Further reading Cinel I, Dellinger RP. Current treatment of severe sepsis. Curr Infect Dis Rep 2006; 8: 358 \200\22365. Dellinger RP, Carlet JM, Masur H, et al. Surviving sepsis campaign guidelines for managemen t of severe sepsis and septic shock. Crit Care Med 2004; 32: 858 \200\22373. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit C are Med 2006; 34: 1589 \200\22396. Marik PE. Fever in the ICU. Chest 2000; 117: 855 \200\22369. McDonald LC. Trends in antimic robial resistance in health care \200\223 associated pathogens and effect on treatment. Cli n Infect Dis 2006; 42: S65 \200\22371. 230 S IYER Antifungals infusion-related reactions such as fever, chills and rigors that can be prevented or reduce d either by slowing the rate of infusion or by pre-medication with antihistamines/ hydrocor tisone and paracetamol. Dose-limiting nephro- toxity; usually reversible on discontinuation of therapy. Monitoring with estimated GFR (eGFR) is recommended. 6 Lipid-based formulation s due to their altered pharmaco- In a critical care setting, systemic antifungal agents may be prescribed to treat or preven t infections in two broad cat- egories of patients: those with classic risk factors such as prolonged neutropenia, haematopoietic stem cell trans- plantation (HSCT) or HIV infection/ AIDS, who may be admitted to ICU for advanced supportive care; and a broad group of less se verely immunocompromised critically ill patients; who may also be susceptible to these infe ctions. During the last decade, the landscape of invasive fungal infections has changed sig ni \201 cantly with regards to the epi- demiology, diagnosis and therapeutic options. Alth ough the incidence of invasive fungal infection has also increased in line with the broaden ing spectrum of the \200\230at-risk \200\231 popula- tion, parallel developments in antifu ngal chemotherapy have brought optimism of improved outcome for patients. Systemic antifung al agents used to treat invasive mycoses and mucocutaneous forms of candidiasis are describ ed in this chapter. Although Pneumocystis jirovecii (formerly Pneumocystis carinii) now is classi \201 ed among the fungi, tra- ditional therapy has been with trimethoprim \200\223s ulfameth- oxazole and hence is not described here. The echinocandin class of antifungal dru gs (described later) are active against the cyst form of P. jirovecii and offer a potential for prophy- lactic therapy, but they lack activity against the trophozoite form causing pn eumonia. There are three main families of systemic antifungal agents: 1 Polyenes, e.g. amph otericin B: conventional amphoter- icin B deoxycholate (cAMB (Fungizone)) and lipid-based p reparations such as liposomal amphotericin B (L-AMB (Ambisome)), amphotericin B lipid compl ex (ABLC (Abelcet)), amphotericin B colloidal dispersion (ABCD (Amphocil, Amphotec)) logical distributions are less toxic than cAMB. \200 These permit higher doses to be administered with- out dose-limiting side effects of cAMB. These can be used safely use in patients intolerant of cAMB, particulary those with renal i nsuf \201 ciency or at risk for developing nephrotoxity. None of the lipid fomulations has been proven supe- rior to cAMB in treatment of infections caused by Candida or Aspergillus spp. There is no difference in ef \201 cacy between the three lipid-based formulations, t hough infusion-related side effects such as fever, rigors and hypotension are more common w ith ABCD and the toxicity pro \201 le of L-AMB has been shown to be better than that of AB LC. However, there is a wide variation in the drug acquisi- tion costs. Lipid formulations are more expensive than cAMD, and L-AMB is the most expensive lipid formu- lation. The choi ce of formulation should be individual patient based. 7 Drug interactions. Amphotericin B can augment nephro- toxicity of gentamicin, cyclosporin and certain antican- cer drugs. Azoles The azoles are a large group of synthetic agents. Mechanism of action: fungal cell m embrane active agents that act by Inhibiting the cytochrome P450- (CYP-450) dependent funga l enzyme lanosterol demethylase, thereby inhibiting ergosterol synthesis and disrupting cel l mem- brane activity. 2 Azoles: 1st-generation triazoles: \202 uconazole (Di \202 ucan), itraco- nazole (Sporanox; Janssen-Cilag) Newer triazoles: voriconazole (Vfend, P \201 zer), posacona- zole (Noxa \201 l, Schering-Plow) Fluconazole \200 3 Echinocandins: caspofungin (Cancidas, MSD), micafun- gin (Mycamine, Astellas) and anidula fungin (Eraxis: P \201 zer) Spectrum of activity includes Candida albicans, C. parapsi- losis, C. tropicalis and Crypto coccus neoformans Blastomyces dermatidis, Coccidioides immitis, Histoplasma capsulatum, and Paracoccidioides spp C. krusei and C. glabrata tend to be resistant. It has no activity against Aspergillus spp. Fluconazole has an excellent safety pro \201 le and is availa- bl e in oral and IV formulations; it is 100% bioavailable by the oral route and the generic dr ug is inexpensive com- pared with proprietary voriconazole and posaconazole. Itraconazole h as broader activity against yeasts and is also active against Aspergillus spp. Itraconazole has less reliable gastric absorption and greater potential for drug interactions. Voricona zole has a broader spectrum of activity against all species of Candida including C. krusei and C. glabrata, and is also active against \202 uconazole-resistant C. albicans. It is t he only antifungal drug approved for primary treat- ment of invasive aspergillosis. It is a vailable in oral and IV formulation. Blood concentrations are highly variable and require m onitoring when used to treat invasive mycoses, and has multiple drug interactions. 4 Miscellaneous: \202 ucytosine Amphotericin B 1 A polyene antibiotic derived from Streptomyces nodosus. 2 Introduced in 19 59 (without any randomized trials) for treatment of many invasive fungal infections, it has been the workhorse of antifungals. It is considered to be the \200\230gold standard \200 \231 for antifungal therapy and is the only anti- fungal with an indication for initial the rapy of many fungal infections. 3 Mechanism of action: it binds ergosterol in the fungal cell (absent in mammalian cells) w all rendering the cell leaky and resulting in cell death. 4 Broad spectrum of activity against most fungi that cause human disease. Aspergillus terre us, Scedosporium spp., Trichosporon spp. and Candida lusitaniae are resistant. Its spectrum is not in \202 uenced by the choice of formulation. 5 Adverse effects: parenteral administration of the conven- tional amphotericin B is often associated with unpleasant 231 CHAPTER 15.2 Antifungals Posaconazole is the newest triazole with an extended spectrum of activity against yeasts, m olds and dimor- phic fungi. It is licensed by the EC for the treatment of invasive aspergil losis, fusariosis, chromoblastomycosis and coccidiodomycosis in adults who are refractory, or intolerant of other antifungals. It is also indicated for prophylaxis of invasive fungal infections in high-risk hae- matological malignancy patients and HSCT recipients on high d ose immunosuppressive therapy for graft vs host disease. It is available only as an oral su spension and has a lower drug interaction pro \201 le compared with other triazoles Micafungin and Anidulafungin These are not yet licensed in the EU. \200 Micafungin is FDA approved for antifungal prophylaxis in HSCT recipients and in treatment o f oesophageal candi- diasis. It requires no loading dose, Anidulafungin is FDA-approved for the treatment of oesophageal candidiasis, candidaemia and deep-tissue candidiasis. It is u nique because it undergoes slow biotransformation in humans rather than being metabo- lized . In clinical trials it has demonstrated superiority to \202 uconazole for treatment of o esophageal candidiasis. Neither micafungin nor anidulafungin need dose adjust- ment with he patic or renal impairment. Echinocandins \200 Echinocandins are naturally occurring and synthetic lipopeptide antifungal agents. Mechanis m of action: inhibit fungal cell wall synthesis through non-competitive inhibition of 1,3-B -D-glucan synthase, an essential component of fungal cell wall, absent in mammalian cells. Spectrum of activity: echinocandins are fungicidal against Candida spp., including \202 u conazole-resistant isolates, and fungistatic against Aspergillus spp. They lack activity ag ainst Cryptococcus neoformans, Trichosporon spp., Fusarium spp. and the zygomycetes (Rhizop us, Mucor, etc.) Echinocandins \200\231 unique mechanism of action at the fungal cell wall offers a sound theoretic potential for synergy with cell membrane-active polyenes (AMB) and triazoles ( \202 uconazole, voriconazole) in combination therapy for mold infections. Als o, absence of cross-resistance with azoles is advantageous in treatment of fluconazole- res istant candidiasis. Oral bioavailability is only 3% so IV route of administra- tion is requ ired. Their excellent safety pro \201 le, very low potential for CYP450-mediated drug inte ractions and tolerability in critically ill patients with renal and/or hepatic impair- ment and polypharmacy in units with high rates of tria- zole-resistant non-albicans Candida inf ections makes this class of drugs the standard of care for ICU patients. High drug acquisit ion costs is the major limiting factor to their wider use in ICUs. Flucytosine Flucytosine (5-FC) is a synthetic pyrimidine that gets incor- porated into RNA, replacing u racil, thereby disrupting pro- tein synthesis in the susceptible fungal cells. \200 It has a very limited spectrum of activity that includes Candida spp, Cryptococcus neoforma ns and Cladosporium spp. It is available as oral and IV formulations. The oral drug is almo st completely absorbed but it requires blood level monitoring due to risk of bone marrow su ppression. Mainly used in combination therapy with AMB in treat- ment of cryptococcal menin gitis Important considerations about use of antifungals in critically ill patients 1 These drugs have been designed, developed and clini- cally validated for use in patients with hematolog ical malignancies, HSCT or HIV/AIDS patients. Patients with baseline characteristics that a re commonly seen in ICU patients were excluded in clinical trial validation studies. 2 Ther efore, the pharmacokinetics and pharmacodynamic parameters, drug interactions with other dr ugs, safety data in renal and/or hepatic impairment must be cau- tiously extrapolated with these caveats. 3 The role of experts such as hematologists, HIV physi- cians and antimicrobial stewardship teams including a clinical microbiologist and antimicrobial and ICU special- ist pharmacis t cannot be overemphasized. Further reading Bellman R. Clinical pharmacokinetics of systemically administered Caspofungin Caspofungin is indicated for the treatment of invasive can- didiasis (candidaem ia, oesophageal candidiasis) in adult patients, \200\230salvage therapy \200\231 of invasi ve aspergillosis in adult patients and empirical therapy for presumed fungal infec- tions ( such as Candida or Aspergillus) in febrile neutropenic adult patients. A dose regimen of a single 70mg loading dose on day 1, followed by 50mg daily thereafter is recommended. Caspof ungin dose should be halved in patients with mod- erate hepatic insuf \201 ciency (Child \200\223Pugh score 7 \200\2239). No dose adjustment is required with renal impairment. antimycotics. Curr Clin Pharmacol 2007; 2: 37. Meersseman W, Lagrou K, et al. Invasive aspergillosis in the ICU: an emerging disease. Intensive Care Med 2007; 33: 1679 \200\22381. Metcalf SC, Dockrell DH. Improved outcomes associated with advances in therapy for invasive fungal infections in immunocom- promised hosts. J Infect 2007; 55: 287 \200\22399. Toya SP, Douskou M. Candiduria in intensive care units: association with heavy colonization and candidaemia. J Hosp Infect 2007; 6: 201 \200\2236. 232 N VIRGINCAR Antiviral agents Ganciclovir can cause myelosuppression, rash, liver func- tion test abnormalities and CNS s ide effects, from head- ache to convulsions and coma. Ganciclovir is used in life-threateni ng CMV pneumonia and in CMV retinitis (see Table 15.3.1). Antiviral agents target different stages in the life cycle of viral pathogens such as inhib ition of viral cell attach- ment and entry, prevention of viral uncoating, viral genome rep lication (e.g. scyclovir), and viral assembly and maturation. In immunocompetent patients, acute virus infections are cleared by the patient \200\231s immune system itself; most anti vi- ral agents are used in the management of persistent infec- tions. However, acute viral meningitis and meningoencephalitis are important causes of admission to hospital. An esti- mated incidence of 5 \200\22315 cases per 100 000/yr of viral men- ingitis occurs in the UK , enterovirus being the most common pathogen. Herpes simplex virus (HSV) CNS infections aff ect all ages and cause most fatal cases of encephalitis. The arboviruses, a group of >500 a rthropod- transmitted viruses, are the leading cause of encephalitis worldwide. This chapte r addresses antivirals commonly used in the ICU. Foscarnet This is an inorganic pyrophosphate analog which revers- ibly and non-competitivel y inhibits the activity of the viral DNA polymerase. Foscarnet is inhibitory for most ganci - clovir-resistant CMV, and acyclovir-resistant HSV and vari- cella-zoster (VZV) strains. C MV and HSV can become resistant to foscarnet due to point mutations in DNA polymerase of th ese viruses. Nephrotoxicity and metabolic abnormalities such as hypocalcaemia, hypercalcaem ia, hypomagnesaemia and hypophosphataemia are common side effects. Foscarnet has been used to treat gancyclovir-resistant CMV retinitis and acyclovir-resistant mucocutaneous HSV infe ctions (see Table 15.3.3 1). Acyclovir Acyclovir a nucleoside analog and requires intracellular activation to exert anti viral activity. It is active against her- pesviruses. Acyclovir is a preferred substrate fo r the viral thymidine kinase (TK) that phosphorylates acyclovir to acyclovir monophosphate within virus-infected cells. Acyclovir monophosphate is then progressively transformed by c el- lular kinases to acyclovir diphosphate and acyclovir tri- phosphate, which competitivel y inhibits the viral DNA polymerase and blocks viral DNA synthesis. Resistance to acyclovir in herpesviruses is due to the lack of production of viral TK, altered TK substrate speci \201 city and altered viral DNA polymerase. These viral enzyme changes are due to point mu tations or base insertions or deletions in the corresponding genes. Acyclovir has been asso ciated with nausea, diarrhea, rash, headache, renal insuf \201 ciency and neurotoxicity. A cyclovir dose adjustments are needed for renal insuf \201 ciency. Acyclovir is effective i n primary and recurrent genital as well as orolabial HSV infections. Systemic acyclovir is used to treat HSV encephalitis (see Table 15.3.1). Acyclovir is also effective for treating varicella and herpes zoster infec- tions in immunocompromised patients. Cidofovir Cidofovir is a nucleoside phosphonate analog that must be phosphorylated to its d iphosphoryl derivative by cellu- lar phosphorylating enzymes. Codofovir diphosphate is a co mpetitive inhibitor of the viral DNA polymerase, which leads to cessation of viral DNA chai n elongation. It has inhibitory activity against herpes viruses and other DNA viruses such as papilloma, pox and adenoviruses. Table 15.3.1 Antiviral agents and adult doses Viral infection Drug Adult dosage Herpes simplex virus Genital herpes Acyclovir 400mg PO tid or 200mg PO 5 times/day for 7 \200\22310 days Encephalitis Acyclovir 10 \200\22315mg/kg/8h IV for 14 \200\22321 days Cytomegalovirus Retinitis Ganciclovir 5mg/kg/12h IV for 14 \200\22321 days Foscarnet 60mg/kg/8h IV for 14 \200\22321 days Ganciclovir Ganciclovir is a nucleoside derivative that is available for the treatment of c ytomegalovirus (CMV) infections. Ganciclovir must be phosphorylated to ganciclovir triphosp hate to exert its antiviral activity. In CMV-infected cells, the UL97 gene of CMV encodes a protein kinase that phosphorylates ganciclovir to ganciclovir monophos- phate, with cellul ar kinase performing futher phosphoryla- tion to the triphosphate which inhibits the CMV DN A polymerase. Resistance in CMV isolates is due to, reduced intracellular ganciclovir phosp horylation caused by point mutations or deletions in the phosphotransferase encoded by the UL97 gene and, point mutations in viral DNA polymerase. Cidofovir 5mg/kg IV once weekly x2 then every other week In \202 uenza virus In \202 uenza A and B viruses Oseltamivir 75mg PO bid for 5 days Varicella-zoster virus Acyclovir 10mg/kg/8h IV for 7 \200\22310 days Varicella in immunocompromised hosts Herpes zoster in normal hosts Acyclovir 800mg PO 5 times daily for 7 \200\22310 days Acyclovir 10mg/kg/8h IV for 7 \200\22310 days Herpes zoster in immunocompromised hosts 233 CHAPTER 15.3 Antiviral agents Further reading CDSC. Viral meningitis associated with increase in echovirus type Cidofovir is also inhibitory for acyclovir-resistant HSV strains and ganciclovir-resistant CMV. Fever, nausea, headache, rash, anterior uveitis, nephrotoxic- ity and neutropenia are some of the principal side effects of cidofovir. Monitor renal function and neutrophil coun t within 24h before each dose. IV cidofovir is approved for the treatment of CMV retinitis in AIDS patients. 13. Commun Dis Rep CDR Wkly 2000; 10: 277 \200\2238. Chou S, Guentzel S, Michels KR, et al. Frequency of UL97 phospho- transferase mutations rel ated to ganciclovir resistance in clinical cytomegalovirus isolates. J Infect Dis. 1995; 17 2: 239 \200\22342. Coen DM, Richman DDAntiviral agents. In: Knipe DM, Howley PM, eds. Fields virology, 5th edn , Vol. 1. Philadelphia, PA: Lippincott Williams & Wilkins, 2007: 447 \200\22385. Erice A. Antiviral susceptibitily testing. In: Storch GA, ed. Essentials Oseltamivir This is a neuraminidase inhibitor which is effective for prophylaxis and treatm ent of both in \202 uenza A and B. High level resistance because of histidine to tyrosine muta- tion in codon 274 of the N1 neuraminidase can emerge during treatment of H1N1 and in some patients treated for H5N1 infections. Oseltamivir is generally well tolerated. Long-te rm prophy- laxis is associated with headache, rash, hepatic in \202 amma- tion thrombocyto penia and CNS toxicity, such as hallucination and extrapyramidal signs. Early treatment of acute in \202 uenza reduces time to func- tional recovery by 1 \200\2233 days, and also de creases the risk of lower respiratory tract complications leading to hospitali- zation. For treatment of pandemic \202 u, readers should refer to Health Protection Agency and Depar tment of Health, UK latest pandemic \202 u guidelines. of diagnostic virology, Churchill Livingstone, 2000: 271 \200\22389. Gaudreau A, Hill E, Balfour HH, et al. Phenotypic and genotypic characterization of acyclov ir-resistant herpes simplex viruses from immunocompromised patients. J Infect Dis. 1998; 17 8: 297 \200\223303. Hayden FG. Antiviral drugs (other than anti-retrovirals). In: Mandell, Douglas and Bennett \200\231s, Principles and practice of infectious diseases, 6th edn, Vol 1. Philadelphia, PA : Elsevier Churchill Livingstone, 2005: 514 \200\22351. Ho DD, Hirsch MS. Acute viral encephalitis. Med Clin North Am 1985; 69: 415. Lurain NS, Thompson KD, Holmes EW, et al. Point mutations in the DNA polymerase gene of hum an cytomegalovirus that result in resistance to antiviral agents. J Virol 1992; 66: 7146 \200\223715. 234 R KEAYS & NA BARRETT N-Acetylcysteine Modes of action N-Acetylcysteine (NAC) is the acetylated form of the amino acid L-cysteine. It is a sulfhydryl group donor and a precursor for glutathione production. Its primary sys temic use is as an antioxidant as it can directly scavenge oxygen radicals, and act indirec tly by boosting glutathione levels. It enhances NO synthesis and cGMP levels, resulting in vasodilation and inhibition of platelet aggregation. It also cleaves disul \201 de bonds, converting them to sulfhy- dryl groups and thereby reducing the chain length of mucoprotein s in lung secretions, enabling easier clearance. exception of liver failure due to amanita phalloides inges- tion and carbon tetrachloride, chloroform or potassium permanganate poisoning. Nevertheless, it continues to be recommende d as adjunctive therapy in acute liver failure. Radiocontrast-induced nephropathy. NAC appe ars to have some bene \201 t in preventing this problem, particularly those patients with pre-existing chronic renal impairment Acute respiratory distress syndrome: despite initial sugges- tions that NAC may improve oxygenation and reduce ventilator-dependent days, no con vincing bene \201 t has been demonstrated to date Sepsis and multi-organ failure: many stu dies have shown an increase in cardiac index with NAC. Initiation of NAC treatment after th e initial 24h post-hospital admission is not of any bene \201 t and may be detrimental. Wh ether there is a reduction in proin \202 ammatory cytokine levels in sepsis is still debat ed. Myocardial ischaemia: the combination of oral NAC and transdermal nitroglycerin has bee n shown to reduce the incidence of refractory angina, MI and death in patients with angina. Unfortunately severe headaches are associ- ated with this combination. In AMI, it may impr ove car- diac function post-thrombolysis . Other lung diseases: in cystic \201 brosis, NA C use has not shown any improvement in lung function; however, there is some recent evidenc e it can modulate lung in \202 amma- tion. NAC may promote some marginal bene \201 ts in idio- pathic pulmonary \201 brosis. Heavy metal poisoning: NAC has the ability to chelate some heavy metals and improve their excretion rates. HIV/AIDS: longer term administration of NAC has been shown to improve immune function and serum albumin levels in HIV-infected p atients Uses \200 Paracetamol poisoning. Glutathione is a powerful endog- enous antioxidant but becomes rapid ly depleted in para- cetamol poisoning if normal hepatic conjugation pathways become satura ted, resulting in a greater pro- portion of paracetamol being converted to N-acetyl-p- benz oquinone imine (NAPQI) by the CYP2E1 mixed-function oxidase enzyme. This unstable and toxic metabolite is normally rendered non-toxic by conjuga- tion with glutathione. When glutathi one levels are depleted by 70%, hepatotoxicity is likely as NAPQI is free to cause widespr ead damage to hepatocytes in a familiar centrilobular pattern. Decision to treat in para- c etamol poisoning is based upon the paracetamol blood level and known time of ingestion usin g a nomogram. COPD. There is some evidence that oral NAC can pre- vent or reduce the number of acute exacerbations in COPD. See notes. The evidence for other uses of NAC is dis- cuss ed below. Routes \200 IV \200 Oral \200 Nebulized Drug dosages Whilst there is consensus regarding the doses required in paracetamol poisoning, clinical s tudies conducted on the ef \201 cacy of NAC for other indications have often used a differ ent dosing regimen. The IV doses given below are for paracetamol poisoning. \200 Side effects/complications Anaphylactoid reactions: incidence 0.2%. Mostly this is lim- it ed to urticarial rashes and pruritis, but 10% of those affected can experience hypotension and/or bronchospasm Nebulized NAC causes bronchorrhoea which may cause problems in those wi th an inadequate cough. In intubated patients, secretions may increase. Occasionally bronch os- pasm can occur. IV co-administration of certain drugs can lead to precipita- tion, nota bly erythromycin, tetracyclines and ampiciliin. IV administration: it is available in ampoules at concentra- tions of 10 or 20% which can b e diluted in 5% dextrose solutions. Initial treatment is 150mg/kg over 15min then 50mg/kg o ver 4h, followed by 100mg/kg over 16h. This last infusion rate can be continued past 24h of treat- ment. Oral administration: 400 \200\2231200mg/day. Nebulized: the 20% solution is h ighly osmotic and can be too irritant to be delivered undiluted. Dilution should be with sa line or water for injection. Regimes can be varied, but 6 \200\22310ml of a 10% solution 3 \200\2234 times per day is usual. \200 Notes \200 Paracetamol poisoning: any patient who might have liver enzyme induction due to concurrent medication or chronic alcohol abuse, or who might have glutathione depletion prior to overd ose due to malnutrition, HIV, etc., should be considered for NAC treatment at blood paracet amol levels below the normal treatment line on the nomogram. Non-paracetamol-induced liver failure. Despite reports of improvements in hepatosplanchnic perfusion and some measures of hepatic function, little good evidence exists to support the use of NAC in this situation, with the Further reading Brok J, Buckley N, Gluud C. Interventions for paracetamol (aceta- minophen) overdoses. Cochrane Database Syst Rev 2006; (2): CD003328. Kramer BK, Hoffmann U. Bene \201 t of acetylcysteine for prevention of contrast-induced ne phropathy after primary angioplasty. Nat Clin Pract Nephrol 2007; 3: 10 \200\22311. Sklar GE, Subramaniam M. Acetylcysteine treatment for non-aceta- minophen-induced acute liv er failure. Ann Pharmacother 2004; 38: 498 \200\223500. This page intentionally left blank 236 M SHANKER HARI & D WYNCOLL Activated protein C Introduction The microcirculation in sepsis is characterized by unre- stricted and/or inapp ropriate activation of coagulation and in \202 ammatory pathways, resulting in tissue hypo perfusion. The protein C anticoagulant pathway composed of thrombin, thrombomodulin, endoth elial protein C recep- tor (EPCR), protein C and protein S is essential for the negative co ntrol of both coagulation and in \202 ammation. Within this complex system, activated prot ein C (APC) serves as a key regulator in preserving the internal milieu and restoring the m icrocirculation, through its potent cyto- protective and anticoagulant properties. Drotreco gin alfa (activated) (DrotAA), a synthetic form of APC, was approved in 2002 for use in pat ients with severe sepsis and multiple organ failure. trial in 131 patients with severe sepsis. The dose selected was that which had greatest eff ect on D-dimer level. Pharmacokinetics DrotAA infusion shows linear pharmacokinetics with rapid achievement of st eady state and prompt decline in plasma activity with t1/2 A and t1/2 B of 13min and 1.6h, respectively. Plasma DrotAA activity reduces by 80% 1h after drug dis- continuation. Indications The key to appropriate use of DrotAA lies in the early assessment of the risk o f death. However, there is still no consensus on a good operational de \201 nition of \200\230high risk \200\231 in patients with severe sepsis. In the USA, DrotAA is rec- ommen ded in patients \200\230at high risk of death, e.g. those with an APACHE II score of 25 \200\231 since subset analysis demon- strated that the treatment bene \201 t in the PROWES S trial was in this subgroup. In the EU, DrotAA is licensed for patients with \200\230seve re sepsis and multiple organ dysfunc- tion \200\231, irrespective of pre-treatment APACHE I I score. The PROWESS trial demonstrated an increased treatment effect as the number of orga n dysfunctions increased. DrotAA is indicated in adult patients with severe sepsis who are at high risk for death. Risk for death is currently best determined by clinical judgment an d presence of organ dysfunction. Chemistry APC is an anticoagulant glycoprotein with serine protease activity and has a mole cular mass of 55kDa. DrotAA is a recombinant form of human APC, and is prepared using a hum an cell line that processes the complimentary DNA for inactive protein C zymogen. Following post-transla- tional modi \201 cations, the secreted recombinant protein C is activated b y cleavage with thrombin. The activated prod- uct \200\224APC \200\224is then puri \201 ed and presented in a powder form for IV infusion. Mode of action The cytoprotective and anticoagulant actions are probably responsible for th e clinical bene \201 ts observed with DrotAA. There is an ongoing debate as to which of th e varied modes of action is most important, but the major clinical bene \201 ts are attrib uted to the cytoprotective actions. Outcome data Clinical trials in adults The PROWESS trial (n = 1690), was the \201 rst pha se III multi-center RCT of DrotAA in adults. The trial demon- strated a 19.4% relative redu ction and 6.1% absolute reduction in 28-day mortality. To obtain additional ef \201 cacy a nd safety data prior to licensing, a single-arm open-label study known as the ENHANCE trial (n = 2434) was per- formed. Using similar entry criteria, the trial showed a mortality rat e similar to that in PROWESS (25.3% vs 24.7%) in the DrotAA treatment arm, thereby con \201 rming ef \201 cacy. The subsequent ADDRESS trial (n = 2613), was a multi- center RCT enrolling patients with severe sepsis and low risk of death. This trial failed to show a mo rtality bene \201 t with DrotAA, suggesting that the favorable risk \200\223bene \201 t p ro \201 le may only be apparent in patients at high risk of death. Cytoprotective actions The cytoprotective effects of APC are mediated through the cellular receptors EPCR and protease-activated recep- tor 1 (PAR1). Stimulation of these receptors l eads to alter- ation in gene expression profiles, resulting in anti-in \202 ammatory and a ntiapoptotic activity, and endothe- lial barrier stabilization. Antiapoptotic actions \200 Alteration in activity of apoptotic inhibitors and apop- totic transcription factors Endothelial barrier stabilization \200 Clinical trials in children The RESOLVE trial (n = 477) was a multi-center RCT in pediatric patients, and could not replicate the mortality bene \201 ts observed in the adult studie s. Although there was no overall difference in the bleeding events during the 28 day study period, CNS bleeding events were more com- mon with DrotAA treatment compared with placebo. Interestingly, in children with severe sepsis and dissemi- nated intravascular coagulation , there were strong trends towards improvement in mortality. Upregulation of sphingokinase reduces endothelial per- meability and stabilizes the cellula r cytoskeleton Anti-in \202 ammatory actions \200 Inhibits translocation of nuclear factor- B Anticoagulant effects \200 Activation of the \201 brinolytic pathway by inactivating plasminogen activator inhibitor Complexing with protein S and directly inhibiting factor Va and VIIIa preventing thrombin formation Inhibiting proin \202 ammatory cytokine-mediated release of tissue factor from m onocytes and endothelial cells Registries Descriptive analyzes of national audits and registries have con \201 rmed the m ortality bene \201 t reported in the clinical tri- als. The findings of the Promoting Glob al Research Excellence in Severe Sepsis (PROGRESS) database of 12 492 patients with severe sepsis from 37 countries showed that the adjusted odds ratio (OR) for hospital Dose DrotAA is administered IV as a continuous infusion at 24mcg/kg/h for 96h. The currentl y recommended dose and duration of infusion were selected from a phase II clinical 237 CHAPTER 15.5 Activated protein C Table 15.5.1 Incidence of serious bleeding and fatal ICH events in the PROWESS, ADDRESS and XPRESS trials Trial PROWESS (n = 1690) ADDRESS (n = 2613) XPRESS (n = 1994) DrotAA Placebo DrotAA Placebo Heparin + DrotAA Placebo + DrotAA Serious bleeding events During infusion 2.4% 1% 2.4% 1.2% 2.3% 2.5% 0 \200\22328 days 3.5% 2% 3.9% 2.2% 3.9% 5.2% Fatal CNS bleeding events During infusion 0 \200\22328 days 0.2% 0.2% 0 0.1% 0 0.2% 0.1% 0.1% 0.1% 0.3% 0.2% 0.4% mortality associated with DrotAA was 0.75, and a greater treatment effect was seen for pati ents with \211 3 organs in failure. The OR of mortality associated with DrotAA treatment h as been variously reported from other regis- tries from the UK, Poland, Belgium and Italy a s between 0.65 and 0.85. preserved ef \201 cacy of DrotAA treatment and no harmful interactions between heparin and DrotAA. Antiplatelet drugs and warfarin The use of these antiplatelet drugs and anticoagulants does not represent an absolute contraindication to the use of DrotAA provided coagulation abnor malities are corrected prior to starting DrotAA infusion. Exclusion criteria and contraindications The main exclusion criteria used in the clinical t rials are summarized below. Controversy Over the last few years there has been signi \201 cant debate as to the report ed ef \201 cacy and the risk \200\223bene \201 t pro \201 le of DrotAA. The questions re garding the perceived ef \201 cacy of DrotAA arise from various aspects of the conduct of the PROWESS trial, and the relatively high cost of the drug. The mortality bene \201 t rep orted in the PROWESS trial has not been replicated in all patient groups with severe sepsis , and consequently some clinicians have ongoing skepticism. In the light of these issues an d an assumption that there is still clinical equipoise among critical care physicians, a se c- ond randomized double-blind placebo-controlled trial is planned to be underway by 2009, called the PROWESS Shock trial. Increased bleeding risk \200 \200 \200 \200 \200 \200 Platelet count <30 000/mm3 Warfarin use within the preceding 7 days Acetylsalicylic acid do se >650mg/day Surgery within the preceding 12h Head trauma or stroke within 3 months GI ble eding within 6 weeks Expected survival <24h or moribund state Known hypercoagulable conditions Altered immune sy stem function \200 \200 \200 HIV infection with a last known CD4 count of <50/mm3 History of organ transplantation Advan ced cancer Further reading Abraham E, Laterre PF, Garg R, et al. Drotrecogin alfa (activated) for adul ts with severe sepsis and a low risk of death. N Engl J Med 2005; 353: 1332 \200\22341. Severe chronic illness \200 Chronic renal failure requiring haemodialysis or perito- neal dialysis Known or suspected p ortosystemic hypertension, chronic jaundice, cirrhosis, or chronic ascites Bernard GR, Vincent JL, Laterre PF, et al. Ef \201 cacy and safety of recombinant human ac tivated protein C for severe sepsis. N Engl J Med 2001; 344: 699 \200\223709. Bernard GR, Wright TJ, Ely EW, et al. Safety and dose-relationship of recombinant human act ivated protein C (rhAPC) on coagu- lopathy in severe sepsis. Crit Care Med 2001; 29: 2051 \200\22359. Acute pancreatitis with no established source of infection Complications Bleeding is the most common adverse event observed with DrotAA. \200\230Seri ous \200\231 bleeding was de \201 ned in the trials as any intracranial hemorrhage (ICH), any life-threatening bleeding, any bleeding event classi \201 ed as serious by the investi gator or any bleeding that required the administra- tion of 3 units of packed red cells on two consecutive days. Table 15.5.1 shows the incidence of serious bleeding and fatal ICH ev ents in three of the larger trials involving DrotAA. Eichacker PQ, Natanson C. Increasing evidence that the risks of rhAPC may outweigh its bene \201 ts. Intensive Care Med 2007; 33: 396 \200\22399. Laurent OM, Berislav VZ, Grif \201 n JH. The cytoprotective protein C pathway. Blood 2007; 109: 3161 \200\22372. Levi M, Levy M, Williams MD, et al. Prophylactic heparin in patients with severe sepsis tre ated with drotrecogin alfa (activated). Am J Respir Crit Care Med 2007; 176: 483 \200\22390 . Nadel S, Goldstein B, Williams MD, et al. Drotrecogin alfa (acti- vated) in children with s evere sepsis: a multicentre phase III ran- domised controlled trial. Lancet 2007; 369: 836 \200\22343. Drug interactions Heparin The XPRESS trial (n = 1994), was a phase IV multi-center RCT comp aring DrotAA with or without concomitant heparin use in patients with severe sepsis. The tr ial showed Vincent JL, Bernard GR, Beale R, et al. Drotrecogin alfa (activated) treatment in severe se psis from the global open-label trial ENHANCE: further evidence for survival and safety and implica- tions for early treatment. Crit Care Med 2005; 33: 2266 \200\22377. This page intentionally left blank 239 Chapter 16 Resuscitation Chapter contents Basic and advanced resuscitation 240 Post-cardiac arrest management 242 Fluid challenge 244 240 J NOLAN Basic and advanced resuscitation Advanced life support The ALS algorithm enables a standardized approach to car- diac arrest management (see Appendix 1). Cardiac arrest rhythms are classi \201 ed as: \200 Recovery from cardiac arrest depends on an intact \200\230Chain of Survival \200\231, whic h comprises: \200 \200 \200 \200 Early recognition and call for help Early CPR Early de \201 brillation Post resuscitation care. Shockable rhythms \200\224VF/VT. In adults, the most common rhythm at the time of cardiac a rrest out of hospital is VF, which may be preceded by a period of VT, by a bradyar- rhythmi a or, less commonly, supraventricular tachycardia (SVT). Non-shockable rhythms \200\224asys tole and PEA. Prevention \200 In-hospital cardiac arrests are usually not sudden or unpredictable: in 80% there is deter ioration in clinical signs during the preceding few hours. The cardiac arrest rhythm is usu ally pulseless electrical activity (PEA) or asystole, and prognosis is poor. Earlier recogn ition and treatment can prevent some car- diac arrests, deaths and unanticipated ICU admiss ions. Strategies such as critical care outreach and medical emergency teams might reduce th e incidence of cardiac arrest, but this has been dif \201 cult to prove. Earlier recogniti on also enables a do not attempt resuscitation (DNAR) decision to be applied, if this is ap propriate. Treatment of shockable rhythms \200 Start CPR and assess rhythm. If using an old monophasic defibrillator, consider resuming ch est compressions while charging the de \201 brillator (older equipment is slow to charge). See Chapter 2.1 for more detail on de \201 brilla- tion. Give one shock of 150 \200\22320 0J biphasic (360J monophasic). Immediately resume chest compressions (CV ratio 30:2) withou t reassessing the rhythm or feeling for a pulse. Continue CPR for 2min, then pause brie \202 y to check the monitor: If VF/VT persists: \200 \200 In-hospital resuscitation After in-hospital cardiac arrest, the division between basic life support (BLS) and advanced life support (ALS) is arbi- trary; in practice, in-hospital res uscitation is a continuum. For all in-hospital cardiac arrests, ensure that: \200 \200 