199 CHAPTER 12.3 Gut motility agents \200 \200 Gastroparesis and diabetes Critical illness and diabetes melllitus are both associated with delayed gastric emptying. Furthermore, 1/3 of ICU patients have diabetes mellitus. It has therefore been thought that critically ill diabetic patients are at increased risk of gastr oparesis. Studies comparing NG feeding of diabetic and non-diabetic patients have shown no differ- ence in gastric motility during critical illness. However, NG feeds are liquid meal s and their absorption has been shown to be variable, whereas gastric emptying after a soli d or semi-solid meal is consistently slow in diabetic patients. Diabetic patients in critic al care should therefore receive the same treatment as their non-diabetic counterparts. Acu te hyperglycaemia is thought to result in reduced antral motility, in increased pyloric pre ssures and in decreased compliance of the gastric fundus, leading to slow gastric emptying. It is also thought that delayed gastric emptying itself leads to poor glycaemic control. H yperglycaemia attenuates the effects of prokinetic drugs. Therefore, hyperglycaemia needs t o be treated diligently and without delay. Optimizing glycaemic control Medications \200\224erythromycin and metoclopramide Placement of jejunostomy feeding tubes. Further reading Abell T, Lou J, Tabbaa M, et al. Gastric electrical stimulation for gastrop aresis improves nutritional parameters at short, interme- diate, and long-term follow-up. J Parenter Enteral Nutr 2003; 27: 277 \200\22381. Berne JD, Norwood SH, McAuley CE, et al. Erythromycin reduces delayed gastric emptying in c ritically ill trauma patients: a rando- mised, controlled trial. J Trauma 2002; 53: 422 \200\2235. Chapman M, Fraser R, Vozzo R, et al. Antor-pyloro-duodenal motor responses to gastric and d uodenal nutrient in critically ill patients. Gut 2005; 54: 1384 \200\22390. Feldman M, Smith HJ. Effect of cisapride on gastric emptying of indi- gestible solids in pa tients with gastroparesis diabeticorum. A comparison with metoclopramide and placebo. Gastr oenterology 1987; 92: 171. Grif \201 th, D, McNally A, Therese RN, et al. Intravenous erythromycin facilitates bedsid e placement of postpyloric feeding tubes in criti- cally ill adults: a double-blind, random ized, placebo-controlled study. Crit Care Med 2003; 31: 39 \200\22344. Horowitz M, Wishart JM, Jones LK, et al. Gastric emptying in diabe- Treatment A pilot study of injecting botulinum toxin into the pylorus of oesophagectomy pat ients has shown promising results: no patient who received the injection developed delayed gastric emptying or aspiration pneumonia in the post- operative period. After a median foll ow-up time of 5.3 months, only 1 out of 12 patients had required intervention for symptoms of gastric stasis. Patients not responding to supportive measures and medi- cal treatment n eed to be considered for early jejunal (post- pyloric) feeding tube placement. Other surgic al treatments are not suitable for ICUs, including the pioneered tech- nique from the USA w here gastric motility is achieved by enteric electrical stimulation with an implantable gas tric pacing device. tes: an overview. Diabet Med 1996; 13(9 Suppl 5): 16 \200\22322. Maganti K, Onyemere K, Jones MP. Oral erythromycin and sympto- matic relief of gastroparesi s. A systematic review. Am J Gastroenterol 2003; 98: 259 Mutlu GM, Mutlu EA, Factor P. GI complications in patients receiv- ing mechanical ventilation. Chest 2001; 119: 1222 \200\22341. Schmidt HB, Werdan K, Muller-Werdan U. Autonomic dysfunction in the ICU patient. Curr Opin Crit Care 2001; 7: 314 \200\22322. Umperrriez GE, Isaacs SD, Bazargan N, et al. Hyperglycaeamia: an independent marker of in-h ospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab 2002; 87: 978 \200\22382. Wehrmann T, Lembcke B, Caspary WF. Influence of cisapride on antroduodenal motor function in healthy subjects and diabetics with autonomic neuropathy. Aliment Pharmac ol Ther 1991; 5: 599. Summary \200 Supportive measures \200\224gastric decompression, hydra- tion, minimizing use of opioids 200 A WALDEN Antidiarrhoeals Dose: 4mg PO initially then 2mg following each loose stool, max 16mg daily. Side effects: d izziness, drowsiness, urticaria, paralytic ileus. Reduce dose in hepatic impairment. Diarrhea is a common problem in critically ill patients. Incidences vary from 14.7 to 38%. Diarrhea in this setting can lead to excess \202 uid shifts, resulting in haemodynamic in stability and electrolyte disturbances. In addition, skin care problems related to the butt ocks and perineum are an issue. As a general rule, diarrhea due to infective causes should be passed without any attempt to reduce the frequency or consistency of the stool. In the s ituation where infective causes are excluded and where other measures such as changing the feeding regimen have been attempted, then resort to antidiarrhoeal drugs may be appropriate . Codeine phosphate \200 Indication: symptomatic treatment of acute diarrhea and chronic diarrhea. Dose: 30mg qds PO . Side effects: nausea, drowsiness, respiratory depression, hypotension. Caution in respira tory disease; reduce dose in renal failure; may precipitate coma in liver disease. \200 Risk factors and causes of diarrhea A broad differentiation of diarrhea into infective and non-infective causes is a useful sta rting point for deciding on the role of antidiarrhoeals. Where infectious agents are identi \201 ed, then appropriate antibiotic treatment should lead to resolution of the symptoms. Clostridium dif \201 cile is the main cause of antibiotic-induced diarrhea in the UK, and treatment with metronidazole or vancomycin is indicated. Where infection is excluded, then drug=induced causes should be sought: \200 \200 \200 \200 \200 Co-phenotrope \200 \200 Indication: adjunct to rehydration in acute diarrhea. Dose: 2.5mg/25mcg PO, initially 4 tab lets then 2 tablets every 6h. Side effects: see codeine phosphate and atropine. Cautions: s ee codeine phosphate. \200 Antispasmodics These are antimuscarinics (see also diphenoxylate above) and help to reduce gut motility, but are especially useful at alleviating the spasms associated with both acut e and chronic diarrhea. Tertiary amines such as atropine tend to be better absorbed than th e quarternary amines such as propanthiline and hyoscine; however, the latter agents tend to cross the blood \200\223brain barrier less due to their reduced lipid solubility. Oral abs orption is poor for all these agents, but hyoscine is used IV to good effect during endosco py. Side effects are as for all muscarinics, and include bradycardia, dry mouth, photophobi a and urinary retention. Laxatives Antibiotics Magnesium-containing oral medications H2 receptor antagonists Proton pump inhibitors. Where possible, these medications should be discontinued. Other risk factors, where modi \201 able, should be addressed. These include: \200 \200 \200 \200 \200 Hypothermia/fever Hypoalbuminaemia Re-use of previously suspended oral feed Malnutrition Se psis syndrome. Atropine \200 Indication: symptomatic relief of GI disorders associated with muscle spasm. Dose: 600 \200 \2231200mcg od PO. Side effects: bradycardia, urinary retention, nausea, vom- iting, giddin ess. May precipitate angle-closure glaucoma. Caution in Down syndrome or tachycardia. \200 Once all these factors have been addressed, then by a diag- nosis of exclusion it can be as sumed that the diarrhea is related to enteral feeding. Enteral feeding-associated diarrhea remains the most common cause of diarrhea in critically ill patients. Treatment involves ce ssation of feed or antidiarrhoeal drugs Hyoscine butylbromide (Buscopan ) \200 Indication: symptomatic relief of GI disorders associated with muscle spasm. Dose: 20mg qds PO/IV. Side effects: see atropine. Cautions: see atropine. Antidiarrhoeal drugs These can be roughly divided into antimotility drugs, anantispasmodics and bulk-forming drugs. \200 \200 Antimotility drugs These drugs act to slow down peristalsis in the gut and thus increase th e transit time in the colon, allowing for more absorption of water and solute. Commonly use d opiates include loperamide and codeine phosphate. The side effects of opiates include dep endence, and nausea and vomiting. Co-phenotrope (Lomotil ) is a combination of diphenoxyla te, an opioid derivative, and atropine sulpfate in proportions of 100 parts to 1 part, resp ectively. Side effects of this drug mainly relate to the opioid. Bulk-forming agents These agents are essentially \201 bre replacements and act by increas ing fecal mass. They can act as laxatives in patients with small, hard stools but are also useful in the diarrhea associated with diverticular disease. Included in this class are isp aghula husk and methylcellulose. The main concern with these drugs is that adequate oral hy dration is main- tained, as there is a risk of intestinal obstruction Ispaghula husk (Fybog el ) \200 \200 Indication: diarrhea associated with diverticular disease. Dose: 3.5g od PO, Loperamide \200 Indication: symptomatic treatment of acute diarrhea and chronic diarrhea. 201 CHAPTER 12.4 Antidiarrhoeals \200 \200 \200 \200 Galacto-oligosaccharides Soya-oligosaccharides Xylo-oligosaccharides Isomalto-oligosacchari des Pyrodextrins Side effects: \202 atulence, abdominal distension, intestinal obstruction. Ensure adequat e \202 uid intake orally. Methylcellulose \200 Indication: diarrhea associated with diverticular dis- ease. Dose: 4mg PO initially then 2m g following each loose stool, max 16mg daily. Side effects: see Ispaghula. Cautions: see Is paghula. They clearly have a place in the treatment of recurrent C. dif \201 cile diarrhea, but no large studies to date have been performed in critically ill patients to examine their role in these patients. \200 Synbiotics Combinations of probiotics with prebiotics are termed synbiotics. The principles are the same as for prebiotics and probiotics. One study examined the administration of an infusion of Bi \201 dobacterium lactis, Lactobacillus acido- philus, Lactobacillus bulgar icus, Streptococcus thermophilus and oligofructose to critically ill patients and found the y favorably altered the upper GI bacterial milieu, but there was no clear clinical bene \201 t. Enteral supplements Recent research into the role of \201 bre and into live micro- bial f eed supplements has shown promise in the treatment of enteral feeding induced diarrhea. Soluble \201 bre The physiological effects of \201 bre on the gut include: \200 \200 \200 \200 Prolongation of intestinal transit time. Generation of short chain fatty acids. Reduction i n C. dif \201 cile toxin production. Binding of bile salts. Further reading Bleichner G, Blehaut H, Mentac H et al. Sacchromyces boulardii prevents dia rrhea in critically ill tube fed patients. Intensive Care Med 1997; 23: 517 \200\22323. It is therefore not surprising that they may be bene \201 cial in enteral feeding-associat ed diarrhea. Indeed in a rand- omized, double-blinded study, they have been shown to reduce the severity and time of diarrhea. This was only in sepsis related patients and only in a small number (25 patients). Elpern EH, Stutz L, Peterson S, et al. Outcomes associated with enteral tube feedings in a medical intensive care unit. Am J Crit Care 2004; 13: 221 \200\2237. Jain PK, McNaught CE, Anderson AD, et al. In \202 uence of symbiotic containing Lactobacil lus acidophilus La5, Bi \201 dobacterium lactis Bb12, Streptococcus thermophilus, Lactobac illus bulgaricus and oligofructose on gut barrier function and sepsis in critically ill pat ients: a randomized, controlled trial. Clin Nutr 2004; 23: 467 \200\22375. Montejo JC. Ente ral nutrition-related gastrointestinal complications in critically ill patients: a multicen tre study. The Nutritional and Metabolic Working Group of the Spanish Society of Intensive Care Medicine. Intens Care Med 1999; 25: 95 \200\223101. Probiotics A probiotic is a live microbial feed supplement that improves intestinal microbi al balance. They are found in enriched commercial products such as cheeses and yogurts. Sac charomyces boulardii has been shown to reduce the incidence of enteral feeding-associated d iarrhea in a series of 128 critical care patients. These were patients with sepsis, so it i s not certain whether this can be extrapolated to the general adult ICU population. Spapen H, Diltoer M, Van Malderen C, et al. Soluble \201 ber reduces the incidence of dia rrhea in septic patients receiving total enteral nutrition: a prospective, double blind, ra ndomized, and controlled trial. Clin Nutr 2001; 20: 301 \200\2235. Wiesen P, Van Gossum A, Preiser J-C. Diarrhea in the critically ill. Prebiotics Prebiotics are food ingredients that are non-digestible and bene \201 t the hos t by stimulating the growth of certain bacteria in the colon. Commonly used prebiotics incl ude: \200 \200 Curr Opin Crit Care 2006; 12: 149 \200\22354. Inulin Fructo-oligosaccharides 202 J KAUSE Constipation in critical care very effective, but they can cause diarrhea with resulting dehydration and loss of potassiu m and other electrolytes. They also are more likely than other types of laxatives to cause intestinal cramping. Parasypathomimetics (neostig- mine and pyridostigmine) enhance parasym pathetic activity in the gut and increase GI motility. They are rarely used for this effect , as bowel obstruction needs to be excluded before use. They should not be used shortly aft er bowel anastomosis. Constipation is a common problem, affecting 20% of the general population. Constipation is more prevalent in ICU patients, often due to medication but also due to lack of normal phys iological function, such as balanced diet, exercise and biofeedback. This aspect of critica l care management can be overlooked when management of life-threatening conditions takes pr ecedence. Constipation is unpleasant for the patient: common symptoms are \202 atulence, bloating, abdominal pain and feeling of incomplete emptying, over- \202 ow diarrhea, naus ea and vomiting. Ventilatory weaning and urinary function can also be affected. Constipatio n may be due to colonic \200\230inertia \200\231, due to a primary disease of the colon (s tricture, cancer, anal \201 ssure), or a secondary phenomenon due to metabolic disturbanc es (hypercalcaemia, hypothyroidism, diabetes mellitus) or neu- rological disorders (Parkins onism and spinal cord lesions). Constipation as a disorder of pelvic \202 oor dysfunction occurs when colonic transit time is normal, but stool is stored in the rectum for prolonge d periods of time. It is imperative to con \201 rm the diagnosis of constipation, and to e xclude an underlying condition, before starting medical treatment. Where possible, any unde rlying cause should also be treated. In the critical care environment, medications are ofte n responsible for constipation, see Table 12.5.1 for examples. Osmotic laxatives These increase the amount of water in the large bowel either by drawing \202 uid into to bowel or by retaining the \202 uid they were administered with. Hyperosmolar laxatives The semi-synthetic substance lactulose is the most com- monly used s ubstance in this category. The result is osmotic diarrhea with low fecal pH, which discoura ges the prolif- eration of ammonia-forming organisms. Marcrogols (e.g. Movicol) are inert p olymers of ethylene glycol, which sequester \202 uid in the bowel. Lactulose is used in t he treat- ment of hepatic encephalopathy. Saline laxatives These contain non-absorbable ions such as magnesium, sulfate, phosphate an d citrate (e.g. magnesium hydrox- ide, magnesium sulfate, sodium phosphate, sodium cit- rat e, phosphate enema). Saline laxatives act within a few hours and are therefore useful in cr itical care. The magne- sium in magnesium-containing laxatives is partially absorbed from t he intestine and into the circulation, hence caution in chronic renal failure with long-ter m use of magnesium- containing laxatives. Table 12.5.1 Types of medications causing constipation Antihistamines Anticholinergics Anticholinergics Antidepressants Bulk-forming laxatives Fiber is de \201 ned as material made by plants that is not digeste d by the human GI tract. Fiber is one of the main- stays in the treatment of constipation. Dietary intake of \201 bre in the form of fruit and vegetable is impractical for most ICU patients. Many types of \201 bre within the intestine bind to water and keep the water w ithin the intestine. The \201 bre adds bulk (volume) to the stool and the water softens t he stool. Increased bulk leads to increased peristalsis. The effect of bulk-forming laxativ es may take some time to develop. Adequate \202 uid intake must be maintained during trea tment to avoid bowel obstruction. Commonly used agents contain ispagula husk (Fybogel, Fibr elief, Isogel, Regulan). Anticholinergics Iron supplements Cation-containing agents Aluminum (antacids, sucralfate) Opiates Neurally active agents Antihypertensives Ganglion blockers Vinca alkaloids Calcium channel blockers 5-HT3 antagonists Emollient laxatives Emollient laxatives are generally known as stool softeners. They are us ed rarely in the current management of acute constipation. They contain docusate (e.g. Cola ce), which is a wetting agent that enhances the mixing of water with stool within the colon . Although docusate generally is safe, it may allow the absorption of mineral oil and some medi- cations from the intestine. The use of emollient laxatives is not recommended togethe r with mineral oil or with some prescription medications. Emollient laxatives are commonly used when there is a need to soften the stool temporarily and make defecation easier (e.g. after surgery, childbirth or heart attacks). They are also used for individuals with hemorr hoids or anal \201 ssures. Other examples of stool softeners are the following Treatments Some ICUs have developed treatment protocols for the management of constipation. Bowel protocols may be use- ful in special situations (e.g. liver disease and spinal cord injury). The main advantage of a bowel protocol is regular assessment of bowel function. Stimulant laxatives Stimulant laxatives act by increasing peristalsis and by increasing the amounts of water in the stool, either by reducing the absorption of the water in the colon or by causing active secretion of water in the small intestine. The most commonly used sti mulant laxatives are anthraqui- nones, i.e. senna and danthron; bisacodyl and docusate sodi um are also stimulant laxatives. Stimulant laxatives are 203 CHAPTER 12.5 Constipation in critical care Enemas There are many different types of enemas. By distending the rectum, all enemas (even the simplest type, the tap water enema) stimulate the colon to contract and eliminate stoo l. Other types of enemas have additional mechanisms of action. For example, saline enemas c ause water to be drawn into the colon. Phosphate enemas (e.g. Fleet) stimu- late the muscle s of the colon. Mineral oil enemas lubricate and soften hard stool. Emollient enemas (e.g. Colace Microenema) contain agents that soften the stool. Enemas are particularly useful whe n there is fecal impaction, which is hardening of stool in the rectum. The frequent use of enemas can cause disturbances of the \202 uids and electro- lytes in the body. This is es pecially true of tap water enemas. reducing or inhibiting GI ammonia production and by removal of ammonia from the gut. Miscellaneous drugs Several prescribed drugs that are used to treat medical diseases consis tently cause (as a side effect) loose stools, even diarrhea. There are several small studie s that have examined these drugs for the treatment of constipation. Colchicine is a drug th at has been used for decades to treat gout. Colchicine has also been demonstrated to reliev e constipation effectively in patients without gout. Misoprostil (Cytotec) is a drug used p rimarily for pre- venting stomach ulcers caused by NSAIDs such as ibupro- fen. Diarrhea is one of its consistent side effects. Several studies have shown that misoprostil is effectiv e in the short- term treatment of constipation. Misoprostil is expensive, and it is not cle ar if it will remain effective and safe with long-term use. Orlistat (Xenical) is a drug th at is used primarily for reducing weight. It works by blocking the enzymes within the intes tine that digest fat. In studies, orlistat has been shown to be effective in treating const ipation. Orlistat has few signi \201 cant side effects as very small amounts of the drug a re absorbed from the intestine. Suppositories As is the case with enemas, different types of suppositories have different m echanisms of action. There are stimulant suppositories containing bisacodyl (e.g. Dulcolax) . Glycerin suppositories are believed to have their effect by irritating the rectum Special situations Palliative care in this setting, it is important to consider differentia l diag- noses, such as malignant bowel obstruction, epidural cord compression, hypercalcaem ia and medications as the cause of constipation. Symptom relief is paramount. Protocols for management of constipation have been developed locally in the UK and by the hospice moveme nt and are freely available online, e.g. http://www.cancerhelp. org.uk/help/default.asp?pag e=1436 Conclusion For the treatment of constipation arising due an intensive care admission, stimu lant and osmotic laxatives should be used as \201 rst-line treatment as soon as the probl em is identi \201 ed. For patients with pre-existing constipation, treat- ment should be r estarted as soon as possible. This may be more urgent in special circumstances such as spin al cord injury or liver failure. Further reading AGA guideline: constipation. Gastroenterology 2000; 119: 1761. Als-Nielsen, B Gluud L, Gluud C. Nonabsorbable dissacharides for hepatic encephalopathy. Cochrane Datab ase Syst Rev 2004; (2): CD003044. Spinal cord injury Bowel dysfunction is common and disabling after spinal cord injury. The goal of treatment is to establish predicta- ble and timely bowel evacuation as soon as poss ible, preventing constipation, fecal impaction or incontinence. BNF section 1.6 http://www.bnf.org/bnf/bnf/cur- Liver failure In patients with hepatic encephalopathy, plasma ammonia levels are high and t reatment with lactulose is aimed at rent/1001.htm Locke GR III. AGA technical review on constipation. Gastroenterology 2000; 119: 1766. This page intentionally left blank 205 Chapter 13 Neurological drugs Chapter contents Opioid and non-opioid analgesics in the ICU 206 Sedation management in ICU 208 Muscle relax ants 210 Anticonvulsant drugs 212 Cerebroprotective agents 214 Mannitol and hypertonic sali ne 216 206 A LAWSON Opioid and non-opioid analgesics in the ICU Opioid analgesics Opioid analgesic drugs remain the mainstay of pain relief in the Critical Care Unit. Abnormal GI function in the critically sick consequently makes enteral administ ration undesirable. IV administration remains the mainstay. Pharmacokinetic considerations consequent upon organ dysfunction leading to altered absorption, distribution and metabolis m usually play the most important role in the choice of agent. Most analgesics used on the ICU are metabolized via phase I or II pathways, and they are generally effectively metabo- lized in all but those with severe liver dysfunction. Metabolism is generally affected by l iver blood \202 ow rather than hepatocyte function. Opioids exert their analgesic action by binding to the opioid receptors at both spinal and supraspinal sites. Unwanted effects i nclude bradycar- dia, miosis, hypothermia, nausea, urinary retention, respira- tory depress ion and constipation. Alfentanil is a phenylpiperidine synthetic opioid. It has similar pharmacodynamic propertie s to the other newer opioids, but it shows considerable variability in its pharma- cokineti c pro \201 le from patient to patient. Interindividual variability in alfentanil clearance is likely to result from differences in hepatic P450-3A4 expression and to P450- 3A4-relat ed drug interactions. Remifentanil has an extremely short context-sensitive half- life and is independent of hepatic and renal function . In the cardiac- and neuro-ICU setting, remif entanil \200\231s short half-life is especially desirable. It allows good neurological asse ss- ment when required, profound haemodynamic stability and early extubation after bypass s urgery. One study suggests that the intraoperative use might even reduce the need for a pos t-operative ICU stay after major abdominal surgery. Table 13.1.1 outlines commonly use regi mes for opioid infusion in Critical Care Units. Route of administration The IV route is the most reliable way of delivering opioids in the critically ill. Extradural opioids have been used, often in combination with local anesthet ics; inhalational and transmucosal opioids are only rarely used. Patient-controlled modes o f administration require a fully conscious and orientated patient, and are therefore only o f limited value in the CCU. Table 13.1.1 Infusion rates for commonly used opioids in critical care Drug MEAC ng/ml t1/2 terminal (min) Dose mcg/kg/h Alfentanil Fentanyl Sufentanil Remifentanil n/a 50 \200\223100 1 \200\2233 0.2 \200\2230.5 90 185 160 \200\223210 10 \200\22320 30 \200\22360 1 \200\2235 0.2 \200\2231.0 30 \200\22360 Choice of drug The most commonly used opioids are morphine, fentanyl, alfentanil and remife ntanil Morphine 10 \200\22330 100 \200\223180 50 \200\223100 MEAC = minimally effective analgesic concentration. Morphine Morphine is the most often prescribed agent because of its low cost, excellent ana lgesic ef \201 cacy and euphoric effects. It has a peak effect within 20min, and duration of action between 2 and 7h. It has low lipid solubility and volume of distribution, and its duration of action is determined by hepatic metabolism. It is metabolized by the liver to the water-soluble morphine-6-glucuronide and morphine- 3-glucuronide, which are then renall y excreted. Morphine- 6-glucuronide is 2 \200\223800 times analgesically more potent than m orphine and accumulates in renal dysfunction. This can lead to unwanted prolonged sedation and respiratory depression Morphine-3-glucuronide is not analgesically active. Non-opioid analgesics Non-steroidal anti-in \202 ammatory drugs (NSAIDs) NSAIDs have opioi d-sparing effects and have both central and peripheral sites of analgesic activity. The use in the criti- cally ill is however controversial. Their metabolism and excretion is depend ent on liver and kidney function, both of which pathways are frequently impaired in the ICU patient. NSAIDs decrease the prostaglandin-dependent renal blood \202 ow and are associa ted with an increased gastric ulceration risk. It seems prudent to avoid this class in the critically ill in the absence of any de \201 nite gain to be had. A new class of agents ha s been developed that selectively inhibit the inducible cyclo-oxygenase enzyme, COX-2. By s paring physiological tissue prostaglandin production while inhibiting the COX-2-related in \202 ammatory processes, these agents are thought to offer the potential of effective anal gesia with fewer side effects than previous NSAIDs. They have been shown to be as effective as NSAIDs in the management of post-operative analgesia. Adverse effects on renal blood \202 ow, which are similar those of to conven- tional NSAIDs, and concerns regarding potent ial prothrom- botic effects of at least some of the COX-2 agents, will limit their use in t he critically ill patient. Fentanyl, alfentanil and remifentanil Fentanyl is a synthetic opioid; it is the preferred a nalgesic agent for critically ill patients with haemodynamic instabil- ity and for patients manifesting symptoms of histamine release with morphine or morphine allergy. Fentanyl is 5 0 \200\223100 times more potent than morphine; it has extremely low bioavailability and the refore can be given by any route other than the GI tract. It is extremely lipid soluble and has an onset of action within 30s, with a peak effect in 5 \200\22315min. It has a short h alf-life of 30 \200\22360min following redistribution, but accumulation in peripheral compa rtments can increase the half-life to 9 \200\22316h. Fentanyl is metabolized in the liver t o pharmacologically inactive metabolites, which are renally excreted. In criti- cally ill p atients with renal failure there is an increase in the volume of distribution and half-life of fentanyl. Fentanyl has minimal cardiovascular effects compared with morphine. Following a long infusion of fentanyl, accumulation may cause prolonged respiratory depression. Ketamine This IV anesthetic agent has intense analgesic properties even at subanaesthetic l evels, maintaining the airway, and has stimulatory effects on the respiratory and cardio- v ascular system. It is used in specific painful proce- dures, particularly in burn patients for dressing changes. 207 CHAPTER 13.1 Opioid and non-opioid analgesics in the ICU Hallucinations and emergence phenomena can be attenu- ated by the co-administration of benz odiazepines. There is furthermore some evidence, that ketamine can be useful in chronic pai n states such as central pain, complex regional pain syndrome, \201 bromyalgia and neurop athic pain. Either alone or in combination with opioids it provides rapid, effective and pr olonged analgesia . stimulation (TENS), acupuncture, aromatherapy, etc., should not be withheld. Anecdotal evid ence suggests a bene \201 t from acupuncture in neuropathic pain, and reduced seda- tive a nd analgesic requirements following aromatherapy. Summary Opioids are the most commonly used analgesic agents, often giving in combination wi th sedative drugs. There is no doubt that this method is effective and cheap, and staff hav e a wealth of experience in its use. However, such regimes do not provide satisfactory pain relief in all patients. What is needed to avoid patients experiencing pain while in Ithe C U is individualized, goal-directed analgesic regimes in their own right, not as a side effe ct of sedation. In con- cert with analgesia, anxiety, the physical environment and the pati ent \200\231s sleeping pattern need to be considered. Adherence to a clear protocol may be as important as choice of medication. Further reading Barr J, Donner A. Optimal intravenous dosing strategies for seda- tives and analgesics in the intensive care unit. Crit Care Cli n 1995; 11: 827 \200\22347. Neuropathic pain agents Some patients may be suffering from or develop neuro- pathic pain. This sort of pain may be dif \201 cult to manage with standard analgesics, and considerati on should be given to adding in speci \201 c drugs for neuropathic pain as outlined in Tab le 13.1.2. Patients may also have pre-existing neuro- pathic pain problems; medication shou ld be continued where possible. Table 13.1.2 Adjuvant therapies for pain in critical care. Drug Dose mg Neuropathic pain Sleep PTSD Tricyclic antidepressants Gabapentin 20 \200\223100 nocte + ++ + Breen D, Karabinis A, Malbrain M, et al. Decreased duration of mechanical ventilation when comparing analgesia-based sedation using remifentanil with standard hypnotic-based sedation for up to 10 days in intensive care unit patients: a randomized trial. Crit Care. 2005; 9: R200 \200\22310. 100 \200\223900 ++ + +? Pregabalin 25 \200\223300 ++ + +? PTSD = post-traumatic stress disorder. Curtis SP, Ng J, Yu Q, et al. Renal effects of etoricoxib and comparator nonsteroidal anti- in \202 ammatory drugs in controlled clinical trials. Clin Ther 2004; 26: 70 \200\22383. Adjuvant therapies Especially in patients with features of chronic pain or altered sleep pa tterns, tricyclic antidepressants have been used extensively. There might be a rationale fo r using these drugs in the medium- to long-stay patient where a constel- lation of pain, an xiety and depression co-exists, possibly along with a disturbed sleep pattern. There is evi dence that the usage of tricyclics, and possibly some of the drugs used to treat neuropathi c pain, may reduce the development of post-traumatic stress disorder (PTSD) in ICU survivor s. Kuhlen R, Putensen C. Remifentanil for analgesia-based sedation in the intensive care unit. Crit Care 2004; 8: 13 \200\2234. Muellejans B, Matthey T, Scholpp J, et al. Sedation in the intensive care unit with remifen tanil/propofol versus midazolam/fentanyl: a randomized, open-label, pharmacoeconomic trial. Crit Care 2006; 10: R91. Roemsing J, Moeniche S. A systematic review of COX-2 inhibitors compared with traditional N SAIDs, or different COX-2 inhibitors for post-opereative pain. Acta Anaesthesiol Scand 2004 ; 48: 525 \200\22346. Wilson W, Smedira N, Fink C, et al. Ordering and administration of se datives and analgesics during the withholding and withdrawal of life support from criticall y ill patients. JAMA 1992; 267: 949 \200\22353. http://www.anzca.edu.au/publications/acutep ain. Alternative therapies No evidence exits to support the use of alternative thera- pies in th e critically ill. In the absence of any untoward effects, however, the use of transcutaneou s electrical nerve htm 208 DH CONWAY & R BEDAIR Sedation management in ICU Drugs with sedative, analgesic and neuromuscular blocking activity are used in different co mbinations to facilitate care of the critically ill. Sedative agents alleviate anxiety, red uce the stress response and improve tolerance of ICU inter- ventions. Tolerance to benzodiazepines may occur within hours to several days of therapy, and escalat ing doses of midazolam have been reported. Benzodiazepines can also cause delir- ium (both hypo- and hyperactive forms). Propofol Propofol is a non-water-soluble propylphenol formulated as an aqueous emulsion in intralipid solution. It is a short- acting GABA agonist with sedative and hypnotic effects but no analgesic properties. The plasma level of propofol rapidly falls after discontinuati on, and recovery time is short compared with other sedatives. This is due to redis- tributi on from plasma to the tissues. With prolonged infusions, the tissues become saturated and r ecovery is longer. No changes in kinetic parameters have been reported in patients with ren al or hepatic dysfunction. Propofol improves control of ICP and decreases CBF and metabolis m. Rapid awakening from propofol makes it useful for patients in whom frequent neurological assess- ment is needed. Propofol causes a dose-dependent drop in blood pressure through re duced SVR and bradycardia. Also, the lipid base of propofol can function as a medium for ba cterial growth, and long-term or high dose infusions may result in hyper- triglyceridaemia, and some cases of pancreatitis have been reported. Propofol infusion syndrome is a rare bu t lethal complica- tion. It is reported in pediatric and occasionally in adult critical car e. There is a severe metabolic acidosis, rhab- domyolysis, haemodynamic collapse and bradyc ardia pro- gressing to asystole. This may be due to impaired fatty acid oxidation or inhibi tion of phosphorylation in the mito- chondria. Risk factors include hypoxia, sepsis, cerebr al injury and high propofol dose. Whilst propofol has experimental evidence of anticonvul- sant activity in animal models, abnormal epileptiform movement has been reported in clinica l anesthetic practice. Indications for use of sedation 1 To maintain patient comfort while being managed within critical care areas. 2 To facilitate compliance with mechanical ventilation. 3 To help control raised ICP. 4 To manage anxiety, agitation and delirium. 5 To augment analgesia through the opiate-sparing e ffect of some sedative agents. Prior to starting sedation, any underlying cause of discom- fort or agitation should be tre ated. Furthermore, the unde- sirable effects of sedative infusions should be considered, as sedative use can complicate neurological assessment, prolong the duration of mechanical ve ntilation and increase length of stay in the ICU and the hospital . The amnesic properties of some sedatives may modify post-traumatic stress (PTSD) by reducing recollection of unple asant or frightening memories. Unfortunately, overse- dation and withdrawal can contribute to PTSD symptoms. Sedative agents A number of drug classes with distinct features are available. Sedation can be administered by intermittent bolus dose or continuous infusion. IV infusions provide co nstant levels of sedation to increase patient comfort. However, their use is an independent predictor of increased length of stay in the ICU and the hospital . Determining appropriat e dosing of drugs can be dif \201 cult. The decreased protein binding and the impaired ren al and hepatic function that occur in critical illness lead to changes in half-life and vol ume of distribution. Benzodiazepines Benzodiazepines are the most commonly used sedatives. They act on benzodiaz epine receptors, which enhance the effect of -aminobutyric acid (GABA) on chloride channe ls, causing intracellular in \202 ux of chloride ions. This increases resting membrane pot ential, inhibiting excitation. They have anxiolytic, anticonvulsant, amnesic and centrally mediated muscle relaxant properties. \200 Etomidate Etomidate is now rarely used in the ICU because it is asso- ciated with adrenocor tical insufficiency and has been shown to increase mortality in critically ill patients. Butyrophenones Haloperidol has sedative effects, and boluses are used to alleviate delirium . Haloperidol infusions have been used successfully in the management of agitated patients in critical care. There is a risk of complete heart block, ventricular tachycardia and QTc prolongation \200\224with the accompanying possibility of torsades de pointes. Diazepam has a rapid onset of action, and patients gen- erally will awaken rapidly after a bolus dose. With con- tinuous infusions, the half-life and active diazepam metabolites lead to a prolonged sedative effect. Lorazepam is eliminated by conjugation to inactive glu- cu ronides. It has a slower onset of action, making it less useful for acute agitation, and a prolonged half-life, mak- ing it dif \201 cult to titrate. Midazolam has a rapid onset of action and a short half- life, making it ideal for the critically ill. Accumulation and pro longed sedative effects are reported in critically ill patients who are obese, in renal fai lure or have low serum albumin Prolonged sedative effects may also be caused by the accum ulation of the active metabolite, - hydroxymidazolam, or its conjugated salt. Phenothiazines Phenothiazines block muscarinic, 1-adrenergic, H1 histaminic, DA1 and DA2 receptors. They have antipsychotic properties that are mainly due to their DA2 receptor blo cking activity in the limbic system. Chlorpromazine 50 \200\223100mg can be administered IM , but IV bolus doses (2.5 \200\22310mg) cause severe hypotension. An infusion of 10 \200 \22320mg/h is less likely to compromise blood pressure. Central 2 agonists These include clonidine and dexmedetomidine. Dexmedetomidine is a selective 2 agonist. It has sedative and analgesic-sparing properties, and produces anxiolysis 209 CHAPTER 13.2 Sedation management in ICU to collect. A de \201 ned sedation goal, using sedation scales, can reduce length of stay.