                                                                    avoiding peaks and troughs associated with bolus doses, there is also an
                                          Mode of                  Tracheal tube    increased risk of inadvertent overdose or accumulation.
                                          ventilation                                  The analgesic needs of most patients can best be met with regular bolus
                                                                                    doses of analgesic titrated against repeated assessment of the pain. A
Fig. 1 Factors contributing to patient discomfort.                                  patient- or nurse-controlled syringe pump driver will deliver a bolus of a
                                                                                    predetermined amount of drug when triggered to do so. There is usually a
                                                                                    predetermined ‘lockout’ safety period during which further requests for
16.6.1 Sedation and analgesia                                                       bolus doses will be ignored. Morphine is the drug most commonly given in
                                                                                    this manner, but diamorphine, pethidine, and fentanyl can also be used. A
in the critically ill                                                               loading dose may be needed before starting.

G. R. Park and B. Ward
                                                                                    Hazards of sedation and analgesia
Sedation and analgesia are used to increase patient comfort by minimizing           The use of drugs for sedation and analgesia involves risks to the patient.
the pain and anxiety produced by illness and its treatment. Factors contrib-        These include:
uting to patient discomfort are shown in Fig. 1.                                    (1) over-sedation or a prolonged sedative effect caused by poor elimin-
   The relief of pain is an obvious part of being comfortable, but the role of          ation in the critically ill;
sedation is more complex. The term sedation covers a broad range of con-            (2) hypotension/myocardial depression;
scious states, from almost wide awake to deeply unresponsive. The ‘ideal’
level of sedation for most patients is at ease, without signs of anxiety or         (3) antitussive effects leading to failure to clear pulmonary secretions;
agitation and easily rousable from light sleep. Sedation is needed for a var-       (4) hypoventilation, delaying weaning;
iety of reasons, including:                                                         (5) toxic effects due to accumulation of sedative/analgesic agents or their
(1) reduction of anxiety caused by fear, inability to communicate, loss of              metabolites; and
    control, or unfamiliar environment;                                             (6) expense, both of the drugs and their adverse effects.
(2) allowing patients to tolerate treatment—e.g. stops them pulling out the             There are many reasons why the behaviour of drugs administered to the
    tracheal tube;                                                                  critically ill patient may be abnormal. These include:
(3) allowing patterns of ventilation to be imposed which do not synchron-           (1) hepatic failure leading to poor metabolism or biliary excretion of the
    ize with a normal breathing pattern;                                                drug;
(4) prevention of awareness when neuromuscular paralysis is used;                   (2) renal failure leading to decreased excretion of the drug or its metabol-
(5) minimizing distress during uncomfortable procedures;                                ites;
(6) allowing sleep; and                                                             (3) haemofiltration/dialysis may have unpredictable effects on clearance of
(7) control of fits.                                                                     the drug or its metabolites;
    Patients will usually tolerate a tracheal tube without the need for par-        (4) reduced plasma protein levels (e.g. albumin) may lead to increased free
alysis if the ventilator is properly set and they are properly sedated. The             (active) drug levels;
indications for neuromuscular relaxation in the critically ill are listed           (5) volume of distribution may be affected by oedema, ascites, or hyper/
below: the use of muscle relaxants is otherwise avoided.                                hypovolaemia;
2                                                                      16   cr itical care medicine

                     Agitated                                                           combination with morphine in order to achieve both analgesia and sed-
                     Awake                                     X                        ation. Midazolam is primarily metabolized by the liver, and accumulation
                                                                                        occurs in liver failure. The (phase I) metabolic product,
                     Roused by voice                       X       X         X
                                                                                        l-hydroxymidazolam has around 10 per cent of the activity of the parent
    Sedation score

                     Roused by tracheal suction                                  X      drug. In renal failure, accumulation of l-hydroxymidazolam glucuronide
                     Unrousable                                                         (the phase II metabolic product) can cause prolonged sedation or coma.
                                                                                        This has been used as an alternative to midazolam. It undergoes metabol-
                     Pain     YES/NO                       N   Y   N         N   N      ism only by glucuronidation to render it water soluble. This makes it less
                     Comfortable on ventilator    YES/NO   Y   Y   Y         Y   Y      likely for the parent drug to accumulate. It is dissolved in propylene gly-
    Fig. 2 The Addenbrooke’s Sedation Score.
    (6) interactions between drugs; and                                                 Diazepam is rarely used in the critically ill, having been replaced by mid-
                                                                                        azolam. It has a much longer duration of action and has many metabolites
    (7) solvent toxicity.                                                               with significant activity of their own. This increases the risk of accumu-
         The risks of using drugs can me minimized by a knowledge of their              lation.
    routes of breakdown and excretion. Agents that are unlikely to accumulate
    should be chosen when possible. Drugs with more than one site of metab-             Propofol
    olism, or those which can undergo non-organ-based breakdown are pre-                Propofol (2,6-di-isopropylphenol) was introduced as an anaesthetic agent
    ferred. The risk of accumulation of a sedative drug can be reduced by               but is widely used for sedation in the critically ill as a continuous infusion.
    stopping it every 24 h whenever possible and letting the patient recover            Emergence from sedation is rapid and without hangover effect. Propofol is
    from its effects. If the patient wakes or becomes restless, the drug can be         a respiratory depressant, and prolonged apnoea can occur after bolus doses.
    restarted knowing that accumulation has not occurred.                               Hypotension associated with propofol use is common in the critically ill
        To avoid under- or over-sedation, drugs need some assessment of their           and is dose related. Although metabolized primarily in the liver, extrahe-
    effects. Because of the many components which are involved in sedation,             patic breakdown does occur. There are no active metabolites and propofol
    no simple method exists. Although work is progressing on physical                   does not accumulate in hepatic or renal failure to a significant extent. How-
    methods of assessing the level of sedation (e.g. spectral analysis of electro-      ever, because it is formulated in soya bean extract, prolonged infusion
    encephalogram waveforms), the most commonly used methods rely on                    (more than 48 h) can lead to hyperlipidaemia. Propofol is expensive, and
    bedside observations. We use a scoring system comprising several different          its use is often limited to those patients who require short-term sedation
    elements (Fig. 2) (see below). The key to avoiding under- or over-sedation          only.
    is regular assessment of the patient and adjustment of the sedation regimen
    accordingly.                                                                        Dexmedetomidine
                                                                                        Dexmedetomidine is a potent, highly selective, α2-adrenoceptor agonist. It
                                                                                        has sedative, anxiolytic, amnesic, and sympatholytic effects. In addition,
    Psychological disturbances                                                          dexmedetomidine appears to reduce requirements for opioid analgesia.
    Severe illness, the intensive care environment, and drugs usually prevent           These effects are mediated centrally at post-synaptic α2-receptors. In con-
    patients from sleeping normally. Deprivation of sleep, especially if pro-           trast to the agents already discussed, dexmedetomidine does not seem to
    longed, combined with the fear of dying may make some patients psych-               cause respiratory depression, and exhibits remarkable cardiovascular sta-
    otic. Close attention to environment (e.g. normal day/night light levels,           bility. Because of these features, there is currently great interest in the use of
    noise etc.) may help. Drugs may be of some benefit, but can cause pro-               this agent.
    longed sedation. If the patient has a prolonged recovery phase then depres-
    sion is common. Antidepressants are rarely of value and can have toxic
    effects.                                                                            The intravenous anaesthetic agent thiopentone retains certain specialized
                                                                                        indications, for example use in status epilepticus or to reduce raised intra-
                                                                                        cerebral pressure. Thiopentone has a half-life of 11 h, and prolonged infu-
                                                                                        sion (i.e. > 24 h) is usually associated with extremely prolonged action.
    Drug treatment
    Before using drugs, causes of pain and agitation such as a full bladder or          Combinations of agents
    rectum should be excluded.                                                          Sedative drugs often act via differing mechanisms and so have slightly dif-
                                                                                        ferent actions. This difference can be used to advantage. For example pro-
    Sedative drugs                                                                      pofol is mostly an hypnotic, whilst midazolam is a good anxiolytic and
                                                                                        amnesic agent as well as producing hypnosis. In combination they are
    There are two main types of drugs, those principally sedative and those
    mostly analgesic. The agents most commonly used for sedation are the
    benzodiazepine midazolam and the anaesthetic agent propofol. These, and
    other agents commonly used for sedation in the intensive care unit, are             Analgesic drugs
    described below.                                                                    Opioid drugs remain the mainstay of analgesic treatment in the critically ill,
                                                                                        and morphine is the most common choice. Some properties of the opioid
    Midazolam                                                                           drugs used in the critically ill are listed in Table 1.
    Midazolam is a water-soluble benzodiazepine, which can be given periph-
    erally without causing thrombophlebitis or pain. Like all benzodiazepines it        Morphine
    has sedative, amnesic, anxiolytic, and anticonvulsive properties. It has a          Morphine is a cheap and effective analgesic agent and is the opioid against
    rapid onset, short half-life (approximately 2 h), and is commonly used in           which others are judged. It has both analgesic and sedative effects, although
                                          16.6.1   sedation and analgesia in the cr itically ill                                                                                3

                                      Table: 1 Properties of opioid drugs
                                      Opioid                   Onset of            Suitable*         Liable to              Liable to
                                                               action              for PCAS/         accumulate in          accumulate in
                                                                                   NCAS              hepatic failure        renal failure
                                      Morphine                 Slow                Yes               Yes                    Yes
                                      Diamorphine              Moderate            Yes               Yes                    Yes
                                      Pethidine                Moderate            Yes               Yes                    Yes
                                      Fentanyl                 Fast                Yes               Yes                    Yes
                                      Alfentanil               Very fast           No                Yes                    No
                                      Remifentanil             Very fast           No                No                     No
                                      PCAS, patient-controlled analgesia system; NCAS, Nurse-controlled analgesia system.
                                      *Except with special supervision.

an excessive dose would be required to produce adequate sedation by its use                  small delays, such as the time taken to make up a new syringe, can leave the
alone. It is often given with a benzodiazepine, such as midazolam, to                        patient without analgesia.
achieve analgesia and sedation. It is the standard agent for use in patient-
and nurse-controlled syringe pumps. Morphine is metabolized in the liver,
forming two major metabolites—morphine 3-glucuronide (M3G) and                               Sedative and analgesic antagonists
morphine 6-glucuronide (M6G), both of which are active. M6G is a potent
analgesic, whilst M3G is thought to be antianalgesic.                                        When accumulation of a drug or its metabolite is suspected as the cause of
                                                                                             prolonged sedation, the diagnosis can be confirmed with the use of ant-
                                                                                             agonists. Naloxone will quickly (but temporarily) reverse the effects of opi-
                                                                                             ates, whilst flumazenil is a benzodiazepine antagonist. Their use is not
Pethidine is a synthetic compound and was originally developed as an                         recommended in patients suffering from head injury. Large doses of either
anticholinergic agent. It does tend to cause anticholinergic effects, such as                antagonist given quickly can produce sudden arousal, causing agitation.
dry mouth, blurred vision, and tachycardia. It is claimed that pethidine                     When using naloxone, the sudden reversal of analgesia can cause a massive
induces less constriction of the biliary sphincter than morphine, and per-                   outpouring of catecholamines and precipitate arrhythmias.
haps the only indication for its use is in patients with biliary pathology. It is
metabolized in the liver to form norpethidine, pethidinic acid, and pethid-
ine-N-oxide. These metabolites are excreted by the kidneys, and in renal
failure significant amounts of norpethidine may accumulate, leading to                        Regional and epidural anaesthesia
grand mal convulsions.                                                                       For analgesia after certain surgical procedures or trauma, regional and epi-
                                                                                             dural techniques can be extremely effective. Lumbar or thoracic epidurals
Fentanyl                                                                                     can prevent hypoventilation and diaphragmatic splinting caused by pain
Fentanyl is approximately 100 times as potent as morphine, and has a rapid                   after abdominal or thoracic procedures and fractured ribs, whilst avoiding
onset of action (3 min). In low doses the analgesic effect of fentanyl ends                  the side-effects of high-dose opioids. The problem of correct placement of
after about 20 min by its rapid redistribution around the body. With larger                  regional blocks in critically ill patients is a considerable one, and compli-
doses, tissues may become saturated and drug action is prolonged, termin-                    cations (such as pneumothorax following intercostal block) must be care-
ation depending on the slow process of N-demethylation in the liver. The                     fully considered. Epidural analgesia, although desirable, may be
major metabolite, norfentanyl, is excreted by the kidneys, and its accumu-                   contraindicated in the critically ill patient because of coagulopathy or
lation may cause toxic delirium in patients with renal failure. Accumulation                 sepsis.
of fentanyl itself may occur in hepatic failure, causing prolonged effect.
Fentanyl has a potent apnoeic effect, and in large doses, fentanyl can pro-
duce muscle rigidity, particularly of the chest wall.                                        Further reading
                                                                                             Bion JF, Oh TE (1997). Sedation in intensive care. In: Oh TE, ed. Intensive care
Alfentanil                                                                                        manual, pp 672–8. Butterworth Heineman, Oxford. [An overview of the
Alfentanil is approximately 10 to 20 times as potent as morphine, and has a                       principles and practice of sedation in intensive care.]
very fast onset time (1 min). The effects of alfentanil are short lived                      Burns AM, Shelly MP, Park GR (1992). The use of sedative agents in critically
(approximately 10 to 15 min), ending by redistribution to tissues. Because                        ill patients. Drugs 43, 507–15. [A full review of the drugs used to sedate
of this, alfentanil is unsuitable for use in patient-controlled syringe pumps,                    critically ill patients.]
and it is administered by continuous infusion. Elimination takes place                       Carrupt PA et al. (1991). Morphine 6-glucuronide and morphine
almost exclusively in the liver, and alfentanil is the current drug of choice in                  3-glucuronide as molecular chameleons with unexpected lipophilicity.
severe renal impairment. It can accumulate in hepatic failure, cirrhosis, or                      Journal of Medical Chemistry 34, 1272–5. [An important paper that
                                                                                                  describes how metabolites that should be inactive change their
when hepatic enzyme inhibitors such as cimetidine are used.
                                                                                                  configuration to become active.]
                                                                                             Park GR (1996). Molecular mechanisms of drug metabolism in the critically ill.
Remifentanil                                                                                      British Journal of Anaesthesia 77, 32–49. [Describes the problems of drug
Remifentanil is a relatively new agent which may prove to have pharmaco-                          elimination, solvent toxicity, and makes brief mention of protein binding
logical properties useful in critically ill patients. It has a fast onset of action               in the critically ill.]
and a very short half-life (10 to 21 min). Remifentanil has an ester linkage                 Park GR, Sladen RN, eds (1995). Sedation and analgesia in the critically ill, pp
within its structure, which is broken down by a non-specific, non-saturable                        18–50. Blackwell Science, Oxford. [A multinational book that describes
enzyme system present in plasma. This breakdown pathway means that                                sedation in various diseases, rather than looking at the use of individual
accumulation does not occur, and the drug wears off rapidly even after                            drugs.]
prolonged infusions and in renal or hepatic failure. Remifentanil must be                    Shapiro BA et al. (1995). Practice parameters for intravenous analgesia and
given by constant infusion, indeed the effects wear off so rapidly that even                      sedation for adult patients in the intensive care unit: an executive
4                                                                16   cr itical care medicine

         summary. Critical Care Medicine 23, 1596–600. [An American consensus               achnoid space), or communicating (where there is a defect in CSF
         document on how to provide sedation and analgesia in the critically ill.]          reabsorption).
    Shelly MP, Pomfrett CJD (1999). Assessment of sedation and analgesia and
                                                                                      4. Space-occupying lesions (SOLs), which may be chronic (for example,
         muscle relaxation in the intensive care unit. Current Opinion in Critical
                                                                                         intracranial tumours) or acute (for example, intracranial haematomas
         Care 5, 269–73. [A paper reviewing clinical as well as experimental
         methods of assessing sedation and analgesia.]
                                                                                         associated with trauma).
    Tryba M, Kulka PJ (1993). Critical care pharmacotherapy. Drugs 45, 338–52.
         [Interesting review looking at propofol, isoflurane, clonidine, and           Temporal patterns of ICP change
         sufentanil for sedation. Also reviews H2- receptor antagonists and
         sucralfate against gastrointestinal bleeding.]                               Initial increases in intracranial volume are buffered by the displacement or
    Venn R et al. (1999). Monitoring the depth of sedation. Clinical Intensive Care   reduction in volume of other contents. Thus, cerebral oedema may result in
         10, 81–9. [A review on how to measure sedation and analgesia in the          compression of the ventricles, with translocation of CSF to the spinal sub-
         critically ill.]                                                             arachnoid space, and compression of cerebral vasculature. Over longer
                                                                                      periods, normal brain may be compressed and CSF production dimin-
                                                                                      ished. The relationship between intracranial volume (ICV) and ICP is
                                                                                      commonly depicted as a hyperbolic curve, with an initial flat part during
                                                                                      which compensatory mechanisms are effective, moving after their progres-
                                                                                      sive exhaustion to a steep phase when even small increases in intracranial
    16.6.2 Management of raised                                                       volume produce large increases in ICP. However, the extent and efficiency
                                                                                      with which these mechanisms buffer increases in volume depend on the
    intracranial pressure                                                             speed of disease progression, and given these considerations it is more

    David K. Menon
    Introduction                                                                                          CSF                                             ICP

    The normal intracranial pressure (ICP), measured at the level of the fora-                           CP
    men of Monro, is between 5 and 15 mmHg in supine subjects. Intracranial
    hypertension (ICP >20 mmHg) is a common accompaniment of many                             Arterial                                Venous
    central nervous system (CNS) diseases, when it is often the most important
    cause of symptoms and modulator of outcome, and—in fatal cases—
    frequently the immediate cause of death.                                                                       Brain
    The cranial cavity contains brain (80 per cent), blood (10 per cent), and
    cerebrospinal fluid (10 per cent). These incompressible contents are con-          (a)                           SSAS
    tained in a rigid skull with a fixed capacity, hence an increase in volume of
    any of these contents, or the presence of any space-occupying pathology,                                                              Pressure
    results in an increase in ICP unless one of the other constituents can be                                                                             ICP       100
    displaced or its volume decreased (Fig. 1). This principle is referred to as                         CSF
    the Monroe–Kelley doctrine. Increases in intracranial volume may be                                  CP
    caused by:
    1. Brain oedema, which may have different pathogenic mechanisms:                          Arterial                                   Venous
        u    cytotoxic oedema occurs as a result of cell swelling, most com-
             monly due to ischaemic energy depletion and rises in intracellular
             sodium and water;                                                                                        Brain
                                                                                                         Sol                        AV
        u    vasogenic oedema results from an increased permeability of the
             blood–brain barrier with an expansion of the extracellular fluid
        u    interstitial oedema occurs in the context of hydrocephalus, where
             increased intraventricular cerebrospinal fluid (CSF) pressures            (b)                            SSAS
             result in permeation of CSF into adjacent brain, typically in the
             frontal periventricular regions.                                         Fig. 1 Schematic diagram showing intracranial contents in the normal brain (A)
    2. Vascular engorgement, which results from an increased cerebral blood           and with elevated intracranial pressure (B). Note that cerebrospinal fluid (CSF)
       volume. This may be due to the vasodilatation that accompanies nor-            produced by the choroids plexus (CP), circulates freely, passing through the
       mal or abnormal (for example, epileptiform) neuronal activity. In              foramen magnum (FM) into the spinal subarachnoid space (SSAS), before
       other situations vasodilatation may be due to the loss of vasoregula-          absorption by arachnoid villi (AV) in the cerebral venous sinuses. Increases in ICP
                                                                                      may be due to brain oedema, vascular engorgement, space-occupying lesions
       tion, either due to disease (vasoparalysis), or to the effect of potent
                                                                                      (SOL), or impaired CSF circulation or absorption. Compensatory mechanisms
       physiological (carbon dioxide) or pharmacological (nitrates and other
                                                                                      include translocation of CSF to the SSAS, and compression of cerebral vascular
       nitric oxide donors) cerebral vasodilators.
                                                                                      beds. The ICP trace shows a higher mean value, and the inability of the non-
    3. Hydrocephalus, which may be non-communicating (where an obstruc-               compliant brain to cope with increased blood during each systole results in an
       tion prevents the ventricular system communicating with the subar-             increased pulsatility of the ICP waveform.

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