Drug Use Treatment with Levosimendan is usually initiated with a 10 minute loading bolus of 3 to 6 mcg/kg followed by a 24h continuous infusion of 0.05 to 0.2 mcg/kg/min. If the pati ent has hypotension, one should either skip the loading dose or associate Norepinephrine in low dose. Most patients show improvement in hemodynamic function during the next 24h, usua lly heralded by a signi \201 cant increase in urine output and a signi \201 cant decrease in the PCWP. This diu- retic effect is often the cause of electrolyte imbalance that has b een associated with arrhythmia. Magnesium and potassium should be pre-emptively administrat ed in order to prevent arrhythmia unless there is a contra-indication such as renal failure . Levosimendan improves coronary blood \202 ow, decreases myocardial oxygen extraction, and improves ischaemic myocardium performance. This was \201 rst shown in animals and health y humans, but was later shown in patients with congestive HF, acute myocardial infarction ( AMI), after PCI of AMI patients with LV dysfunction and after coronary artery bypass grafti ng (CABG) where, despite improved cardiac performance, it did not increase myocardial oxyge n consumption or change myocardial substrate utilization. Levosimendan has a half-life of approximately 1.3 hours. The drug is metabolized by the liv er and has two active metabolites, OR-1855 and OR-1896, with long half-lives (75-78 hours), that are excreted by the kidney and prolong the duration of the hemodynamic effects of the ir parent compound. This long half-life is markedly increased in patients with severe chron ic renal failure or end-stage renal disease undergoing haemodialysis as compared with healt hy subjects. As a powerful vasodilator, levosimendan may be a harm- ful drug. Although this drug has a m inor in \202 uence on myo- cardial oxygen demand per se, in patients with active ischemia or obstructive CAD, levosimendan induced hypo- tension, especially in the hypovolemic patie nt, may precipi- tate tachycardia, aggravate ischemia, and increase myocardial damage, wors ening long term prognosis. Hypotensive patients or patients with active ischemia are not go od can- didates for levosimendan administration and should have these problems addressed \201 rst. Clinical Studies Several clinical trials have shown the bene \201 cial effect of levosimen dan on short-term hemodynamic and clinical signs in patients with AHF. Kivikko et al (DATE) reported a 30% increase in CO and a 50% decrease in PCWP after 24 hours infusion in class III-IV heart failure patients. The Levosimendan Infusion versus DObutamine (LIDO) study enr olled 203 patients with severe low-output heart failure and compared the effects of levosim endan with those of dobutamine in a double blind fashion over 24 hours. The primary end poi nt of hemodynamic improvement (an increase of 30% or more in cardiac output, and a decrease In countries where it is available, early levosimendan infusion can be considered for patie nts who remain symp- tomatic with dyspnea at rest despite initial therapy, partic- ularly t hose with a history of chronic heart failure, chronically treated with beta-blockers. It ha s also been used to restore right or left ventricular function in patients after cardiac su rgery, in unresponsive cardiogenic shock after heart transplantation primary graft failure, and RV dysfunction in acute respiratory distress syndrome patients. 191 CHAPTER 11.10 Levosimendan References Gheorghiade M, Teerlink JR, Mebazaa A. Pharmacology of new agents for acute hear t failure syndromes. Am J Cardiol. 2005; 96(6A): 68G-73G. Michaels AD, McKeown B, Kostal M, et al. Effects of intravenous levosimendan on human coron ary vasomotor regulation, left ventricular wall stress, and myocardial oxygen uptake. Circu lation 2005; 111(12): 1504-9. De Luca L, Proietti P, Celotto A, et al. Levosimendan improves hemodynamics and coronary \202 ow reserve after percutaneous coronary intervention in patients with acute myocardial infarc- tion and left ventricular dysfunction. Am Heart J 2005; 150(3): 563-8. De Luca L, Colucci WS, Nieminen MS, et al. Evidence-based use of levosimendan in different clinical settings. Eur Heart J. 2006; 27(16): 1908-20. Kass DA, Solaro RJ. Mechanisms and use of calcium-sensitizing agents in the failing heart. Circulation 2006; 113(2): 305-15. Follath F, Cleland JG, Just H, et al. (2002) Ef \201 cacy and safety of intravenous levosi mendan compared with dobutamine in severe low-output heart failure (the LIDO study): a rand omized double- blind trial. Lancet 2002; 360(9328): 196-202. Givertz MM, Andreou C, Conrad CH, Colucci WS. Direct myocar- dial effects of levosimendan i n humans with left ventricular dys- function: alteration of force-frequency and relaxation- frequency relationships. Circulation 2007; 115(10): 1218-24. Mebazaa A, Nieminen MS, Packer M, et al. Levosimendan vs dob- utamine for patients with acu te decompensated heart failure: the SURVIVE Randomized Trial. Jama 2007; 297(17): 1883-91. Morelli A, Teboul JL, Maggiore SM, et al. Effects of levosimendan on right ventricular afte rload in patients with acute respiratory distress syndrome: a pilot study. Crit Care Med 20 06; 34(9): 2287-93. Toller WG, Stranz C. Levosimendan, a new inotropic and vasodila- tor agent. Anesthesiology 2006; 104(3): 556-69. This page intentionally left blank 193 Chapter 12 Gastrointestinal drugs Chapter contents H2 blockers and proton pump inhibitors 194 Antiemetics 196 Gut motility agents 198 Antidiar rhoeals 200 Constipation in critical care 202 194 K DELL H2 blockers and proton pump inhibitors Physiology of acid secretion There is continual basal acid secretion and an increase after meals, from the parietal cells in the body and fundus of the stomach. The dominant mechanis m for acid secre- tion is mediated by histamine from enterochromaf \201 n cells, in turn s timulated by gastrin, released from antral G cells in response to amino acids. Other stimul i acting on parietal cells include acetylcholine, gastrin, calcium and pituitary adenylate cyclase-activating polypeptide. Lansoprazole is a weak inducer of cytochrome P450, affect- ing the metabolism of phenytoin, theophylline and warfarin. Pantoprazole does not inhibit or induce the cytochrome P450 sys tem. Pathophysiology of stress ulcers Factors contributing to mucosal disease \200 Defects in gastric glycoprotein mucus. This is contrib- uted to by re \202 uxed bile salts and uraemic toxins. Gastric acid hypersecretion. Although acid secretion in most criticall y ill patients is normal or subnormal, in patients with head injuries and extensive burns t here can be hypersecretion. Ischaemia. Even with apparently normal systemic circula- tion, visceral perfusion can be decreased, decreasing secretion of mucus and bicarbonate. Helicob acter pylori infection. This has not been well stud- ied in the critically ill. Pharmacology Histamine receptor-2 blockers (H2Bs) \200 \200 can cause bradycardia on rapid injection have a short half-life, resulting in an elevated p H for 4 \200\2238h after an intravenous bolus possess a degree of renal elimination and the refore require dose adjustment with renal impairment cimetidine is known to be an enzyme in hibitor increasing the plasma levels of many drugs, e.g theophylline, metro- nidazole, diaz epam and phenytoin exhibit tachyphylaxis or tolerance. Coagulation effects In vitro studies have shown at a pH of 6.4 the effectiveness of coagula tion and platelet aggregation is halved. A further drop in pH to 5.4 results in practical c essation of coagula- tion and platelet aggregation activity. Clot lysis by pepsin is inhibi ted if pH is >4. The literature has suggested aims of treatment are: \200 \200 This feature of tolerance is demonstrated in a trial where healthy volunteers were exposed to two drugs in a crossover fashion. Results are shown in Table 12.1.1 from continuous infu sions, but similar results were obtained for intermittent dosing. pH during days 1, 2 and 3 is displayed as a median value, and the percentage time spent above a pH value of 4 and 6. A pH >4 to prevent stress ulceration A pH >6 to prevent clot lysis with an acute GI bleed Stress ulcer prophylaxis The signi \201 cant study in this area that gives us both de \201 ni- tions and risk factors for stress ulcers is by the Canadian Critical Care Trials G roups, led by Cook, and published in 1994. It was a prospective, multi-center, cohort study involving 2252 patients in four university-af \201 liated, medical \200\223 surgical ICUs . Table 12.1.1 Effects of ranitidine and omeprazole on intragastric pH Day 1 Day 2 Day 3 Ranitidine median pH Omeprazole median pH Ranitidine % time pH >4 Omeprazole % time pH >4 R anitidine % time pH >6 5 >6 70% 95% 30% 3 >6 38% >99% <11% 2.7 >6 26% >99% <11% De \201 nitions \200 \200 Occult bleeding: guaiac +ve gastric aspirate or stool Overt bleeding: haematemesis, haemato chezia or malaena Clinically signi \201 cant bleeding: haemodynamic change or need for tra nsfusion Omeprazole % time pH >6 59% >70% >70% Ranitidine \200\22450mg loading dose + 0.25mg/kg/h infusion or 100mg qds. Omeprazole \200 \22480mg loading dose + 8mg/h infusion or 80mg loading dose + 40mg qds. Risk factors Mechanical ventilation >48h There is a 16-fold increase risk of bleeding; odds ratio 15.6 (P <0.001) Proton pump inhibtiors (PPIs) \200 do not exhibit tachyphylaxis \200 have an eliminatio n half-life of 1h \200 bind irreversibly to the H+/K+ ATPase proton pump and thus requir e the synthesis of new pump enzyme to terminate their effect \200\224a process that can tak e up to 48h do not require dose adjustment in the elderly or those with renal impairment ma y need dose adjustment in hepatic impairment do exhibit drug interactions. Coagulopathy There is a 4-fold increase in the risk of bleeding; odds ratio 4.3 (P <0.001) Of 847 patients with one of these two risk factors, 3.7% had clinically signi \201 cant bl eeding, and of 1405 patients without risk factors, 0.1% had clinically signi \201 cant ble eding. Bene \201 ts of prophylaxis H2Bs In Cook \200\231s meta-analysis of 1996 which included 72 18 patients, it was shown that in patients given H2Bs the prevalence of clinically signi \201 cant bleeding has an odds ratio of 0.44 (95% con \201 dence interval (CI), 0.212 \200 \2230.88) vs placebo/no therapy, and an odds ratio of 0.86 (95% CI, 0.46 \200\2231.59) vs a ntacids. \200 Omeprazole reduces the clearance of carbamazepine, diazepam and phenytoin. 195 CHAPTER 12.1 H2 blockers and proton pump inhibitors However, in the more recent meta-analysis by Messori, which excluded studies using cimetidi ne and only used pla- cebo-controlled trials and therefore only had 398 patients, ranitidin e was not shown to have a treatment effect on clinically important bleeding. This paper dis cussed the need for an RCT, but there was dif \201 culty in the ethics in using a placebo control. It also asked the question of whether it realistic to expect cimetidine to be effe ctive and ranitidine ineffective as their results seemed to show. H2Bs are unlikely to be effective in active bleeding, or pre- venting rebleeding after haem ostasis from endoscopic injection or thermo/electro-coagulation. PPIs are effective in prev enting rebleeding after haemosta- sis as they raise pH close to neutrality and allow the fo rma- tion of stable clots. This topic has been the subject of a Cochrane Review in 2007. Th e rate of rebleeding was decreased from 17.3 to 10.6%. Use of PPIs decreased the need for s urgery (odds ratio 0.61, 95% CI 0.48 \200\2230.78). Overall they found no difference in all -cause mortality, apart from the Asian studies in which mortality was reduced. One regimen used is omeprazole 80mg bolus + 8mg/h for 3 days and 20mg/day for 2 months. This decreased transfu- sion requirements, decreased the rate of rebleeding from 20 to 4% in the \201 rs t 3 days (number needced to treat of 5 \200\2236). In addition, studies have shown the use of PPIs in preventing rebleeding to be cost-effective. PPIs There have been few studies evaluating PPIs speci \201 cally for stress ulcer prophyl axis, resulting in insuf \201 cient evidence of superiority. Their use is, however, becomi ng more popular. Studies have shown that enteral or IV administration of a PPI does maintai n a pH of at least 4. Risks of prophylaxis Ventilator-associated pneumonia There remains concern over a possible increased rate of VAP in those treated with prophylaxis. The proposed mechanism is through aspiration of colonized secretions. A large randomized study comparing the use of sulcralfa te (no pH effect) and ranitidine found no difference in the rate of VAP. However, this area remains controversial. In addition, the use of PPIs and H2Bs has been associated with decr eased neutrophil function and lower production of reactive oxygen intermediates. This has u ncertain clinical signi \201 cance; interpreted as deleterious for control of infec- tion or bene \201 cial in aiding ulcer healing and preventing systemic in \202 ammation. Further reading Abpi Compendium of Data Sheets and Summaries of Product Characteristics. Datapharm Publications Ltd, 2000. Conrad S. Acute upper gastrointestinal bleeding in critically ill patients: causes and trea tment modalities. Crit Care Med 2002; 30: S365 \200\2238. Cook DJ, Fuller HD, Guyatt GH, et al. Risk factors for gastrointesti- nal bleeding in criti cally ill patients: Canadian Critical Care Trials Groups. N Eng J Med 1994; 330: 397 \200 \22381. Cook DJ, Grif \201 th LE, Walter SD, et al. The attributable mortality and length of inten sive care unit stay of clinically important gastrointestinal bleeding in critically ill pat ients. Crit Care 2001; 5: 368 \200\22375. Infectious gastroenteritis Increased rates of infection are proposed due to loss of the pro tective role of gastric acid as a bactericidal barrier. Patients treated with PPIs and achl orhydric patients have been shown to be at risk of upper GI colonization and infections, in cluding Clostridium dif \201 cile disease. Cook D, Guyatt G, Marshall J, et al. A comparision of sucralfate and ranitidine for the pre vention of upper gastrointestinal bleeding in patients requiring mechanical ventilation. Ca nadian Critical Care Trials Group. N Engl J Med 1998; 338: 791 \200\2237. Cook DJ, Reeve BK, Guyatt GH, et al. Stress ulcer prophylaxis in critically ill patients: r esolving discordant meta-analyzes. JAMA 1996; 275: 308 \200\22314. Outcomes Patients who develop clinically important GI bleeding have a higher mortality. Thi s equates to a 20 \200\22330% increase in absolute risk of mortality and an increase of 1 \200\2234 in relative risk. Length of ICU stay is also extended by 4 \200\2238 days. It is disappointing that prophylaxis has not demonstrated a sta- tistically signi \201 cant red uction in mortality despite >50 ran- domized trials and several meta-analyzes. HR2Bs do red uce the rate of clinically signi \201 cant GI bleeding by 50%, and hence the associated co sts of endoscopic treatment. The evidence supports a broad range of practice patterns. Fennerty MB. Pathophysiology of the upper gastrointestinal tract in the critically ill pati ent: rationale for the therapeutic bene \201 ts of acid suppression. Crit Care Med 2002; 3 0: S351 \200\2235. Messori A, Trippoli , Vaiani M, et al. Bleeding and pneumonia in intensive care patients gi ven ranitidine and sucralfate for prevention of stress ulcer: meta-analysis of randomized c ontrolled trials. BMJ 2000; 321: 1103. Netzer P, Gaia C, Sandoz M, et al. Effect of repeated injection and continuous infusion of omeprazole and ranitidine on intragastric pH over 72 hours. Am J Gastroenterol 1999; 94: 35 1 \200\2237. Treatment of acute bleeding after endoscopy Up to 20% of patients rebleed after endoscopic treatment, particularly those noted to have a visible non-bleeding ves- sel, adherent clot or ulcer size >1cm. 196 A WALDEN Antiemetics Nausea and vomiting are protective re \202 exes designed to prevent the body from ingestin g noxious substances. Vomiting is the forceful expulsion of the contents of the upper GI tr act through the mouth and associated with contraction of the abdominal muscles. Nausea is t he unpleasant sensation that precedes vomiting. The genesis of nausea and vomiting in criti cally ill patients has myriad causes. Included in these is post-operative nausea and vomiti ng (PONV), ileus and gastroparesis, use of opiate analgesia and sepsis. Symptoms of nausea and emesis may be overlooked when dealing with a complex patient with multiple problems. Pr olonged recovery times in post-surgical patients and risk of aspiration pneumonitis are cle ar reasons why nausea and vomiting should be adequately treated in critically ill patients. To understand the principle actions of antiemetic drugs it is useful to know the mechanism s underlying nausea and vomiting. Somatomotor neurons supplying the diaphragm and muscles of the anterior abdominal wall. Aut onomic and somatic output to the anal and bladder sphincters to prevent expulsion in respon se to large increases in intra-abdominal pressure. Parasympathetic output to the heart and salivary glands leading to bradycardia and salivation. Sympathetic output to skin constrict ors resulting in skin pallor. Antiemetic drugs Anticholinergics These drugs act by direct effects on the vestibular pathw ay but also have effects on modulation of impulses from the gut. Scopolamine can be used tr ansdermally and is effective when applied preoperatively. Scopolamine \200 \200 Mechanisms of nausea and vomiting Vomiting center The vomiting re \202 ex is initiated by the vomiting nucleus situated in the medulla oblongata. Afferent impulses from numerous oth er areas of the nervous system synapse in the vomiting center: \200 \200 \200 \200 Indication: motion sickness or pre-medication. Dose: 1mg patch applied 5 \200\2236h before journey/operation. Lasts 72h. Side effects: drowsiness, dry mouth, dizziness, blurred visio n and dif \201 culty micturating. Caution in renal or hepatic dysfunction. Cortical input from pain, memory, anticipation or fear Sensory inputs from smell and taste Direct vagal afferents from the GI tract Impulses coordinated in the chemoreceptor trigger zone via the nucleus tractus solitarius Antihistamines Predominant effects are on the vestibular pathways so especially useful in m otion sickness disorders and middle ear surgery. Drugs include cinnarizine, cyclizine and p romet- hazine. Drowsiness is a common side effect. Chemoreceptor trigger zone (CTZ) The CTZ is a collection of cells found on the Area Postrem a on the surface of the brain. It lacks an effective blood \200\223brain barrier and so is sensitive to input of noxious stimuli within both the CSF and the blood. As such, opiates, chemother- apy and anesthetics all act via the CTZ. Vagal afferents from the GI tract synap se in the CTZ in addition to direct stimulation of the vomiting center. Cyclizine \200 \200 \200 Indication: nausea and vomiting; motion sickness Dose: 50mg tds IV/PO/IM. Side effects: dro wsiness, dry mouth, blurred vision, dif \201 - culty micturating. Avoid in liver disease, safe in renal impairment. Antidopaminergics Non-specific antagonism of dopamine receptors, but antiemetic effects are modulated by the D2 subtype. These drug types are useful where the main mechanism of emesi s is in the CTZ (e.g. opiate side effect). Three classes: benza- mides (domperidone, metocl opramide) are both prokinetics and antiemetics; phenothiazines (prochlorperazine and chlo- rpromazine) have weak antimuscarinic effects in addition; butyrophenones (droperidol, halop eridol) are similar in effects to phenothiazines. Neurotransmitters Many neurotransmitters are implicated in the process of nausea and vomiti ng, but only six have been involved in pharmacological attempts to treat nausea and vomitin g: \200 Serotonin receptors (5-HT) are found on vagal afferents and in high concentrations within t he CTZ. The 5-HT3 subgroup is especially prominent. Histamine is implicated in the transmis sion of impulses from the vestibular system, but is also involved in gut neural output. The H1 receptor subtype predominates. Dopamine is found in high concentrations in the CTZ espe cially the D2 subgroup. Acetylcholine is involved in vestibular transmission of impulses. S ubstance P acts upon neurokinin-1 (NK-1) receptors which are involved in multiple pathways. Cannabinoid receptors (CB1) are found in the vomiting center and again are involved in mul tiple pathways. Agonism of these receptors allays emesis. Metoclopramide \200 \200 \200 Indication: nausea and vomiting due to GI disorders. Dose: 10mg tds IV/PO/IM. Side effects: extrapyramidal disorders, drowsiness, neuroleptic malignant syndrome, arrhythmias. Reduce dose in hepatic or renal impairment (increased risk of extapyramidal side effects). Chlorpromazine \200 \200 \200 Indication: nausea and vomiting. Dose: 25 \200\22350mg qds IV/PO/IM. Side effects: extrapyr amidal, drowsiness, neuroleptic malignant syndrome, arrhythmias, hypotension. Reduce dose a nd use with caution in hepatic or renal failure. Motor outputs Once the inputs have been processed in the vomiting center, there is a combin ation of neural outputs: \200 Vagal afferents to the esophagus, stomach and small intestine (giant retrograde contraction ). 197 CHAPTER 12.2 Antiemetics Side effects: drowsiness, euphoria, dry mouth, sleep disturbance. Avoid if history of psych iatric disturbance; contraindicated in severe hepatic impairment. 5-HT3 receptor antagonists The advent of 5-HT3 receptor antagonists in the mid-1980s revolu tionized the treatment of chemotherapy-induced emesis. Since then, they have been found to be useful in many other clinical contexts. Drugs in this class include ondansetron, granise tron and tropisetron. Miscellaneous agents Specific 5-HT1A agonists such as buspirone have been shown in humans t o reduce emesis following cisplatin chemotherapy, but they are not licensed as antiemetics. GABAB receptor agonists such as baclofen have also shown some antiemetic activity in neuro logically impaired children. Granisetron \200 Indication: chemotherapy-induced nausea and vomiting; prophylaxis and treatment of PONV. Do se: 1mg bd IV. Side effects: diarrhea, abdominal pain, QT prolonga- tion. Avoid in cardiac conduction disorders. Safe in hepatic and renal impairment. \200 Clinical approach PONV Scoring systems for PONV have been well validated, with the risk of it rising from 10% with no risk factors up to 80% with 4 risk factors. This makes stratifyi ng patients simple and the administration of prophylactic antiemetics appropriate. Metoclop ramide, dexamethasone and 5-HT3 receptor antagonists in combination are commonly used. Corticosteroids The mechanism of steroids acting as antiemetics is not clear. In humans und ergoing chemotherapy, the rate of cisplatin-induced emesis is inversely related to the seru m cortisol level, suggesting a link. The presumed mechanism is by effects on eicasonoid met abolism. Dexamethasone is the most commonly used drug in this class, and appears to be espe cially ef \201 cacious in PONV. On the ICU Clearly the use of different agents in critically ill patients will depend on th e clinical scenario and the side effect pro \201 le. Simple measures such as the insertion of NG tubes to decompress the stomach and adequate pain relief help to reduce the incidenc e of nausea and vomiting. Prokinetics such as metoclopramide have a role as \201 rst-line agents, but some care must be taken in prescribing phenothiazines and butyrophenones in vi ew of their risk of cardiac side effects. Dexamethasone will have effects on the glycaemic control of a patient, which remains integral to intensive care practice, so they are not co mmonly used. The 5-HT3 receptor antag- onists have a reasonable side effect pro \201 le an d, while more expensive than some other agents, can be used with relative safety. The role of more novel agents such as aprepitant and can- nabinoids is unclear. Dexamethasone \200 Indication: nausea and vomiting from chemotherapy or in the prophylaxis of PONV. Dose: 4 \200\2238mg od IV/PO. Side effects: peptic ulceration, proximal myopathy, dysphoria, hyperg lycaemia, immunosuppression. Care in infection and reduce dose in renal or hepatic impairme nt. Adrenal suppression on withdrawal after prolonged treatment. \200 Neurokinin-1 (NK1) receptor antagonists Substance P is the endogenous stimulant at this rec eptor, and antagonism of its effects provides antiemetic actions against a large array of s timuli. In view of this, they are assumed to work at the level of the brainstem, although t his has not been clari \201 ed yet. Aprepitant is the only drug in this class licensed at present and has a narrow indication in delayed phase chemotherapy-induced emesis. Further reading Andrews PLR, Rudd JA. The role of tachykinins and the tachykinin NK1 recept or in nausea and emesis. In: Holzer P, ed. Handbook of experimental pharmacology. Berlin: S pringer, 2004: 359 \200\223440. Hornby PJ. Central neurocircuitry associated with emesis. Am J Med Aprepitant \200 2001; 111: 106S \200\22312S. Indication: adjunct to dexamethasone and 5-HT3 antago- nists in emetic chemotherapy. Dose: 125mg IV pre-chemotherapy, Then 80mg od for 2 days. Side effects: hiccoughs, diarrhea, cons tipation. Reduce dose in hepatic impairment. Hursti TJ, Fredrikson M, Steinbeck G, et al. Endogenous cortisol exerts antiemetic effects similar to that of endogenous corticos- teroids. Br J Cancer 1993; 68: 112 \200\2234. Kreis ME. Postoperative nausea and vomiting. Auton Neurosci 2006; \200 129: 86 \200\22391. Miner WJ, Sanger GJ. Inhibition of cisplatin induced vomiting by selective 5-hydroxytriptam ine M-receptor antagonism. Br J Pharmacol 1986; 88: 497 \200\2239. Cannabinoid CB1 receptor agonist The proposed area of activity is in the vomiting center an d so are broad-spectrum antiemetics. In clinical practice, they tend to be used in chemothe rapy-induced emesis. Nabilone is the best known of this class of drugs. Sanger GJ, Andrews PLR. Treatment of nausea and vomiting: gaps in our knowledge. Auton Neurosci 2006; 129: 3 \200\22316. Nabilone \200 \200 Indication: adjunct in emetic chemotherapy. Dose: 1 \200\2232mg bd po. 198 J KAUSE Gut motility agents Introduction Delayed gastric emptying (also referred to as gastric stasis and gastroparesis ) is common in critical illness. Critical care management should include \200 The main limitations for the use of erythromycin are its side effects: gastrointestinal tox icity, ototoxicity, pseudomembranous colitis and prolongation of the QTc interval. Therefor e, erythromycin should only be used in the short term and with caution if administered simu ltane- ously with the enzyme inhibitors CYP3A4. The potential epidemiological impact of the increased macrolide use and evidence of the spread of resistance should be borne in mind w hen using erythromycin as a prokinetic agent in critically ill patients. Erythromycin can b e recommended, if patients have failed other treatments for impaired gastrointestinal dysmo tility and are intolerant of metoclopramide. supportive measures (hydration, nutrition, placement of gastric tube for decompression) min imizing use of opioids optimizing glycaemic control and medications. \200 Normal gastric emptying reflects a coordinated effort between different regions of the stom ach and the duode- num, as well as complex extrinsic modulation by the CNS and distal gut f actors: normal gastric emptying consists of fundic relaxation to accommodate food, antral c ontractions to break up large food particles, pyloric relaxation to allow food to exit the stomach, and antropyloroduodenal coordi- nation of motor events. Gastric dysmotility includ es delayed gastric emptying (gastroparesis), rapid gastric emptying (as seen in dumping syn drome) and other motor dysfunc- tions such as impaired fundic distension most commonly foun d in functional dyspepsia. The importance of these gas- tric dysrhythmias is uncertain. Cri tically ill patients (without diabetes mellitus) are thought to have disturbed motility of the proximal stomach and loss of fundic wave activity. There is enhanced pyloric pressure a nd reduced antral pressure. The feedback loop of bulky duodenal nutrients leading to pylori c relaxation is absent, further contributing to delayed gastric emptying. Erythromycin vs metoclopramide A small RCT comparing IV administration of erythromycin and metoclopramide concluded that erythromycin is more effective than metoclopramide in treatin g feed intolerance. The effectiveness of both treatments declined rapidly over time, but co mbination therapy of both medications proved more successful in reducing gastric aspirates (day 1 = 92% and day 6 = 67%). Metoclopramide Metoclopramide has antiemetic and prokinetic properties. It is a useful alte rnative for those who cannot take erythro- mycin or as an adjunct to erythromycin therapy. Metoclopramide acts by blocking D2 receptors in the GI tract. Its side effects are due to i ts central phenothiazine-like action on dopaminergic pathways, which has made the drug less popular in recent years. However, during short-term use, the risk of tardive dyskinesia is minimal. Injection of an antiparkinsonian drug, such as procyclidine, will control dystoni c attacks. The advantage of the drug is that it can be given enterally in tablet or liquid form or by slow IV injection at a dose of 10mg tds (up to 40mg per day can be tolerated by adults). Indications Gut motility agents are indicated in patients with large nasogastric aspirates, vomiting and paralytic ileus. The following factors should be considered before prescribin g gut motility agents. \200 Patients on critical care units are frequently prescribed PPIs, which can delay gastric emp tying. Consider using H2 antagonists as an alternative agent. Tachyphylaxis occurs with con ventional prokinetics after only a few days of treatment. Consider switching or combining g ut motility agents. Enteral nutrition is always desirable, and clinicians should persevere in establishing enteral feeding (oral, NG and NJ) according to local protocols. Enteral fee ding is best established with low fat feed without non-digestible \201 bre; continuous fe ed or fre- quent small meals. Domperidone Oral metoclopramide and domperidone are equally effec- tive in alleviating the symptoms of gastroparesis in diabe- tes, but no evidence for IV use/ICU available to date. Domperidone acts on the CTZ and has the advantage over metoclopramide that it is less likel y to cause sedation and dystonias, because it does not readily cross the blood \200\223 bra in barrier. Cisapride Stimulates 5-HT4 receptors, resulting in acetylcholine release from the myenteric plexus. Effects are abolished by atropine. This leads to increased antral and duodenal con tractility, which is maintained over long-term treatment (1yr), in healthy subjects and in various gastric stasis syndromes. Cisapride may be more potent and better tolerated than eq uivalent doses of metoclopramide Dose-dependent side effects include abdominal discomfort a nd increased bowel frequency. The main drawback of cisapride is the signi \201 cant drug i nterac- tions with medications that are metabolized by cytochrome P450-3A4 which have led t o arrhythmias and death. Its use is therefore restricted. The dose is 10mg qds, usually in liquid form. Erythromycin IV erythromycin is the treatment of choice during acute episodes of delayed ga stric emptying. Infusions produce high amplitude gastric propulsive contractions, which the n dump food residue into the duodenum. Erythromycin also stimulates fundic contractility an d inhibits the accommoda- tion response of the stomach after food. An RCT with small number s showed that IV erythromycin improves gastric motility and early nutritional intake in cri tically injured patients. Within the dosage range of 70 \200\223200mg this is a dose-indepe ndent effect. A single bolus dose of IV eryth- romycin facilitates active bedside placement of post-pyloric feeding tubes in critically ill adult patients. Evidence supporting the us e of oral erythromycin remains generally weak. A dose of up to 250mg qds can be used. 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 