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 Give a further (2nd) shock of 150 \200\223360J biphasic (360J monophasic). Resume CPR immed iately and continue for 2min. Pause brie \202 y to check the monitor; if VF/VT persists, g ive adrenaline 1mg IV followed immediately by a (3rd) shock of 150 \200\223360J biphasic (3 60J monophasic). Do not delay a shock to wait for adrenaline \200\224if the adrenaline is n ot ready, give it after delivery of the shock. Resume CPR immediately and continue for 2min . Pause brie \202 y to check the monitor; if VF/VT persists, give amiodarone 300mg IV foll owed immediately by a (4th) shock of 150 \200\223360J biphasic (360J monophasic). Resume CP R immediately and continue for 2min. Give adrenaline 1mg IV immediately before alternate sh ocks (i.e. approximately every 3 \200\2235min). Give further shocks after each 2min period of CPR and after con \201 rming that VF/VT persists. \200 cardiorespiratory arrest is recognized immediately help is summoned using a standard teleph one number \200\224 it should be 2222 in the UK CPR is started immediately a compression:ve ntilation (CV) ratio of 30:2 is used. \200 \200 Risks to the rescuer There are few reports of harm to rescuers from doing CPR. \200 Wear gloves. Eye protection, aprons and face masks, may be necessary. Infection risk is low er than perceived. There are reports of infections with tuberculosis (TB), and severe acute respiratory distress syndrome (SARS). HIV transmission has never been reported. \200 If organized electrical activity compatible with a cardiac output is seen, check for a puls e: \200 \200 Mechanism for the production of blood \202 ow during chest compressions \200 If a pulse is present, start post-resuscitation care. If no pulse is present, continue CPR and switch to the non-shockable algorithm. Chest compressions generate blood \202 ow by increasing intrathoracic pressure and compre ssing the heart directly; however, perfusion of the brain and myocardium is, at best, 25% o f normal. The CPP achieved during CPR correlates with restora- tion of spontaneous circulat ion (ROSC). In the presence of VF, chest compressions increase the amplitude and frequency of the VF waveform and the likelihood that attempted defibrillation will be successful. Pau ses in chest compressions of as little as 10s before shock delivery reduce the chances of s uccessful de \201 bril- lation. Frequent interruptions in chest compressions reduce surviv al from cardiac arrest. Each time chest compressions are stopped the CPP decreases rapidly and takes time to reach previous levels once chest com- pressions are resumed. If asystole is seen, continue CPR and switch to the non- shockable algorithm. Precordial thump \200 If the onset of VF/VT is both witnessed and monitored, give a precordial thump if a de \201 brillator is not available for immediate delivery of a shock. The mechanical energy of the precordial thump is con- verted to electrical energy, which may be suf \201 cient to achieve cardioversion. A precordial thump is most likely to be successful in con- verting V T to sinus rhythm. Successful treatment of VF by precordial thump is much less likely unles s the thump is given within the \201 rst 10s of VF onset. 241 CHAPTER 16.1 Basic and advanced resuscitation \200 \200 \200 \200 Hypothermia Tension pneumothorax Tamponade Toxic substances Thromboembolism (pulmonary embo lism or coronary thrombosis). Treatment of PEA \200 Start CPR 30:2. \200 Give adrenaline 1mg IV as soon as intravascu lar access is achieved. Continue CPR 30:2 until the airway is secured \200\224then continue chest compressions without pausing during ventilation. Recheck the rhythm every 2min and c heck for a pulse if organized electrical activity is seen Give further adrenaline 1mg IV ev ery 3 \200\2235 min (alternate loops) until ROSC is achieved Post-resuscitation care See Chapter 16.2. Outcome Despite developments in the emergency services, the out- come from out-of-hospital cardiac arrest (OHCA) remains very poor, with survival to hospital discharge of 5 \200\223 10%. After in-hospital cardiac arrest, the survival to hospital dis- charge is 15 \200\2232 0% (40% after VF and 6% after PEA or asys- tole). The majority of survivors have a good neu rological recovery. The outcome from cardiac arrest in a critical care area is better than in other in-hospital locations. Treatment of asystole and slow PEA (rate <60/min) \200 Treat as for PEA but inject atropine 3mg after the \201 rst dose of adrenaline is given. Airway and ventilation \200 Many patients on an ICU will already be intubated at the time of cardiac arrest. Tracheal i ntubation provides the most reliable airway during CPR but if a tracheal tube is not alread y in place, attempts at intubation should be made only by trained personnel. A supraglottic airway device (e.g. laryngeal mask airway (LMA) or Proseal LMA) is an alternative to trach eal intu- bation. If a supraglottic airway device has been inserted, attempt continuous che st compressions without stopping for ventilations. If gas leakage is excessive, interrupt t he chest compressions to enable adequate ventilation. CPR on the ICU Many aspects of CPR on the ICU are speci \201 c to this envi- ronment: \200 Most cardiac arrests will be both monitored and wit- nessed. There should be minimal delay before starting CPR. Many patients are already receiving positive pressure ventilation at t he onset of cardiac arrest. Mechanical ventilation can be continued during chest compressio ns, but the airway pressure alarms will be dis- tracting and, if a pressure mode is being u sed, inadequate tidal volumes will be given. Continuous invasive arterial pressure monitori ng is fre- quently in place \200\224this provides some indication of the effectiveness of c hest compressions and is helpful in detecting when ROSC has been achieved. The presence of a CVC is helpful \200\224 drug delivery by this route is both rapid and reliable. \200 Drug delivery \200 Peak drug concentrations are higher and circulation times are shorter when drugs are inject ed into a central vein compared with a peripheral vein. On the ICU, a central venous cathet er (CVC) is often in situ at the time of cardiac arrest. If not in situ, insertion of a CVC is not an immediate priority \200\224it requires inter- ruption of CPR and is associated w ith several potential complications. Peripheral venous cannulation is quicker, easier and s afer. Flush drugs injected peripherally with at least 20ml of \202 uid and elevate the ex tremity for 10 \200\22320s to facilitate drug delivery to the central circulation. Consider the intraosseous route if the IV route is impos- sible. Giving a drug through the tracheal tube results in highly variable, and usually ineffective, plasma drug con- centrations. Further reading Cook TM, Hommers C. New airways for resuscitation? Resuscitation 2006; 69: 371 \200\22387. Edelson DP, Abella BS, Kramer-Johansen J, et al. Effects of compres- sion depth and pre-sho ck pauses predict de \201 brillation failure during cardiac arrest. Resuscitation 2006; 71 : 137 \200\22345. Hillman K, Chen J, Cretikos M, et al. Introduction of the medical emergency team (MET) syst em: a cluster-randomized controlled trial. Lancet 2005; 365: 2091 \200\2237. Reversible causes Identify and treat reversible causes during CPR for all car- diac arrests . This is particularly important in the ICU where potentially reversible causes are more co mmon. \200 \200 \200 Nolan JP, Deakin CD, Soar J, et al. European Resuscitation Council guidelines for resuscita tion 2005. Section 4. Adult advanced life support. Resuscitation 2005; 67 Suppl 1: S39 \200 \22386. Nolan J, Soar J, Lockey A, et al. Advanced life support, 5th edn. London: Resuscitation Council (UK), 2006. Hypoxia Hypovolaemia Hyperkalaemia, hypokalaemia, hypocalcaemia, acidaemia and other metabo lic disorders Sandroni C, Nolan J, Cavallaro F, et al. In-hospital cardiac arrest: incidence, prognosis a nd possible measures to improve survival. Intensive Care Med 2007; 33: 237 \200\22345. 242 J NOLAN Post-cardiac arrest management With the exception of patients resuscitated from a very brief period of cardiac arrest, mos t of those with ROSC will initially be comatose, and many of these will require admission t o an ICU. Unconscious, mechanically ventilated survivors of cardiac arrest account for 5.8% of all admis- sions to ICUs in the UK. Of these, 43% survive to leave the ICU and 30% sur vive to hospital discharge. Two-thirds of patients dying after admission to ICU following o ut-of-hos- pital cardiac arrest (OHCA) die from neurological injury and 25% of patients dyi ng after admission to ICU following in-hospital cardiac arrest die from neurological injury . Early echocardiography will enable the extent of myocar- dial dysfunction to be quanti \201 ed and may guide therapy. Blood pressure control after cardiac arrest In the absence of de \201 nitive data, target the MAP to achieve an adequate urine output, taking into consideration the patient \200\231 s normal blood pressure. Prophylactic antiarrhythmic therapy There are no data to support or refute the use of proph y- lactic antiarrhythmics in patients who have survived cardiac arrest. However, it is reas onable to continue an infusion of an antiarrhythmic drug that restored a stable rhythm suc- cessfully during resuscitation. Airway and ventilation \200 There are no data supporting precise indications for intubation, ventilation and sedation a fter cardiac arrest. Although cerebral autoregulation is either absent or right-shifted in a majority of patients in the acute phase after cardiac arrest, cerebrovascular reactivity to changes in arterial carbon dioxide tension seems to be pre- served. There are no data to support the targeting of a speci \201 c arterial PCO2 after resuscitation from cardiac ar rest \200\224 aim for normocarbia. Disability (optimizing neurological recovery) Cerebral perfusion \200 Immediately after ROSC there is a period of cerebral hyperaemia. After 15 \200\22330min of reperfusion, however, global cerebral blood \202 ow (CBF) decreases and there is generali zed hypoperfusion associated with a decrease in CBF to 50% or less of normal. Normal cereb ral autoregulation is lost, leaving cerebral perfusion dependent on MAP. Under these circum stances, hypotension will compromise CBF severely and will compound any neurological injury ; therefore, maintain MAP at the patient \200\231s normal level. Circulation Coronary revascularization \200 Acute changes in coronary plaque morphology are found in 40 \200\22386% of cardiac arrest s urvivors, and in 15 \200\223 64% in autopsy studies. Primary PCI is the treatment of choice after OHCA and STEMI. The safety of thrombolysis after CPR is well established. Prior CPR is not a contraindication to thrombolysis \200\224 restoration of coronary perfusion is a p riority. If there is evidence of coronary occlusion, consider immediate revascularization b y thrombolysis or PCI. The optimal technique for revascularization will depend on local fac ilities for PCI as well as patient factors. Management of the ventilated, haemodynamically unsta- ble post-cardiac arrest patient in the cardiac catheter laboratory is challenging an d requires the presence of an experienced ICU clinician. Sedation \200 Although it has been common practice to sedate and ventilate patients for up to 24h after R OSC, there are no data to support a de \201 ned period of ventilation, sedation and neurom uscular blockade after cardiac arrest. The duration of sedation and ventilation may be in \202 u- enced by the use of therapeutic hypothermia. There are no data to indicate whether or not the choice of sedation in \202 uences outcome, but short-acting drugs (e.g., propof ol, alfentanil, remifentanil) will enable earlier neurological assessment. \200 Prevention and control of seizures \200 Seizures and/or myoclonus occur in 5 \200\22315% of adult patients who achieve ROSC, and in 10-40% of those who remain comatose. Seizures increase cerebral metabolism by up to 3-fold . Seizures and myoclonus per se are not related signi \201 - cantly to outcome, but status epilepticus and, in particu- lar, status myoclonus are associated with a poor outcome. The re are no studies that address directly the use of prophylactic anticonvulsant drugs after cardiac arrest in adults. Prolonged seizure activity may cause cerebral injury, and should be treated promptly and effectively with benzodi- azepines, phenytoin, sodium valproate, pr opofol or a barbiturate. Clonazepam is the drug of choice for the treatment of myoclonus, b ut sodium valproate and levetiracetam may also be effective. \200 Myocardial dysfunction after cardiac arrest \200 Haemodynamic instability is common after cardiac arrest and manifests as hypotension, low c ardiac index, arrhyth- mias and impaired contractility on echocardiography. This post-resus citation myocardial dysfunction (or myo- cardial stunning) is usually transient and often r everses within 24 \200\22348h. The post-resuscitation period is associated with marked elev ations in plasma cytokine concentrations, manifest- ing as a sepsis-like syndrome and multi ple organ dysfunc- tion, which has recently been termed the post-cardiac arrest syndrome. I nfusion of \202 uids may be required to increase right heart \201 lling pressures or, c onversely, diuretics, vasodilators and inotropes/balloon pump may be needed to treat myo- c ardial dysfunction. In the presence of a signi \201 cant in \202 ammatory response, norad renaline may be required to maintain an adequate blood pressure. Temperature control Treatment of hyperthermia A period of hyperthermia is common in the \201 rst 48h after cardiac arrest. The risk of a poor neurological outcome 243 CHAPTER 16.2 Post-cardiac arrest management increases for each degree of body temperature >37 C. Treat any hyperthermia occurring in t he \201 rst 72h after car- diac arrest with antipyretics or active cooling. and the target range of blood glucose concentrations, should be determined by local policy. Prediction of outcome in comatose survivors after cardiopulmonary resuscitation \200 Therapeutic hypothermia \200 Mild hypothermia started after ROSC reduces the neu- rological injury caused by reperfusion and the post-car- diac arrest syndrome. Based on favorable results from two randomized cli ni- cal trials, unconscious adult patients with spontaneous circulation after out-of-hospit al VF cardiac arrest should be cooled to 32 \200\22334 C. Start cooling as soon as possibl e and continue for at least 24h. Induced hypothermia might also bene \201 t unconscious ad ult patients with spontaneous circulation after OHCA from a non-shockable rhythm, or cardia c arrest in hospi- tal. Rapid infusion of ice-cold \202 uid 30ml/kg is a very effective, simple method for initiating cooling. Treatment can then be continued using either internal (intravascular cooling) or external techniques (e.g. circulating water blankets). Intravas cular cooling enables more precise temperature control. Treat shivering by ensuring adequat e sedation and giving neuromuscular blocking drugs. Bolus doses of neu- romuscular blockers are usually adequate, but infusions are necessary occasionally. Use of continuous neuromus - cular blockade could mask seizure activity. Rewarm the patient slowly (0.25 \200\2230.5 C/h) and avoid hyperthermia. Complications of mild therapeutic hypothermia include increase d infection, cardiovascular instability, coagulopa- thy, hyperglycaemia and electrolyte abn ormalities such as hypophosphataemia and hypomagnesaemia. Predicting the final outcome of individual patients remaining comatose after resuscitation from cardiac arrest is problematic. Prognosis cannot be based reliably on the circumstances surrounding cardiac arrest and CPR. The decision to admit a comatose post-cardiac arrest p atient to ICU should be based predominantly on the patient \200\231s status before the card iac arrest. Absent pupil or corneal re \202 exes within days 1 \200\2233 after CPR, or abs ent or extensor motor responses 3 days after cardiac arrest reliably predict a poor outcome in the normothermic patient. Myoclonic status epilepticus within the \201 rst day after a primary cardiac arrest reliably predicts a poor outcome. Burst suppression or generalized epileptiform discharges on the EEG predict poor outcome, but this is too impre- cise for u se in individual cases. Timely access to EEG recording and interpretation may be a problem on many ICUs. Bilateral absence of the N2O component of the somato- sensory evoked potentia l (SSEP) with median nerve stimulation recorded on days 1 \200\2233 or later accurately pre dicts a poor outcome. A serum neuron-speci \201 c enolase (NSE) concentration >33mcg/l 1 \200\2233 days after CPR accurately predicts a poor outcome. Further reading Adrie C, Adib-Conquy M, Laurent I, et al. Successful cardiopulmo- nary resu scitation after cardiac arrest as a \200\230sepsis-like \200\231 syndrome. Circulation 200 2; 106: 562 \200\2238. Blood glucose control \200 There is a strong association between high blood glu- cose after resuscitation from cardiac arrest and poor neurological outcome. Tight control of blood glucose (4.4 \200\2236.1mmol/ l) has been shown to reduce mortality in critically ill patients, par- ticularly those in I CU for >3 days, but this has not been demonstrated in post-cardiac arrest patients speci \201 cally. Comatose patients are at particular risk from unrecog- nized hypoglycaemia, and the risk of this complication occurring increases as the target blood glucose concen- trat ion is lowered. In common with all critically ill patients, patients admit- ted to a critic al care environment after cardiac arrest should have their blood glucose monitored frequent ly and hyperglycaemia treated with an insulin infusion. The blood glucose concentration tha t triggers insulin therapy, Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose sur- vivors of out-of-hospital cardiac arrest with induced hypother- mia. N Engl J Med 2002; 346: 557 \200\22363. Hypothermia After Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the n eurologic outcome after cardiac arrest. N Engl J Med 2002; 346: 549 \200\22356. Laurent I, Monchi M, Chiche JD, et al. Reversible myocardial dys- function in survivors of out-of-hospital cardiac arrest. J Am Coll Cardiol 2002; 40: 2110 \200\2236. Laver S, Farrow C, Turner D, et al. Mode of death after admission to an intensive care unit following cardiac arrest. Intensive Care Med 2004; 30: 2126 \200\2238. Wijdicks EF, Hijdra A, Young GB, et al. Practice parameter: predic- tion of outcome in coma tose survivors after cardiopulmonary resuscitation (an evidence-based review): report of th e Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006; 67: 203-10. 244 I RECHNER Fluid challenge De \201 nition A \202 uid challenge is a speci \201 c volume of \202 uid given over a speci \201 ed time period in order to determine whether the cardiac output will respond t o further volume. was 2 \200\2235mm Hg it was stopped and the CVP re-measured after 10min. If it was >5mm Hg, it was stopped. The values were 3 \200\2237mmHg if the PAWP was being used. Vincent has re cently modi \201 ed this technique allowing for the continuous monitoring that is now avai lable. He sug- gests a larger volume over a longer time period in line with the regime sugg ested in the surviving sepsis campaign (i.e. 500 \200\2231000ml crystalloid or 300 \200\223 500ml colloid over 30min). Goals should be set at the outset, such as an increase in MAP. B ecause the most serious adverse effect of a \202 uid challenge is acute pulmonary oedema secondary to con- gestive cardiac failure, Vincent suggests setting \200\230safety lim- it s \200\231 such as a set CVP/PAWP which, when reached, alerts the practitioner to stop the infusion. If the MAP is rising along with the CVP, \202 uid can be infused until the desi red MAP is reached. If the CVP is rising without any change in MAP, this indicates the \202 uid challenge is unsuccessful and other forms of circulatory support are required. Rationale Hypovolaemia may due to bleeding, GI, urinary or skin losses, or may be caused by internal losses such as third spacing. Relative hypovolaemia may result from an increase i n venous capacitance secondary to in \202 ammatory proc- esses such as sepsis or pancreati tis, or as a side effect from drugs. Venous return and therefore preload is reduced, leadin g to a reduced stroke volume and cardiac output. Perfusion to vital organs is lowered and w ill lead to pro- gressive organ failure if not corrected. Circulatory support with inotrope s is inappropriate in the hypovolaemic patient and may increase myocardial oxygen demand Ov ert hypovolaemia due to exsanguination is self-evident. However it can be a dif \201 cult diagnosis in the critically ill patient as the clinical signs lack sensitivity and speci \201 city. Type of \202 uid There is no consensus as to the most suitable \202 uid. Colloids are w idely used, as they are believed to stay in the circula- tion longer due to their larger mo lecular weight. This main- tains osmotic pressure, and so a smaller volume can be given com pared with a crystalloid to achieve the same haemodynamic response. Colloids may be blood p roducts (HAS or FFP) or synthetic (modi \201 ed gelatins, dextrans or hydroxyethyl starche s). They have different molecular weights and therefore remain in the circulation for varyi ng amounts of time. They also differ in their safety pro \201 le. Low to medium molecular weight colloids such as gelatins and albumin may leak in to the interstitial space more rap - idly than high molecular weight colloids such as hydroxye- thyl starches. A number of Coc hrane systematic reviews have looked at the difference in mortality when different \202 u ids are used for resuscitation. They found no difference between crystalloids and colloids, no difference between any of the colloids, and no difference between hypertonic and nearly isotonic \202 uids. In the latter two reviews, the authors noted large con \201 dence i ntervals and therefore could not exclude signi \201 cant clinical differences. The choice of \202 uid used should be made on the basis of the underlying disease, the type of \202 uid lost, the severity of circulatory failure, the serum albumin of the patient and th e risk of bleeding. Clinical indicators of hypovolaemia \200 Thirst, dry mouth, reduced skin turgor \200 Ta chycardia, reduced blood pressure, reduced CVP/pul- monary artery wedge pressure (PAWP) Red uced urine output (<0.5ml/kg/h), increased toe \200\223core gap Raised urea, raised sodium, raised lactate, reduced uri- nary sodium (<20mmol/l) Whilst abnormal values suggest hypovolaemia, normal val- ues do not exclude it. Increased v ariations in arterial pulse pressure with breathing in sedated mechanically ventilated pati ents are due to changes in stroke volume that occur with changes in intrathoracic pressure, and may suggest hypovolaemia. Passive leg raising to increase venous return temporarily ca n be used, but may not be reliable in awake patients. Unfortunately there is no linear rela tionship between pres- sure and volume in a vascular compartment that can change its capaci tance 3-fold. Therefore, the response to \202 uid is not reliably predictable for any giv en CVP and may even fall with volume repletion (e.g. in conditions with intense peripheral vasoconstriction such as pre-eclampsia). The CVP may be falsely high if the patient has int rinsic heart or lung disease. A more dynamic measurement of the likely response to \202 u id can be obtained by administering a speci \201 c volume of \202 uid as a \202 uid ch allenge. In order for the \202 uid challenge to result in an increase in stroke volume an d cardiac output, the \202 uid challenge has to increase cardiac preload signi \201 cant ly and this has to increase stroke volume signi \201 cantly. Therefore, the patient can be a non-responder because either preload is not increased or one or both of the ventricles i s operating on the \202 at part of the Frank \200\223Starling curve. Colloids Human albumin Human albumin solution is available as 5 or 20%, the former being us ed for hypovolaemia, the latter for the treatment of hypoalbuminaemia in the presence of sa lt and water overload. In the UK, human albumin is expensive and there are concerns over th e risk of transmission of infections, as with any blood product. A Cochrane systematic revi ew showed no bene \201 t in terms of mortality when albumin was used for resuscitation. Th is review was mainly made up of patients from the SAFE trial, which showed no difference in outcome between normal saline and human albumin when given as a bolus in 7500 patients. Performing a \202 uid challenge To test this mechanism requires a variable amount of \202 uid. Filling pressures represent the net effect of preload, ven- tricular compliance a nd afterload. The initial \202 uid challenge technique proposed by Weil and Henning in 19 79 meas- ured CVP at 10min intervals after 100 \200\223200ml of \202 uid. If the change i n CVP was <2mm Hg, the \202 uid was continued. If it Gelatins Gelatins are produced by the hydrolysis of bovine collagen and then cross-linked w ith urea to produce Haemaccel or 245 CHAPTER 16.3 Fluid challenge succinylated to produce Gelofusine. They remain in the circulation for 2h, with renal excr etion occurring within 48h. They are isotonic and the amount of chloride is lower than norm al saline (145). Haemaccel has a significant amount of calcium (Ca 6.25) and so should not be infused through the same giving set as citrated blood. Gelatins also have the potential to cause allergic reactions. Hypertonic saline Hypertonic solutions are considered to expand intravascu- lar volume by c ausing an osmotic shift of \202 uid from the extracellular and interstitial compartments to the intravas- cular space, thereby increasing blood pressure. The per- ceived advantage is that a small amount can be given over a short period with less risk of interstitial oede ma. In par- ticular it may be the \202 uid of choice in head injuries where the patient i s hypovolaemic, as an increased MAP is required to maintain CPP, but not at the expense of a large \202 uid load that may result in interstitial oedema and brain swelling. The osmo tic gradient may even draw water out of the brain tissue, thereby reducing ICP. However, if the blood \200\223brain barrier is interrupted, the hypertonic saline may in fact pass acr oss, drawing excessive amounts of water with it and thereby increasing intracranial pressur e. Hypertonic solutions may also prevent interstitial oedema whenever there is acute lung i njury such as after trauma or surgery. There are data in animals and humans to suggest that hypertonic saline has a favorable effect on haemaody- namic variables, ICP, and gut and re spiratory function. However, there are no conclusive RCTs in humans at present. Dextrans Dextrans are polysaccharides derived from fermentation of sucrose which is then hy drolysed and fractionated into different molecular weights. Dextran 40 has a molecular weig ht of 40 000Da. It is hyper- tonic and is not used for the treatment of hypovolaemia. It ca n cause renal tubular obstruction and renal failure. Dextran 70 is produced as a 6% solutio n in normal saline or 5% dextrose. Its average molecular weight is 70 000Da. Osmolality is 335mosm/kg and is therefore mildly hyper- tonic. Plasma half-life is 6h. It can precipitate anaphylactic reactions and interfere with haemostasis. Hyroxyethyl starches Hydroxyethyl starches are prepared by hydroxyethyl sub- stitution of a mylopectin, a glucose polymer. They are gen- erally presented in solution in normal saline and so may cause a hyperchloraemic acidosis. They vary in molecular weight but remain in th e intravascular space for at least 6h. Hydroxyethyl starches may have adverse effects on co agu- lation and may also cause intractable itching if large vol- umes are used. Further reading Bunn F, Alderson P, Hawkins V. Colloid solutions for \202 uid resuscita- tion. Cochrane Database Syst Rev 2003; (1): CD001319. Bunn F, Roberts I, Tasker R, et al Hypertonic versus near isotonic crystalloid for \202 uid resuscitation in critically ill patients. Cochrane Database Syst Rev 2004; (3): CD0020 45. Crystalloids Normal saline Normal saline has long been used for resuscitation. However, the high chloride present will result in a hyper- chloraemic acidosis when given in large volu mes. The hyperchloraemic acidosis is caused by the high chloride content of normal saline ( 154mmol). This excess of nega- tive chloride ions lead to a decrease in the strong ion dif- ference, which causes a normal anion gap anion gap metabolic acidosis. Finfer S, Bellomo R, Boyce N, et al. A comparison of albumin and saline for \202 uid resu scitation in the intensive care unit. N Engl J Med 2004; 350: 2247 \200\22356. Roberts I, Alderson P, Bunn F, et al. Colloids versus crystalloids for \202 uid resuscita tion in critically ill patients. Cochrane Database Syst Rev 2004; (4): CD000567. Vincent JL, Weil MH. Fluid challenge revisited. Crit Care Med 2006; 34: 1333 \200\2237. Weil MH, Henning RJ. New concepts in the diagnosis and \202 uid treatment of circulatory shock. Thirteenth annual Becton, Dickinson and Company Oscar Schwidetsky Memorial Lecture. Anesth Analg 1979; 58: 124 \200\22332. Hartmann \200\231s solution. Hartmann \200\231s solution has a lower chloride concentration than normal saline but is mildly hypotonic, so may exacer- bate cerebral oedema in those w ith brain injury. However, its main bene \201 t is that its use is not associated with a n or- mal anion gap acidosis. This page intentionally left blank 247 Chapter 17 Respiratory disorders Chapter contents Upper airway obstruction 248 Respiratory failure 250 Pulmonary collapse and atelectasis 252 Chronic obstructive pulmonary disease (COPD) 254 ARDS: diagnosis 256 ARDS: general managem ent 258 ARDS: ventilatory management 260 Asthma 262 Asthma: ventilatory management 264 Pneu mothorax 266 Empyema 268 Haemoptysis 270 Inhalation injury 272 Pulmonary embolism 274 Commu nity-acquired pneumonia 276 Hospital-acquired pneumonia 278 Pulmonary hypertension 280 248 A KAPILA Upper airway obstruction There are few medical conditions that are as rapidly and predictably lethal as the loss of upper airway patency. Because of the relative infrequency with which upper airway obstructi on (UAO) is encountered by most physicians, opportunities to acquire signi \201 cant clini cal experience are limited. This, combined with the frequently subtle presenta- tion of UAO and the clinician \200\231s inability to visualize the upper airway in its entire extent t hrough routine physical examina- tion, may hamper diagnosis of this condition until a crisi s results. Trauma Burns Neoplasm \200 \200 Pharyngeal, laryngeal and tracheobronchial carcinoma Vocal cord polyposis Congenital \200 \200 Vascular rings Laryngeal webs, laryngocoele Miscellaneous \200 \200 \200 \200 