Critical care medicine

Part 12: Critical Care Medicine 1729   Section 1    R espiratory Critical Care 321 Approach to the Patient with Critical Illness John P Kress, Jesse B Hall ASSESSMENT OF ILLNESS SEVERITY In the ICU, illnesses are frequently categorized by degree of severity Numerous severity-of-illness (SOI) scoring systems have been developed and validated over the past three decades Although these scoring systems have been validated as tools to assess populations of critically ill patients, their utility in predicting individual patient outcomes is not clear SOI scoring systems are important for defining populations of critically ill patients Such systematic scoring allows effective comparison of groups of patients enrolled in clinical trials In verifying a purported benefit of therapy, investigators must be confident that different groups involved in a clinical trial have similar illness severities SOI scores are also useful in guiding hospital administrative policies, directing the allocation of resources such as nursing and ancillary care and assisting in assessments of quality of ICU care over time Scoring system validations are based on the premise that age, chronic medical illnesses, and derangements from normal physiology are associated with increased mortality rates All existing SOI scoring systems are derived from patients who have already been admitted to the ICU SOI scoring systems cannot be used to predict survival in individual patients No established scoring systems that purport to direct clinicians’ decision-making regarding criteria for admission to an ICU are available, although such models are being developed Thus the use of SOI scoring systems to direct therapy and clinical decision-making cannot be recommended at present Instead, these tools should be used as a source of important data to complement clinical bedside decision-making The most commonly utilized scoring systems are the APACHE (Acute Physiology and Chronic Health Evaluation) and the SAPS (Simplified Acute Physiology Score) systems THE APACHE II SCORING SYSTEM The APACHE II system is the most commonly used SOI scoring system in North America Age, type of ICU admission (after elective HPIM19_Part12_p1729-p1798.indd 1729 THE SAPS SCORING SYSTEM The SAPS II score, used more frequently in Europe than in the United States, was derived in a manner similar to the APACHE score This score is not disease specific but rather incorporates three underlying disease variables: AIDS, metastatic cancer, and hematologic malignancy SAPS 3, which utilizes a 1-h rather than a 24-h window for measuring physiologic derangement scores, was developed in 2005 SHOCK See also Chap 324 INITIAL EVALUATION Shock, a common condition necessitating ICU admission or occurring in the course of critical care, is defined by the presence of multisystem end-organ hypoperfusion Clinical indicators include reduced mean arterial pressure (MAP), tachycardia, tachypnea, cool skin and extremities, acute altered mental status, and oliguria Hypotension is usually, though not always, present The end result of multiorgan hypoperfusion is tissue hypoxia, often with accompanying lactic acidosis Since the MAP is the product of cardiac output and systemic vascular resistance (SVR), reductions in blood pressure can be caused by decreases in cardiac output and/or SVR Accordingly, once shock is contemplated, the initial evaluation of a hypotensive patient should include an early bedside assessment of the adequacy of cardiac output (Fig 321-2) Clinical evidence of diminished cardiac output includes a narrow pulse pressure—a marker that correlates with stroke volume— and cool extremities with delayed capillary refill Signs of increased cardiac output include a widened pulse pressure (particularly with a reduced diastolic pressure), warm extremities with bounding pulses, and rapid capillary refill If a hypotensive patient has clinical signs of increased cardiac output, it can be inferred that the reduced blood pressure is from decreased SVR In hypotensive patients with signs of reduced cardiac output, an assessment of intravascular volume status is appropriate A hypotensive patient with decreased intravascular volume status may have a history suggesting hemorrhage or other volume losses (e.g., vomiting, diarrhea, polyuria) Although evidence of a reduced jugular venous pressure (JVP) is often sought, static measures of right atrial pressure not predict fluid responsiveness reliably; the change in right atrial pressure as a function of spontaneous respiration is a better predictor of fluid responsiveness (Fig 321-3) Patients with fluid-responsive (i.e., hypovolemic) shock also may manifest large changes in pulse pressure as a function of respiration during mechanical ventilation (Fig 321-4) A hypotensive patient with increased intravascular volume and cardiac dysfunction may have S3 and/or S4 gallops on examination, increased JVP, extremity edema, and crackles on lung auscultation The chest x-ray may show cardiomegaly, widening of the vascular pedicle, Kerley B lines, and pulmonary edema Chest pain and electrocardiographic changes consistent with ischemia may be noted (Chap 326) In hypotensive patients with clinical evidence of increased cardiac output, a search for causes of decreased SVR is appropriate The CHAPTER 321 Approach to the Patient with Critical Illness The care of critically ill patients requires a thorough understanding of pathophysiology and centers initially on the resuscitation of patients at the extremes of physiologic deterioration This resuscitation is often fast-paced and occurs early, without a detailed awareness of the patient’s chronic medical problems While physiologic stabilization is taking place, intensivists attempt to gather important background medical information to supplement the real-time assessment of the patient’s current physiologic conditions Numerous tools are available to assist intensivists in the accurate assessment of pathophysiology and management of incipient organ failure, offering a window of opportunity for diagnosing and treating underlying disease(s) in a stabilized patient Indeed, the use of invasive interventions such as mechanical ventilation and renal replacement therapy is commonplace in the intensive care unit (ICU) An appreciation of the risks and benefits of such aggressive and often invasive interventions is vital to ensure an optimal outcome Nonetheless, intensivists must recognize when a patient’s chances for recovery are remote or nonexistent and must counsel and comfort dying patients and their significant others Critical care physicians often must redirect the goals of care from resuscitation and cure to comfort when the resolution of an underlying illness is not possible surgery vs nonsurgical or after emergency surgery), chronic health problems, and 12 physiologic variables (the worst values for each in the first 24 h after ICU admission) are used to derive a score The predicted hospital mortality rate is derived from a formula that takes into account the APACHE II score, the need for emergency surgery, and a weighted, disease-specific diagnostic category (Table 321–1) The relationship between APACHE II score and mortality risk is illustrated in Fig 321-1 Updated versions of the APACHE scoring system (APACHE III and APACHE IV) have been published 2/9/15 3:34 PM 1730   TABLE 321-1    Calculation of Acute Physiology and Chronic Health Evaluation II (APACHE II) Scorea Acute Physiology Score Score Rectal temperature (°C) Mean blood pressure (mmHg) Heart rate (beats/min) Respiratory rate (breaths/min) Arterial pH Oxygenation   If FIo > 0.5, use (A − a) Do 2   If FIo ≤ 0.5, use Pao 2 Serum sodium (meq/L) Serum potassium (meq/L) Serum creatinine (mg/dL) Hematocrit (%) WBC count (103/mL) Glasgow Coma Scoreb,c Eye Opening 4—Spontaneous 3—Verbal stimuli 2—Painful stimuli 1—No response ≥41 ≥160 ≥180 ≥50 ≥7.70 39.0–40.9 130–159 140–179 35–49 7.60–7.69 110–129 110–139 ≥500 350–499 200–349 ≥180 ≥7.0 ≥3.5 ≥60 ≥40 160–179 6.0–6.9 2.0–3.4 155–159 38.5–38.9 25–34 7.50–7.59 1.5–1.9 50–59.9 20–39.9 Verbal (Nonintubated) 5—Oriented and talks 4—Disoriented and talks 3—Inappropriate words 2—Incomprehensible sounds 1—No response 150–154 5.5–5.9 46–49.9 15–19.9 36.0–38.4 70–109 70–109 12–24 7.33–7.49 70 130–149 3.5–5.4 0.6–1.4 30–45.9 3–14.9 34.0–35.9 10–11 61–70 3.0–3.4 Verbal (Intubated) 5—Seems able to talk 3—Questionable ability to talk 1—Generally unresponsive PART 12 Points Assigned to Age and Chronic Disease Age, Years Score 1:1 With diminished time to exhale, dynamic hyperinflation leads to increased end-expiratory pressure, similar to ventilator-prescribed PEEP This mode of ventilation has the advantage of improving oxygenation with lower peak pressures than are required for conventional ventilation Although inverse-ratio ventilation can improve oxygenation and can help reduce Fio2 to ≤0.60, thus avoiding possible oxygen toxicity, no benefit in ARDS mortality risk has been demonstrated Recruitment maneuvers that transiently increase PEEP to “recruit” atelectatic lung can also increase oxygenation, but a mortality benefit has not been established In several randomized trials, mechanical ventilation in the prone position improved arterial oxygenation, but its effect on survival and other important clinical outcomes remains uncertain Moreover, unless the critical-care team is experienced in “proning,” repositioning critically ill patients can be hazardous, leading to accidental endotracheal extubation, loss of central venous catheters, and orthopedic injury OTHER STRATEGIES IN MECHANICAL VENTILATION Several additional mechanical-ventilation strategies that use specialized equipment have been tested in ARDS patients; most of these approaches have had mixed or disappointing results in adults High-frequency ventilation (HFV) entails ventilating at extremely high respiratory rates (5–20 cycles per second) and low VTs (1–2 mL/ kg) Use of partial liquid ventilation (PLV) with perfluorocarbon—an inert, high-density liquid that easily solubilizes oxygen and carbon 2/9/15 3:34 PM 1784 have a clinical syndrome profound enough to cause severe respira- tory muscle weakness requiring prolonged mechanical ventilation or resulting in failure to wean Aggressive glycemic control with insulin infusions appears to decrease the risk of critical illness polyneuropathy Treatment is otherwise supportive, with specific intervention directed at treating the underlying illness Although spontaneous recovery is usually seen, the time course may extend over weeks to months and necessitate long-term ventilatory support and care even after the underlying critical illness has resolved PART 12 Critical Care Medicine DISORDERS OF NEUROMUSCULAR TRANSMISSION A defect in neuromuscular transmission may be a source of weakness in critically ill patients Botulism (Chap 178) may be acquired by ingesting botulinum toxin from improperly stored food or may arise from an anaerobic abscess from Clostridium botulinum (wound botulism) Infants can present with generalized weakness from gut-derived Clostridium infection, especially if they are fed honey Diplopia and dysphagia are early signs of foodborne botulism Treatment is mostly supportive, although use of antitoxin early in the course may limit the duration of the neuromuscular blockade General ICU care is similar to patients with Guillain-Barré syndrome or myasthenia gravis with focused care to avoid ulcer formation at pressure points, deep venous thromboprophylaxis, and infection prevention Public health officers should be rapidly informed when the diagnosis is made to prevent further exposure to others from the tainted food or source of wound botulism (such as injection drug use) Undiagnosed myasthenia gravis (Chap 461) may be a consideration in weak ICU patients; however, persistent weakness secondary to impaired neuromuscular junction transmission is almost always due to administration of drugs A number of medications impair neuromuscular transmission; these include antibiotics, especially aminoglycosides, and beta-blocking agents In the ICU, the nondepolarizing neuromuscular blocking agents (nd-NMBAs), also known as muscle relaxants, are most commonly responsible Included in this group of drugs are such agents as pancuronium, vecuronium, rocuronium, and cisatracurium They are often used to facilitate mechanical ventilation or other critical care procedures, but with prolonged use persistent neuromuscular blockade may result in weakness even after discontinuation of these agents hours or days earlier Risk factors for this prolonged action of neuromuscular blocking agents include female sex, metabolic acidosis, and renal failure Prolonged neuromuscular blockade does not appear to produce permanent damage to the PNS Once the offending medications are discontinued, full strength is restored, although this may take days In general, the lowest dose of neuromuscular blocking agent should be used to achieve the desired result and, when these agents are used in the ICU, a peripheral nerve stimulator should be used to monitor neuromuscular junction function MYOPATHY Critically ill patients, especially those with sepsis, frequently develop muscle weakness and wasting, often in the face of seemingly adequate nutritional support Critical illness myopathy is an overall term that describes several different discrete muscle disorders that may occur in critically ill patients The assumption has been that a catabolic myopathy may develop as a result of multiple factors, including elevated cortisol and catecholamine release and other circulating factors induced by the SIRS In this syndrome, known as cachectic myopathy, serum creatine kinase levels and electromyography (EMG) are normal Muscle biopsy shows type II fiber atrophy Panfascicular muscle fiber necrosis may also occur in the setting of profound sepsis This less common acute necrotizing intensive care myopathy is characterized clinically by weakness progressing to a profound level over just a few days There may be associated elevations in serum creatine kinase and urine myoglobin Both EMG and muscle biopsy may be normal initially but eventually show abnormal spontaneous activity and panfascicular necrosis with an accompanying inflammatory reaction Acute rhabdomyolysis can occur from alcohol ingestion or from compartment syndromes HPIM19_Part12_p1729-p1798.indd 1784 A thick-filament myopathy may occur in the setting of glucocorticoid and nd-NMBA use The most frequent scenario in which this is encountered is the asthmatic patient who requires high-dose glucocorticoids and nd-NMBA to facilitate mechanical ventilation This muscle disorder is not due to prolonged action of nd-NMBAs at the neuromuscular junction but, rather, is an actual myopathy with muscle damage; it has occasionally been described with high-dose glucocorticoid use or sepsis alone Clinically this syndrome is most often recognized when a patient fails to wean from mechanical ventilation despite resolution of the primary pulmonary process Pathologically, there may be loss of thick (myosin) filaments Thick-filament critical illness myopathy has a good prognosis If patients survive their underlying critical illness, the myopathy invariably improves and most patients return to normal However, because this syndrome is a result of true muscle damage, not just prolonged blockade at the neuromuscular junction, this process may take weeks or months, and tracheotomy with prolonged ventilatory support may be necessary Some patients have residual long-term weakness, with atrophy and fatigue limiting ambulation At present, it is unclear how to prevent this myopathic complication, except by avoiding use of nd-NMBAs, a strategy not always possible Monitoring with a peripheral nerve stimulator can help to avoid the overuse of these agents However, this is more likely to prevent the complication of prolonged neuromuscular junction blockade than it is to prevent this myopathy SUBARACHNOID HEMORRHAGE Subarachnoid hemorrhage (SAH) renders the brain critically ill from both primary and secondary brain insults Excluding head trauma, the most common cause of SAH is rupture of a saccular aneurysm Other causes include bleeding from a vascular malformation (arteriovenous malformation or dural arteriovenous fistula) and extension into the subarachnoid space from a primary intracerebral hemorrhage Some idiopathic SAHs are localized to the perimesencephalic cisterns and are benign; they probably have a venous or capillary source, and angiography is unrevealing SACCULAR (“BERRY”) ANEURYSM Autopsy and angiography studies have found that about 2% of adults harbor intracranial aneurysms, for a prevalence of million persons in the United States; the aneurysm will rupture, producing SAH, in 25,000–30,000 cases per year For patients who arrive alive at hospital, the mortality rate over the next month is about 45% Of those who survive, more than half are left with major neurologic deficits as a result of the initial hemorrhage, cerebral vasospasm with infarction, or hydrocephalus If the patient survives but the aneurysm is not obliterated, the rate of rebleeding is about 20% in the first weeks, 30% in the first month, and about 3% per year afterward Given these alarming figures, the major therapeutic emphasis is on preventing the predictable early complications of the SAH Unruptured, asymptomatic aneurysms are much less dangerous than a recently ruptured aneurysm The annual risk of rupture for aneurysms 10 mm in size may benefit from prophylactic treatment As with the treatment of asymptomatic carotid stenosis, this risk-benefit ratio strongly depends on the complication rate of treatment Giant aneurysms, those >2.5 cm in diameter, occur at the same sites (see below) as small aneurysms and account for 5% of cases The three most common locations are the terminal internal carotid artery, middle cerebral artery (MCA) bifurcation, and top of the basilar artery Their risk of rupture is ~6% in the first year after identification and may remain high indefinitely They often cause symptoms by compressing the adjacent brain or cranial nerves Mycotic aneurysms are usually located distal to the first bifurcation of major arteries of the circle of Willis Most result from infected emboli due to bacterial endocarditis causing septic degeneration of arteries and subsequent dilation and rupture Whether these lesions 2/9/15 3:34 PM should be sought and repaired prior to rupture or left to heal spontaneously with antibiotic treatment is controversial Pathophysiology  Saccular aneurysms occur at the bifurcations of the large- to medium-sized intracranial arteries; rupture is into the subarachnoid space in the basal cisterns and often into the parenchyma of the adjacent brain Approximately 85% of aneurysms occur in the anterior circulation, mostly on the circle of Willis About 20% of patients have multiple aneurysms, many at mirror sites bilaterally As an aneurysm develops, it typically forms a neck with a dome The length of the neck and the size of the dome vary greatly and are important factors in planning neurosurgical obliteration or endovascular embolization The arterial internal elastic lamina disappears at the base of the neck The media thins, and connective tissue replaces smooth-muscle cells At the site of rupture (most often the dome), the wall thins, and the tear that allows bleeding is often ≤0.5 mm long Aneurysm size and site are important in predicting risk of rupture Those >7 mm in diameter and those at the top of the basilar artery and at the origin of the posterior communicating artery are at greater risk of rupture HPIM19_Part12_p1729-p1798.indd 1785 World Federation of Neurosurgical Societies Grade Hunt-Hess Scale (WFNS) Scale Mild headache, normal mental status, no GCSa score 15, no motor cranial nerve or motor findings deficits Severe headache, normal mental status, GCS score 13–14, no may have cranial nerve deficit motor deficits Somnolent, confused, may have cranial GCS score 13–14, with nerve or mild motor deficit motor deficits Stupor, moderate to severe motor deficit, GCS score 7–12, with or may have intermittent reflex posturing without motor deficits Coma, reflex posturing or flaccid GCS score 3–6, with or without motor deficits Glasgow Coma Scale; see Table 457e-1 a Delayed Neurologic Deficits  There are four major causes of delayed neurologic deficits: rerupture, hydrocephalus, vasospasm, and hyponatremia Rerupture The incidence of rerupture of an untreated aneurysm in the first month following SAH is ~30%, with the peak in the first days Rerupture is associated with a 60% mortality rate and poor outcome Early treatment eliminates this risk Hydrocephalus Acute hydrocephalus can cause stupor and coma and can be mitigated by placement of an external ventricular drain More often, subacute hydrocephalus may develop over a few days or weeks and causes progressive drowsiness or slowed mentation (abulia) with incontinence Hydrocephalus is differentiated from cerebral vasospasm with a CT scan, CT angiogram, transcranial Doppler (TCD) ultrasound, or conventional x-ray angiography Hydrocephalus may clear spontaneously or require temporary ventricular drainage Chronic hydrocephalus may develop weeks to months after SAH and manifest as gait difficulty, incontinence, or impaired mentation Subtle signs may be a lack of initiative in conversation or a failure to recover independence Vasospasm Narrowing of the arteries at the base of the brain following SAH causes symptomatic ischemia and infarction in ~30% of patients and is the major cause of delayed morbidity and death Signs of ischemia appear 4–14 days after the hemorrhage, most often at days The severity and distribution of vasospasm determine whether infarction will occur Delayed vasospasm is believed to result from direct effects of clotted blood and its breakdown products on the arteries within the subarachnoid space In general, the more blood that surrounds the arteries, the greater the chance of symptomatic vasospasm Spasm of major arteries produces symptoms referable to the appropriate vascular territory (Chap 446) All of these focal symptoms may present abruptly, fluctuate, or develop over a few days In most cases, focal spasm is preceded by a decline in mental status Vasospasm can be detected reliably with conventional x-ray angiography, but this invasive procedure is expensive and carries the risk of stroke and other complications TCD ultrasound is based on the principle that the velocity of blood flow within an artery will rise as the lumen diameter is narrowed By directing the probe along the MCA and proximal anterior cerebral artery (ACA), carotid terminus, and vertebral and basilar arteries on a daily or every-other-day basis, vasospasm can be reliably detected and treatments initiated to prevent cerebral ischemia (see below) CT angiography is another method that can detect vasospasm Severe cerebral edema in patients with infarction from vasospasm may increase the ICP enough to reduce cerebral perfusion pressure Treatment may include mannitol, hyperventilation, and hemicraniectomy; moderate hypothermia may have a role as well Hyponatremia Hyponatremia may be profound and can develop quickly in the first weeks following SAH There is both natriuresis and volume depletion with SAH, so that patients become both hyponatremic and hypovolemic Both atrial natriuretic peptide and brain natriuretic peptide have a role in producing this “cerebral CHAPTER 330 Neurologic Critical Care Clinical Manifestations  Most unruptured intracranial aneurysms are completely asymptomatic Symptoms are usually due to rupture and resultant SAH, although some unruptured aneurysms present with mass effect on cranial nerves or brain parenchyma At the moment of aneurysmal rupture with major SAH, the ICP suddenly rises This may account for the sudden transient loss of consciousness that occurs in nearly half of patients Sudden loss of consciousness may be preceded by a brief moment of excruciating headache, but most patients first complain of headache upon regaining consciousness In 10% of cases, aneurysmal bleeding is severe enough to cause loss of consciousness for several days In ~45% of cases, severe headache associated with exertion is the presenting complaint The patient often calls the headache “the worst headache of my life”; however, the most important characteristic is sudden onset Occasionally, these ruptures may present as headache of only moderate intensity or as a change in the patient’s usual headache pattern The headache is usually generalized, often with neck stiffness, and vomiting is common Although sudden headache in the absence of focal neurologic symptoms is the hallmark of aneurysmal rupture, focal neurologic deficits may occur Anterior communicating artery or MCA bifurcation aneurysms may rupture into the adjacent brain or subdural space and form a hematoma large enough to produce mass effect The deficits that result can include hemiparesis, aphasia, and abulia Occasionally, prodromal symptoms suggest the location of a progressively enlarging unruptured aneurysm A third cranial nerve palsy, particularly when associated with pupillary dilation, loss of ipsilateral (but retained contralateral) light reflex, and focal pain above or behind the eye, may occur with an expanding aneurysm at the junction of the posterior communicating artery and the internal carotid artery A sixth nerve palsy may indicate an aneurysm in the cavernous sinus, and visual field defects can occur with an expanding supraclinoid carotid or anterior cerebral artery aneurysm Occipital and posterior cervical pain may signal a posterior inferior cerebellar artery or anterior inferior cerebellar artery aneurysm (Chap 446) Pain in or behind the eye and in the low temple can occur with an expanding MCA aneurysm Thunderclap headache is a variant of migraine that simulates an SAH Before concluding that a patient with sudden, severe headache has thunderclap migraine, a definitive workup for aneurysm or other intracranial pathology is required Aneurysms can undergo small ruptures and leaks of blood into the subarachnoid space, so-called sentinel bleeds Sudden unexplained headache at any location should raise suspicion of SAH and be investigated, because a major hemorrhage may be imminent The initial clinical manifestations of SAH can be graded using the Hunt-Hess or World Federation of Neurosurgical Societies classification schemes (Table 330-3) For ruptured aneurysms, prognosis for good outcomes falls as the grade increases For example, it is unusual for a Hunt-Hess grade patient to die if the aneurysm is treated, but the mortality rate for grade and patients may be as high as 80% 1785   Table 330-3    Grading Scales for Subarachnoid Hemorrhage 2/9/15 3:34 PM 1786 A B unruptured aneurysms exist (Fig 330-7C) At some centers, the ruptured aneurysm can be treated using endovascular techniques at the time of the initial angiogram as a way to expedite treatment and minimize the number of invasive procedures CT angiography is an alternative method for locating the aneurysm and may be sufficient to plan definitive therapy Close monitoring (daily or twice daily) of electrolytes is important because hyponatremia can occur precipitously during the first weeks following SAH (see above) The electrocardiogram (ECG) frequently shows ST-segment and T-wave changes similar to those associated with cardiac ischemia A prolonged QRS complex, increased QT interval, and prominent “peaked” or deeply inverted symmetric T waves are usually secondary to the intracranial hemorrhage There is evidence that structural myocardial lesions produced by circulating catecholamines and excessive discharge of sympathetic neurons may occur after SAH, causing these ECG changes and a reversible cardiomyopathy sufficient to cause shock or congestive heart failure Echocardiography reveals a pattern of regional wall motion abnormalities that follow the distribution of sympathetic nerves rather than the major coronary arteries, with relative sparing of the ventricular wall apex The sympathetic nerves themselves appear to be injured by direct toxicity from the excessive catecholamine release An asymptomatic troponin elevation is common Serious ventricular dysrhythmias occurring in-hospital are unusual TREATMENT C D PART 12 Critical Care Medicine Figure 330-7  Subarachnoid hemorrhage A Computed tomography (CT) angiography revealing an aneurysm of the left superior cerebellar artery B Noncontrast CT scan at the level of the third ventricle revealing subarachnoid blood (bright) in the left sylvian fissure and within the left lateral ventricle C Conventional anteroposterior x-ray angiogram of the right vertebral and basilar artery showing the large aneurysm D Conventional angiogram following coil embolization of the aneurysm, whereby the aneurysm body is filled with platinum coils delivered through a microcatheter navigated from the femoral artery into the aneurysm neck salt-wasting syndrome.” Typically, it clears over the course of 1–2 weeks and, in the setting of SAH, should not be treated with freewater restriction as this may increase the risk of stroke (see below) Laboratory Evaluation and Imaging  (Fig 330-7) The hallmark of aneurysmal rupture is blood in the CSF More than 95% of cases have enough blood to be visualized on a high-quality noncontrast CT scan obtained within 72 h If the scan fails to establish the diagnosis of SAH and no mass lesion or obstructive hydrocephalus is found, a lumbar puncture should be performed to establish the presence of subarachnoid blood Lysis of the red blood cells and subsequent conversion of hemoglobin to bilirubin stains the spinal fluid yellow within 6–12 h This xanthochromic spinal fluid peaks in intensity at 48 h and lasts for 1–4 weeks, depending on the amount of subarachnoid blood The extent and location of subarachnoid blood on a noncontrast CT scan help locate the underlying aneurysm, identify the cause of any neurologic deficit, and predict delayed vasospasm A high incidence of symptomatic vasospasm in the MCA and ACA has been found when early CT scans show subarachnoid clots >5 × mm in the basal cisterns, or layers of blood >1 mm thick in the cerebral fissures CT scans less reliably predict vasospasm in the vertebral, basilar, or posterior cerebral arteries Lumbar puncture prior to an imaging procedure is indicated only if a CT scan is not available at the time of the suspected SAH Once the diagnosis of hemorrhage from a ruptured saccular aneurysm is suspected, four-vessel conventional x-ray angiography (both carotids and both vertebrals) is generally performed to localize and define the anatomic details of the aneurysm and to determine if other HPIM19_Part12_p1729-p1798.indd 1786 Subarachnoid Hemorrhage Early aneurysm repair prevents rerupture and allows the safe application of techniques to improve blood flow (e.g., induced hypertension) should symptomatic vasospasm develop An aneurysm can be “clipped” by a neurosurgeon or “coiled” by an endovascular surgeon Surgical repair involves placing a metal clip across the aneurysm neck, thereby immediately eliminating the risk of rebleeding This approach requires craniotomy and brain retraction, which is associated with neurologic morbidity Endovascular techniques involve placing platinum coils, or other embolic material, within the aneurysm via a catheter that is passed from the femoral artery The aneurysm is packed tightly to enhance thrombosis and over time is walled off from the circulation (Fig 330-7D) There have been two prospective randomized trials of surgery versus endovascular treatment for ruptured aneurysms: the first was the International Subarachnoid Aneurysm Trial (ISAT), which was terminated early when 24% of patients treated with endovascular therapy were dead or dependent at year compared to 31% treated with surgery, a significant 23% relative reduction After years, risk of death was lower in the coiling group, although the proportion of survivors who were independent was the same in both groups Risk of rebleeding was low, but more common in the coiling group These results favoring coiling at year were confirmed in a second trial, although the differences in functional outcome were no longer significant at years Because some aneurysms have a morphology that is not amenable to endovascular treatment, surgery remains an important treatment option Centers that combine both endovascular and neurosurgical expertise likely offer the best outcomes for patients, and there are reliable data showing that specialized aneurysm treatment centers can improve mortality rates The medical management of SAH focuses on protecting the airway, managing blood pressure before and after aneurysm treatment, preventing rebleeding prior to treatment, managing vasospasm, treating hydrocephalus, treating hyponatremia, limiting secondary brain insults, and preventing pulmonary embolus (PE) Intracranial hypertension following aneurysmal rupture occurs secondary to subarachnoid blood, parenchymal hematoma, acute hydrocephalus, or loss of vascular autoregulation Patients who are stuporous should undergo emergent ventriculostomy to measure ICP and to treat high ICP in order to prevent cerebral ischemia Medical therapies designed to combat raised ICP (e.g., osmotic therapy and sedation) can also be used as needed High ICP refractory to treatment is a poor prognostic sign 2/9/15 3:34 PM induced hypertension and hypervolemia generally requires moni- 1787 toring of arterial and central venous pressures; it is best to infuse pressors through a central venous line as well Volume expansion helps prevent hypotension and augments cardiac output If symptomatic vasospasm persists despite optimal medical therapy, intraarterial vasodilators and percutaneous transluminal angioplasty are considered Vasodilatation by direct angioplasty appears to be permanent, allowing hypertensive therapy to be tapered sooner The pharmacologic vasodilators (verapamil and nicardipine) not last more than about 24 h, and therefore multiple treatments may be required until the subarachnoid blood is reabsorbed Although intraarterial papaverine is an effective vasodilator, there is evidence that papaverine may be neurotoxic, so its use should generally be avoided Acute hydrocephalus can cause stupor or coma It may clear spontaneously or require temporary ventricular drainage When chronic hydrocephalus develops, ventricular shunting is the treatment of choice Free-water restriction is contraindicated in patients with SAH at risk for vasospasm because hypovolemia and hypotension may occur and precipitate cerebral ischemia Many patients continue to experience a decline in serum sodium despite receiving parenteral fluids containing normal saline Frequently, supplemental oral salt coupled with normal saline will mitigate hyponatremia, but often patients also require intravenous hypertonic saline Care must be taken not to correct serum sodium too quickly in patients with marked hyponatremia of several days’ duration, as central pontine myelinolysis may occur All patients should have pneumatic compression stockings applied to prevent pulmonary embolism Unfractionated heparin administered subcutaneously for DVT prophylaxis can be initiated immediately following endovascular treatment and within days following craniotomy with surgical clipping and is a useful adjunct to pneumatic compression stockings Treatment of pulmonary embolus depends on whether the aneurysm has been treated and whether or not the patient has had a craniotomy Systemic anticoagulation with heparin is contraindicated in patients with ruptured and untreated aneurysms It is a relative contraindication following craniotomy for several days, and it may delay thrombosis of a coiled aneurysm If DVT or PE occurs within the first days following craniotomy, use of an inferior vena cava filter may be considered to prevent additional pulmonary emboli, whereas systemic anticoagulation with heparin is preferred following successful endovascular treatment CHAPTER 331 Oncologic Emergencies Prior to definitive treatment of the ruptured aneurysm, care is required to maintain adequate cerebral perfusion pressure while avoiding excessive elevation of arterial pressure If the patient is alert, it is reasonable to lower the systolic blood pressure to below 160 mmHg using nicardipine, labetalol, or esmolol If the patient has a depressed level of consciousness, ICP should be measured and the cerebral perfusion pressure targeted to 60–70 mmHg If headache or neck pain is severe, mild sedation and analgesia are prescribed Extreme sedation is avoided if possible because it can obscure the ability to clinically detect changes in neurologic status Adequate hydration is necessary to avoid a decrease in blood volume predisposing to brain ischemia Seizures are uncommon at the onset of aneurysmal rupture The quivering, jerking, and extensor posturing that often accompany loss of consciousness with SAH are probably related to the sharp rise in ICP rather than seizures However, anticonvulsants are sometimes given as prophylactic therapy because a seizure could theoretically promote rebleeding Glucocorticoids may help reduce the head and neck ache caused by the irritative effect of the subarachnoid blood There is no good evidence that they reduce cerebral edema, are neuroprotective, or reduce vascular injury, and their routine use therefore is not recommended Antifibrinolytic agents are not routinely prescribed but may be considered in patients in whom aneurysm treatment cannot proceed immediately They are associated with a reduced incidence of aneurysmal rerupture but may also increase the risk of delayed cerebral infarction and deep vein thrombosis (DVT) Several recent studies suggest that a shorter duration of use (until the aneurysm is secured or for the first days) may decrease rerupture and be safer than found in earlier studies of longer duration treatment Vasospasm remains the leading cause of morbidity and mortality following aneurysmal SAH Treatment with the calcium channel antagonist nimodipine (60 mg PO every h) improves outcome, perhaps by preventing ischemic injury rather than reducing the risk of vasospasm Nimodipine can cause significant hypotension in some patients, which may worsen cerebral ischemia in patients with vasospasm Symptomatic cerebral vasospasm can also be treated by increasing the cerebral perfusion pressure by raising mean arterial pressure through plasma volume expansion and the judicious use of IV vasopressor agents, usually phenylephrine or norepinephrine Raised perfusion pressure has been associated with clinical improvement in many patients, but high arterial pressure may promote rebleeding in unprotected aneurysms Treatment with   Section 4    O ncologic Emergencies 331 Oncologic Emergencies Rasim Gucalp, Janice P Dutcher Emergencies in patients with cancer may be classified into three groups: pressure or obstruction caused by a space-occupying lesion, metabolic or hormonal problems (paraneoplastic syndromes, Chap 121), and treatment-related complications STRUCTURAL-OBSTRUCTIVE ONCOLOGIC EMERGENCIES SUPERIOR VENA CAVA SYNDROME Superior vena cava syndrome (SVCS) is the clinical manifestation of superior vena cava (SVC) obstruction, with severe reduction in venous return from the head, neck, and upper extremities Malignant HPIM19_Part12_p1729-p1798.indd 1787 tumors, such as lung cancer, lymphoma, and metastatic tumors, are responsible for the majority of SVCS cases With the expanding use of intravascular devices (e.g., permanent central venous access catheters, pacemaker/defibrillator leads), the prevalence of benign causes of SVCS is increasing now, accounting for at least 40% of cases Lung cancer, particularly of small-cell and squamous cell histologies, accounts for approximately 85% of all cases of malignant origin In young adults, malignant lymphoma is a leading cause of SVCS Hodgkin’s lymphoma involves the mediastinum more commonly than other lymphomas but rarely causes SVCS When SVCS is noted in a young man with a mediastinal mass, the differential diagnosis is lymphoma versus primary mediastinal germ cell tumor Metastatic cancers to the mediastinal lymph nodes, such as testicular and breast carcinomas, account for a small proportion of cases Other causes include benign tumors, aortic aneurysm, thyromegaly, thrombosis, and fibrosing mediastinitis from prior irradiation, histoplasmosis, or Behçet’s syndrome SVCS as 2/9/15 3:34 PM 1788 the initial manifestation of Behçet’s syndrome may be due to inflam- PART 12 Critical Care Medicine mation of the SVC associated with thrombosis Patients with SVCS usually present with neck and facial swelling (especially around the eyes), dyspnea, and cough Other symptoms include hoarseness, tongue swelling, headaches, nasal congestion, epistaxis, hemoptysis, dysphagia, pain, dizziness, syncope, and lethargy Bending forward or lying down may aggravate the symptoms The characteristic physical findings are dilated neck veins; an increased number of collateral veins covering the anterior chest wall; cyanosis; and edema of the face, arms, and chest Facial swelling and plethora are typically exacerbated when the patient is supine More severe cases include proptosis, glossal and laryngeal edema, and obtundation The clinical picture is milder if the obstruction is located above the azygos vein Symptoms are usually progressive, but in some cases, they may improve as collateral circulation develops Signs and symptoms of cerebral and/or laryngeal edema, though rare, are associated with a poorer prognosis and require urgent evaluation Seizures are more likely related to brain metastases than to cerebral edema from venous occlusion Patients with small-cell lung cancer and SVCS have a higher incidence of brain metastases than those without SVCS Cardiorespiratory symptoms at rest, particularly with positional changes, suggest significant airway and vascular obstruction and limited physiologic reserve Cardiac arrest or respiratory failure can occur, particularly in patients receiving sedatives or undergoing general anesthesia Rarely, esophageal varices may develop These are “downhill” varices based on the direction of blood flow from cephalad to caudad (in contrast to “uphill” varices associated with caudad to cephalad flow from portal hypertension) If the obstruction to the SVC is proximal to the azygous vein, varices develop in the upper one-third of the esophagus If the obstruction involves or is distal to the azygous vein, varices occur in the entire length of the esophagus Variceal bleeding may be a late complication of chronic SVCS Superior vena cava obstruction may lead to bilateral breast edema with bilateral enlarged breast Unilateral breast dilatation may be seen as a consequence of axillary or subclavian vein blockage The diagnosis of SVCS is a clinical one The most significant chest radiographic finding is widening of the superior mediastinum, most commonly on the right side Pleural effusion occurs in only 25% of patients, often on the right side The majority of these effusions are exudative and occasionally chylous However, a normal chest radiograph is still compatible with the diagnosis if other characteristic findings are present Computed tomography (CT) provides the most reliable view of the mediastinal anatomy The diagnosis of SVCS requires diminished or absent opacification of central venous structures with prominent collateral venous circulation Magnetic resonance imaging (MRI) has no advantages over CT Invasive procedures, including bronchoscopy, percutaneous needle biopsy, mediastinoscopy, and even thoracotomy, can be performed by a skilled clinician without any major risk of bleeding Endobronchial or esophageal ultrasoundguided needle aspiration may establish the diagnosis safely For patients with a known cancer, a detailed workup usually is not necessary, and appropriate treatment may be started after obtaining a CT scan of the thorax For those with no history of malignancy, a detailed evaluation is essential to rule out benign causes and determine a specific diagnosis to direct the appropriate therapy TREATMENT Superior Vena Cava Syndrome The one potentially life-threatening complication of a superior mediastinal mass is tracheal obstruction Upper airway obstruction demands emergent therapy Diuretics with a low-salt diet, head elevation, and oxygen may produce temporary symptomatic relief Glucocorticoids may be useful at shrinking lymphoma masses; they are of no benefit in patients with lung cancer Radiation therapy is the primary treatment for SVCS caused by non-small-cell lung cancer and other metastatic solid tumors Chemotherapy is effective when the underlying cancer is small-cell HPIM19_Part12_p1729-p1798.indd 1788 carcinoma of the lung, lymphoma, or germ cell tumor SVCS recurs in 10–30% of patients; it may be palliated with the use of intravascular self-expanding stents (Fig 331-1) Early stenting may be necessary in patients with severe symptoms; however, the prompt increase in venous return after stenting may precipitate heart failure and pulmonary edema Other complications of stent placement include hematoma at the insertion site, SVC perforation, stent migration in the right ventricle, stent fracture, and pulmonary embolism Surgery may provide immediate relief for patients in whom a benign process is the cause Clinical improvement occurs in most patients, although this improvement may be due to the development of adequate collateral circulation The mortality associated with SVCS does not relate to caval obstruction but rather to the underlying cause SVCS AND CENTRAL VENOUS CATHETERS IN ADULTS The use of long-term central venous catheters has become common practice in patients with cancer Major vessel thrombosis may occur In these cases, catheter removal should be combined with anticoagulation to prevent embolization SVCS in this setting, if detected early, can be treated by fibrinolytic therapy without sacrificing the catheter The routine use of low-dose warfarin or low-molecularweight heparin to prevent thrombosis related to permanent central venous access catheters in cancer patients is not recommended PERICARDIAL EFFUSION/TAMPONADE Malignant pericardial disease is found at autopsy in 5–10% of patients with cancer, most frequently with lung cancer, breast cancer, leukemias, and lymphomas Cardiac tamponade as the initial presentation of extrathoracic malignancy is rare The origin is not malignancy in about 50% of cancer patients with symptomatic pericardial disease, but it can be related to irradiation, drug-induced pericarditis, hypothyroidism, idiopathic pericarditis, infection, or autoimmune diseases Two types of radiation pericarditis occur: an acute inflammatory, effusive pericarditis occurring within months of irradiation, which usually resolves spontaneously, and a chronic effusive pericarditis that may appear up to 20 years after radiation therapy and is accompanied by a thickened pericardium Most patients with pericardial metastasis are asymptomatic However, the common symptoms are dyspnea, cough, chest pain, orthopnea, and weakness Pleural effusion, sinus tachycardia, jugular venous distention, hepatomegaly, peripheral edema, and cyanosis are the most frequent physical findings Relatively specific diagnostic findings, such as paradoxical pulse, diminished heart sounds, pulsus alternans (pulse waves alternating between those of greater and lesser amplitude with successive beats), and friction rub are less common than with nonmalignant pericardial disease Chest radiographs and electrocardiogram (ECG) reveal abnormalities in 90% of patients, but half of these abnormalities are nonspecific Echocardiography is the most helpful diagnostic test Pericardial fluid may be serous, serosanguineous, or hemorrhagic, and cytologic examination of pericardial fluid is diagnostic in most patients Measurements of tumor markers in the pericardial fluid are not helpful in the diagnosis of malignant pericardial fluid Pericardioscopy (not widely available) with targeted pericardial and epicardial biopsy may differentiate neoplastic and benign pericardial disease A combination of cytology, pericardial and epicardial biopsy, and guided pericardioscopy gives the best diagnostic yield CT scan findings of irregular pericardial thickening and mediastinal lymphadenopathy suggest this is a malignant pericardial effusion Cancer patients with pericardial effusion containing malignant cells on cytology have a very poor survival, about weeks TREATMENT Pericardial Effusion/Tamponade Pericardiocentesis with or without the introduction of sclerosing agents, the creation of a pericardial window, complete pericardial stripping, cardiac irradiation, or systemic chemotherapy are effective treatments Acute pericardial tamponade with life-threatening hemodynamic instability requires immediate drainage of fluid This 2/9/15 3:34 PM can be quickly achieved by pericardiocentesis The recurrence rate 1789 after percutaneous catheter drainage is about 20% Sclerotherapy (pericardial instillation of bleomycin, mitomycin C, or tetracycline) may decrease recurrences Alternatively, subxiphoid pericardiotomy can be performed in 45 under local anesthesia Thoracoscopic pericardial fenestration can be employed for benign causes; however, 60% of malignant pericardial effusions recur after this procedure In a subset of patients, drainage of the pericardial effusion is paradoxically followed by worsening hemodynamic instability This so-called “postoperative low cardiac output syndrome” occurs in up to 10% of patients undergoing surgical drainage and carries poor short-term survival A C Figure 331–1  Superior vena cava syndrome (SVCS) A Chest radiographs of a 59-year-old man with recurrent SVCS caused by non-small-cell lung cancer showing right paratracheal mass with right pleural effusion B Computed tomography of same patient demonstrating obstruction of the superior vena cava with thrombosis (arrow) by the lung cancer (square) and collaterals (arrowheads) C Balloon angioplasty (arrowhead) with Wallstent (arrow) in same patient HPIM19_Part12_p1729-p1798.indd 1789 TREATMENT CHAPTER 331 Oncologic Emergencies B INTESTINAL OBSTRUCTION Intestinal obstruction and reobstruction are common problems in patients with advanced cancer, particularly colorectal or ovarian carcinoma However, other cancers, such as lung or breast cancer and melanoma, can metastasize within the abdomen, leading to intestinal obstruction Metastatic disease from colorectal, ovarian, pancreatic, gastric, and occasionally breast cancer can lead to peritoneal carcinomatosis, with infiltration of the omentum and peritoneal surface, thus limiting bowel motility Typically, obstruction occurs at multiple sites in peritoneal carcinomatosis Melanoma has a predilection to involve the small bowel; this involvement may be isolated, and resection may result in prolonged survival Intestinal pseudoobstruction is caused by infiltration of the mesentery or bowel muscle by tumor, involvement of the celiac plexus, or paraneoplastic neuropathy in patients with small-cell lung cancer Paraneoplastic neuropathy is associated with IgG antibodies reactive to neurons of the myenteric and submucosal plexuses of the jejunum and stomach Ovarian cancer can lead to authentic luminal obstruction or to pseudoobstruction that results when circumferential invasion of a bowel segment arrests the forward progression of peristaltic contractions The onset of obstruction is usually insidious Pain is the most common symptom and is usually colicky in nature Pain can also be due to abdominal distention, tumor masses, or hepatomegaly Vomiting can be intermittent or continuous Patients with complete obstruction usually have constipation Physical examination may reveal abdominal distention with tympany, ascites, visible peristalsis, high-pitched bowel sounds, and tumor masses Erect plain abdominal films may reveal multiple air-fluid levels and dilation of the small or large bowel Acute cecal dilation to >12–14 cm is considered a surgical emergency because of the high likelihood of rupture CT scan is useful in defining the extent of disease and the exact nature of the obstruction and differentiating benign from malignant causes of obstruction in patients who have undergone surgery for malignancy Malignant obstruction is suggested by a mass at the site of obstruction or prior surgery, adenopathy, or an abrupt transition zone and irregular bowel thickening at the obstruction site Benign obstruction is more likely when CT shows mesenteric vascular changes, a large volume of ascites, or a smooth transition zone and smooth bowel thickening at the obstruction site In challenging patients with obstructive symptoms, particularly low-grade small-bowel obstruction (SBO), CT enteroclysis often can help establish the diagnosis by providing distention of small-bowel loops In this technique, water-soluble contrast is infused through a nasoenteric tube into the duodenum or proximal small bowel followed by CT images The prognosis for the patient with cancer who develops intestinal obstruction is poor; median survival is 3–4 months About 25–30% of patients are found to have intestinal obstruction due to causes other than cancer Adhesions from previous operations are a common benign cause Ileus induced by vinca alkaloids, narcotics, or other drugs is another reversible cause Intestinal Obstruction The management of intestinal obstruction in patients with advanced malignancy depends on the extent of the underlying malignancy, options for further antineoplastic therapy, estimated life expectancy, 2/9/15 3:34 PM 1790 the functional status of the major organs, and the extent of the obstruction The initial management should include surgical evaluation Operation is not always successful and may lead to further complications with a substantial mortality rate (10–20%) Laparoscopy can diagnose and treat malignant bowel obstruction in some cases Selfexpanding metal stents placed in the gastric outlet, duodenum, proximal jejunum, colon, or rectum may palliate obstructive symptoms at those sites without major surgery Patients known to have advanced intraabdominal malignancy should receive a prolonged course of conservative management, including nasogastric decompression Percutaneous endoscopic or surgical gastrostomy tube placement is an option for palliation of nausea and vomiting, the so-called “venting gastrostomy.” Treatment with antiemetics, antispasmodics, and analgesics may allow patients to remain outside the hospital Octreotide may relieve obstructive symptoms through its inhibitory effect on gastrointestinal secretion Glucocorticoids have anti-inflammatory effects and may help the resolution of bowel obstruction They also have antiemetic effects PART 12 Critical Care Medicine URINARY OBSTRUCTION Urinary obstruction may occur in patients with prostatic or gynecologic malignancies, particularly cervical carcinoma; metastatic disease from other primary sites such as carcinomas of the breast, stomach, lung, colon, and pancreas; or lymphomas Radiation therapy to pelvic tumors may cause fibrosis and subsequent ureteral obstruction Bladder outlet obstruction is usually due to prostate and cervical cancers and may lead to bilateral hydronephrosis and renal failure Flank pain is the most common symptom Persistent urinary tract infection, persistent proteinuria, or hematuria in patients with cancer should raise suspicion of ureteral obstruction Total anuria and/or anuria alternating with polyuria may occur A slow, continuous rise in the serum creatinine level necessitates immediate evaluation Renal ultrasound is the safest and cheapest way to identify hydronephrosis The function of an obstructed kidney can be evaluated by a nuclear scan CT scan can reveal the point of obstruction and identify a retroperitoneal mass or adenopathy TREATMENT Urinary Obstruction Obstruction associated with flank pain, sepsis, or fistula formation is an indication for immediate palliative urinary diversion Internal ureteral stents can be placed under local anesthesia Percutaneous nephrostomy offers an alternative approach for drainage The placement of a nephrostomy is associated with a significant rate of pyelonephritis In the case of bladder outlet obstruction due to malignancy, a suprapubic cystostomy can be used for urinary drainage An aggressive intervention with invasive approaches to improve the obstruction should be weighed against the likelihood of antitumor response, and the ability to reverse renal insufficiency should be evaluated MALIGNANT BILIARY OBSTRUCTION This common clinical problem can be caused by a primary carcinoma arising in the pancreas, ampulla of Vater, bile duct, or liver or by metastatic disease to the periductal lymph nodes or liver parenchyma The most common metastatic tumors causing biliary obstruction are gastric, colon, breast, and lung cancers Jaundice, light-colored stools, dark urine, pruritus, and weight loss due to malabsorption are usual symptoms Pain and secondary infection are uncommon in malignant biliary obstruction Ultrasound, CT scan, or percutaneous transhepatic or endoscopic retrograde cholangiography will identify the site and nature of the biliary obstruction TREATMENT Malignant Biliary Obstruction Palliative intervention is indicated only in patients with disabling pruritus resistant to medical treatment, severe malabsorption, or infection Stenting under radiographic control, surgical bypass, HPIM19_Part12_p1729-p1798.indd 1790 or radiation therapy with or without chemotherapy may alleviate the obstruction The choice of therapy should be based on the site of obstruction (proximal vs distal), the type of tumor (sensitive to radiotherapy, chemotherapy, or neither), and the general condition of the patient In the absence of pruritus, biliary obstruction may be a largely asymptomatic cause of death SPINAL CORD COMPRESSION Malignant spinal cord compression (MSCC) is defined as compression of the spinal cord and/or cauda equina by an extradural tumor mass The minimum radiologic evidence for cord compression is indentation of the theca at the level of clinical features Spinal cord compression occurs in 5–10% of patients with cancer Epidural tumor is the first manifestation of malignancy in about 10% of patients The underlying cancer is usually identified during the initial evaluation; lung cancer is the most common cause of MSCC Metastatic tumor involves the vertebral column more often than any other part of the bony skeleton Lung, breast, and prostate cancer are the most frequent offenders Multiple myeloma also has a high incidence of spine involvement Lymphomas, melanoma, renal cell cancer, and genitourinary cancers also cause cord compression The thoracic spine is the most common site (70%), followed by the lumbosacral spine (20%) and the cervical spine (10%) Involvement of multiple sites is most frequent in patients with breast and prostate carcinoma Cord injury develops when metastases to the vertebral body or pedicle enlarge and compress the underlying dura Another cause of cord compression is direct extension of a paravertebral lesion through the intervertebral foramen These cases usually involve a lymphoma, myeloma, or pediatric neoplasm Parenchymal spinal cord metastasis due to hematogenous spread is rare Intramedullary metastases can be seen in lung cancer, breast cancer, renal cancer, melanoma, and lymphoma and are frequently associated with brain metastases and leptomeningeal disease Expanding extradural tumors induce injury through several mechanisms Obstruction of the epidural venous plexus leads to edema Local production of inflammatory cytokines enhances blood flow and edema formation Compression compromises blood flow, leading to ischemia Production of vascular endothelial growth factor is associated with spinal cord hypoxia and has been implicated as a potential cause of damage after spinal cord injury The most common initial symptom in patients with spinal cord compression is localized back pain and tenderness due to involvement of vertebrae by tumor Pain is usually present for days or months before other neurologic findings appear It is exacerbated by movement and by coughing or sneezing It can be differentiated from the pain of disk disease by the fact that it worsens when the patient is supine Radicular pain is less common than localized back pain and usually develops later Radicular pain in the cervical or lumbosacral areas may be unilateral or bilateral Radicular pain from the thoracic roots is often bilateral and is described by patients as a feeling of tight, band-like constriction around the thorax and abdomen Typical cervical radicular pain radiates down the arm; in the lumbar region, the radiation is down the legs Lhermitte’s sign, a tingling or electric sensation down the back and upper and lower limbs upon flexing or extending the neck, may be an early sign of cord compression Loss of bowel or bladder control may be the presenting symptom but usually occurs late in the course Occasionally patients present with ataxia of gait without motor and sensory involvement due to involvement of the spinocerebellar tract On physical examination, pain induced by straight leg raising, neck flexion, or vertebral percussion may help to determine the level of cord compression Patients develop numbness and paresthesias in the extremities or trunk Loss of sensibility to pinprick is as common as loss of sensibility to vibration or position The upper limit of the zone of sensory loss is often one or two vertebrae below the site of compression Motor findings include weakness, spasticity, and abnormal muscle stretching An extensor plantar reflex reflects significant compression Deep tendon reflexes may be brisk Motor and sensory loss usually precedes sphincter disturbance Patients with autonomic dysfunction may present with decreased anal tonus, decreased perineal sensibility, 2/9/15 3:34 PM older patients and postmenopausal women, are due not to cancer but 1791 to osteoporosis Also, a normal appearance on plain films of the spine does not exclude the diagnosis of cancer The role of bone scans in the detection of cord compression is not clear; this method is sensitive but less specific than spinal radiography The full-length image of the cord provided by MRI is the imaging procedure of choice Multiple epidural metastases are noted in 25% of patients with cord compression, and their presence influences treatment plans On T1-weighted images, good contrast is noted between the cord, cerebrospinal fluid, and extradural lesions Owing to its sensitivity in demonstrating the replacement of bone marrow by tumor, MRI can show which parts of a vertebra are involved by tumor MRI also visualizes intraspinal extradural masses compressing the cord T2-weighted images are most useful for the demonstration of intramedullary pathology Gadolinium-enhanced MRI can help to delineate intramedullary disease MRI is as good as or better than myelography plus postmyelogram CT scan in detecting metastatic epidural disease with cord compression Myelography should be reserved for patients who have poor MRIs or who cannot undergo MRI promptly CT scan in conjunction with myelography enhances the detection of small areas of spinal destruction In patients with cord compression and an unknown primary tumor, a simple workup including chest radiography, mammography, measurement of prostate-specific antigen, and abdominal CT usually reveals the underlying malignancy TREATMENT Spinal Cord Compression The treatment of patients with spinal cord compression is aimed at relief of pain and restoration/preservation of neurologic function (Fig 331-2) Management of MSCC requires a multidisciplinary approach Back pain Neurologic exam Suspicious for myelopathy Normal Plain spine x-ray Normal Pain crescendo pattern Lhermitte’s sign Pain aggravated with cough, Valsalva, and recumbency Symptomatic therapy Abnormal High-dose dexamethasone CHAPTER 331 Oncologic Emergencies and a distended bladder The absence of the anal wink reflex or the bulbocavernosus reflex confirms cord involvement In doubtful cases, evaluation of postvoiding urinary residual volume can be helpful A residual volume of >150 mL suggests bladder dysfunction Autonomic dysfunction is an unfavorable prognostic factor Patients with progressive neurologic symptoms should have frequent neurologic examinations and rapid therapeutic intervention Other illnesses that may mimic cord compression include osteoporotic vertebral collapse, disk disease, pyogenic abscess or vertebral tuberculosis, radiation myelopathy, neoplastic leptomeningitis, benign tumors, epidural hematoma, and spinal lipomatosis Cauda equina syndrome is characterized by low back pain; diminished sensation over the buttocks, posterior-superior thighs, and perineal area in a saddle distribution; rectal and bladder dysfunction; sexual impotence; absent bulbocavernous, patellar, and Achilles’ reflexes; and variable amount of lower-extremity weakness This reflects compression of nerve roots as they form the cauda equina after leaving the spinal cord The majority of cauda equine tumors are primary tumors of glial or nerve sheath origin; metastases are very rare Patients with cancer who develop back pain should be evaluated for spinal cord compression as quickly as possible (Fig 331-2) Treatment is more often successful in patients who are ambulatory and still have sphincter control at the time treatment is initiated Patients should have a neurologic examination and plain films of the spine Those whose physical examination suggests cord compression should receive dexamethasone (6 mg intravenously every h), starting immediately Erosion of the pedicles (the “winking owl” sign) is the earliest radiologic finding of vertebral tumor Other radiographic changes include increased intrapedicular distance, vertebral destruction, lytic or sclerotic lesions, scalloped vertebral bodies, and vertebral body collapse Vertebral collapse is not a reliable indicator of the presence of tumor; about 20% of cases of vertebral collapse, particularly those in MRI of spine Epidural metastases No metastases Surgery followed by radiation therapy or radiation therapy alone Symptomatic therapy Bone metastases but no epidural metastases Symptomatic therapy ± radiation therapy Figure 331-2  Management of cancer patients with back pain HPIM19_Part12_p1729-p1798.indd 1791 2/9/15 3:34 PM 1792 PART 12 Critical Care Medicine Radiation therapy plus glucocorticoids is generally the initial treatment of choice for most patients with spinal cord compression Up to 75% of patients treated when still ambulatory remain ambulatory, but only 10% of patients with paraplegia recover walking capacity Indications for surgical intervention include unknown etiology, failure of radiation therapy, a radioresistant tumor type (e.g., melanoma or renal cell cancer), pathologic fracture dislocation, and rapidly evolving neurologic symptoms Laminectomy is done for tissue diagnosis and for the removal of posteriorly localized epidural deposits in the absence of vertebral body disease Because most cases of epidural spinal cord compression are due to anterior or anterolateral extradural disease, resection of the anterior vertebral body along with the tumor, followed by spinal stabilization, has achieved good results A randomized trial showed that patients who underwent an operation followed by radiotherapy (within 14 days) retained the ability to walk significantly longer than those treated with radiotherapy alone Surgically treated patients also maintained continence and neurologic function significantly longer than patients in the radiation group The length of survival was not significantly different in the two groups, although there was a trend toward longer survival in the surgery group The study drew some criticism for the poorer than expected results in the patients who did not go to surgery The benefit of surgery over radiotherapy decreased in patients over age 65 years However, patients should be evaluated for surgery if they are expected to survive longer than months Conventional radiotherapy has a role after surgery Chemotherapy may have a role in patients with chemosensitive tumors who have had prior radiotherapy to the same region and who are not candidates for surgery Most patients with prostate cancer who develop cord compression have already had hormonal therapy; however, for those who have not, androgen deprivation is combined with surgery and radiotherapy Patients who previously received radiotherapy for MSCC with an in-field tumor progression can be treated with reirradiation if they are not surgical candidates Patients with metastatic vertebral tumors may benefit from percutaneous vertebroplasty or kyphoplasty, the injection of acrylic cement into a collapsed vertebra to stabilize the fracture Pain palliation is common, and local antitumor effects have been noted Cement leakage may cause symptoms in about 10% of patients Bisphosphonates may be helpful in prevention of SCC in patients with bony involvement The histology of the tumor is an important determinant of both recovery and survival Rapid onset and progression of signs and symptoms are poor prognostic features INCREASED INTRACRANIAL PRESSURE About 25% of patients with cancer die with intracranial metastases The cancers that most often metastasize to the brain are lung and breast cancers and melanoma Brain metastases often occur in the presence of systemic disease, and they frequently cause major symptoms, disability, and early death The initial presentation of brain metastases from a previously unknown primary cancer is common Lung cancer is most commonly the primary malignancy Chest/ abdomen CT scans and brain MRI as the initial diagnostic studies can identify a biopsy site in most patients The signs and symptoms of a metastatic brain tumor are similar to those of other intracranial expanding lesions: headache, nausea, vomiting, behavioral changes, seizures, and focal, progressive neurologic changes Occasionally the onset is abrupt, resembling a stroke, with the sudden appearance of headache, nausea, vomiting, and neurologic deficits This picture is usually due to hemorrhage into the metastasis Melanoma, germ cell tumors, and renal cell cancers have a particularly high incidence of intracranial bleeding The tumor mass and surrounding edema may cause obstruction of the circulation of cerebrospinal fluid, with resulting hydrocephalus Patients with increased intracranial pressure may have papilledema with visual disturbances and neck stiffness As the mass enlarges, brain tissue may be displaced HPIM19_Part12_p1729-p1798.indd 1792 through the fixed cranial openings, producing various herniation syndromes CT scan and MRI are equally effective in the diagnosis of brain metastases CT scan with contrast should be used as a screening procedure The CT scan shows brain metastases as multiple enhancing lesions of various sizes with surrounding areas of low-density edema If a single lesion or no metastases are visualized by contrast-enhanced CT, MRI of the brain should be performed Gadolinium-enhanced MRI is more sensitive than CT at revealing meningeal involvement and small lesions, particularly in the brainstem or cerebellum Intracranial hypertension (“pseudotumor cerebri”) secondary to tretinoin therapy has been reported TREATMENT Increased Intracranial Pressure Dexamethasone is the best initial treatment for all symptomatic patients with brain metastases Patients with multiple lesions should usually receive whole-brain radiation Patients with a single brain metastasis and with controlled extracranial disease may be treated with surgical excision followed by whole-brain radiation therapy, especially if they are younger than 60 years Radioresistant tumors should be resected if possible Stereotactic radiosurgery (SRS) is recommended in patients with a limited number of brain metastases (one to four) who have stable, systemic disease or reasonable systemic treatment options and for patients who have a small number of metastatic lesions in whom whole-brain radiation therapy has failed With a gamma knife or linear accelerator, multiple small, wellcollimated beams of ionizing radiation destroy lesions seen on MRI Some patients with increased intracranial pressure associated with hydrocephalus may benefit from shunt placement If neurologic deterioration is not reversed with medical therapy, ventriculotomy to remove cerebrospinal fluid (CSF) or craniotomy to remove tumors or hematomas may be necessary NEOPLASTIC MENINGITIS Tumor involving the leptomeninges is a complication of both primary central nervous system (CNS) tumors and tumors that metastasize to the CNS The incidence is estimated at 3–8% of patients with cancer Melanoma, breast and lung cancer, lymphoma (including AIDS-associated), and acute leukemia are the most common causes Synchronous intraparenchymal brain metastases are evident in 11–31% of patients with neoplastic meningitis Leptomeningeal seeding is frequent in patients undergoing resection of brain metastases or receiving stereotactic radiotherapy for brain metastases Patients typically present with multifocal neurologic signs and symptoms, including headache, gait abnormality, mental changes, nausea, vomiting, seizures, back or radicular pain, and limb weakness Signs include cranial nerve palsies, extremity weakness, paresthesia, and decreased deep tendon reflexes Diagnosis is made by demonstrating malignant cells in the CSF; however, up to 40% of patients may have false-negative CSF cytology An elevated CSF protein level is nearly always present (except in HTLV-1–associated adult T cell leukemia) Patients with neurologic signs and symptoms consistent with neoplastic meningitis who have a negative CSF cytology but an elevated CSF protein level should have the spinal tap repeated at least three times for cytologic examination before the diagnosis is rejected MRI findings suggestive of neoplastic meningitis include leptomeningeal, subependymal, dural, or cranial nerve enhancement; superficial cerebral lesions; intradural nodules; and communicating hydrocephalus Spinal cord imaging by MRI is a necessary component of the evaluation of nonleukemia neoplastic meningitis because ~20% of patients have cord abnormalities, including intradural enhancing nodules that are diagnostic for leptomeningeal involvement Cauda equina lesions are common, but lesions may be seen anywhere in the spinal canal The value of MRI for the diagnosis of leptomeningeal disease is limited in patients with hematopoietic malignancy Radiolabeled CSF flow studies are abnormal in up to 70% of patients with neoplastic meningitis; ventricular outlet 2/9/15 3:34 PM obstruction, abnormal flow in the spinal canal, or impaired flow over the cerebral convexities may affect distribution of intrathecal chemotherapy, resulting in decreased efficacy or increased toxicity Radiation therapy may correct CSF flow abnormalities before use of intrathecal chemotherapy Neoplastic meningitis can also lead to intracranial hypertension and hydrocephalus Placement of a ventriculoperitoneal shunt may effectively palliate symptoms in these patients The development of neoplastic meningitis usually occurs in the setting of uncontrolled cancer outside the CNS; thus, prognosis is poor (median survival 10–12 weeks) However, treatment of the neoplastic meningitis may successfully alleviate symptoms and control the CNS spread TREATMENT Neoplastic Meningitis Intrathecal chemotherapy, usually methotrexate, cytarabine, or thiotepa, is delivered by lumbar puncture or by an intraventricular reservoir (Ommaya) An extended-release preparation of cytarabine (Depocyte) has a longer half-life and is more effective than other formulations Among solid tumors, breast cancer responds best to therapy Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) may be effective in non-small-cell lung cancer patients with EGFR mutations and leptomeningeal involvement Patients with neoplastic meningitis from either acute leukemia or lymphoma may be cured of their CNS disease if the systemic disease can be eliminated TREATMENT Seizures Patients in whom seizures due to CNS metastases have been demonstrated should receive anticonvulsive treatment with phenytoin or levetiracetam If this is not effective, valproic acid can be added Prophylactic anticonvulsant therapy is not recommended In postcraniotomy patients, prophylactic antiepileptic drugs should be withdrawn during the first week after surgery Most antiseizure medications including phenytoin induce cytochrome P450 (CYP450), which alters the metabolism of many antitumor agents, HPIM19_Part12_p1729-p1798.indd 1793 PULMONARY AND INTRACEREBRAL LEUKOSTASIS Hyperleukocytosis and the leukostasis syndrome associated with it is a potentially fatal complication of acute leukemia (particularly myeloid leukemia) that can occur when the peripheral blast cell count is >100,000/mL The frequency of hyperleukocytosis is 5–13% in acute myeloid leukemia (AML) and 10–30% in acute lymphoid leukemia; however, leukostasis is rare in lymphoid leukemia At such high blast cell counts, blood viscosity is increased, blood flow is slowed by aggregates of tumor cells, and the primitive myeloid leukemic cells are capable of invading through the endothelium and causing hemorrhage Brain and lung are most commonly affected Patients with brain leukostasis may experience stupor, headache, dizziness, tinnitus, visual disturbances, ataxia, confusion, coma, or sudden death On examination, papilledema, retinal vein distension, retinal hemorrhages, and focal deficit may be present Administration of 600 cGy of whole-brain irradiation can protect against this complication and can be followed by rapid institution of antileukemic therapy Hydroxyurea, 3–5 g, can rapidly reduce a high blast cell count while the accurate diagnostic workup is in progress Pulmonary leukostasis may present as respiratory distress and hypoxemia, and progress to respiratory failure Chest radiographs may be normal but usually show interstitial or alveolar infiltrates Hyperleukocytosis rarely may cause acute leg ischemia, renal vein thrombosis, myocardial ischemia, bowel infraction, and priapism Arterial blood gas results should be interpreted cautiously Rapid consumption of plasma oxygen by the markedly increased number of white blood cells can cause spuriously low arterial oxygen tension Pulse oximetry is the most accurate way of assessing oxygenation in patients with hyperleukocytosis Leukapheresis may be helpful in decreasing circulating blast counts Treatment of the leukemia can result in pulmonary hemorrhage from lysis of blasts in the lung, called leukemic cell lysis pneumopathy Intravascular volume depletion and unnecessary blood transfusions may increase blood viscosity and worsen the leukostasis syndrome Leukostasis is very rarely a feature of the high white cell counts associated with chronic lymphoid or chronic myeloid leukemia When acute promyelocytic leukemia is treated with differentiating agents like tretinoin and arsenic trioxide, cerebral or pulmonary leukostasis may occur as tumor cells differentiate into mature neutrophils This complication can be largely avoided by using cytotoxic chemotherapy or arsenic together with the differentiating agents CHAPTER 331 Oncologic Emergencies SEIZURES Seizures occurring in a patient with cancer can be caused by the tumor itself, by metabolic disturbances, by radiation injury, by cerebral infarctions, by chemotherapy-related encephalopathies, or by CNS infections Metastatic disease to the CNS is the most common cause of seizures in patients with cancer However, seizures occur more frequently in primary brain tumors than in metastatic brain lesions Seizures are a presenting symptom of CNS metastasis in 6–29% of cases Approximately 10% of patients with CNS metastasis eventually develop seizures Tumors that affect the frontal, temporal, and parietal lobes are more commonly associated with seizures than are occipital lesions The presence of frontal lesions correlates with early seizures, and the presence of hemispheric symptoms increases the risk for late seizures Both early and late seizures are uncommon in patients with posterior fossa and sellar lesions Seizures are common in patients with CNS metastases from melanoma and low-grade primary brain tumors Very rarely, cytotoxic drugs such as etoposide, busulfan, ifosfamide, and chlorambucil cause seizures Another cause of seizures related to drug therapy is reversible posterior leukoencephalopathy syndrome (RPLS) RPLS is associated rarely with administration of cisplatin, 5-fluorouracil, bleomycin, vinblastine, vincristine, etoposide, paclitaxel, ifosfamide, cyclophosphamide, doxorubicin, cytarabine, methotrexate, oxaliplatin, cyclosporine, tacrolimus, and vascular endothelial growth factor inhibitors including bevacizumab, aflibercept, sunitinib, sorafenib, pazopanib, and axitinib RPLS occurs in patients undergoing allogeneic bone marrow or solid-organ transplantation RPLS is characterized by headache, altered consciousness, generalized seizures, visual disturbances, hypertension, and posterior cerebral white matter vasogenic edema on CT/MRI Seizures may begin focally but are typically generalized including irinotecan, taxanes, and etoposide as well as molecular 1793 targeted agents, including imatinib, gefitinib, erlotinib, tipifarnib, sorafenib, sunitinib, temsirolimus, everolimus, and vemurafenib Levetiracetam and topiramate are anticonvulsant agents not metabolized by the hepatic CYP450 system and not alter the metabolism of antitumor agents They have become the preferred drugs Surgical resection and other antitumor treatments such as radiotherapy and chemotherapy may improve seizure control HEMOPTYSIS Hemoptysis may be caused by nonmalignant conditions, but lung cancer accounts for a large proportion of cases Up to 20% of patients with lung cancer have hemoptysis some time in their course Endobronchial metastases from carcinoid tumors, breast cancer, colon cancer, kidney cancer, and melanoma may also cause hemoptysis The volume of bleeding is often difficult to gauge Massive hemoptysis is defined as >200–600 mL of blood produced in 24 h However, any hemoptysis should be considered massive if it threatens life When respiratory difficulty occurs, hemoptysis should be treated emergently The first priorities are to maintain the airway, optimize oxygenation, and stabilize the hemodynamic status If the bleeding side is known, the patient should be placed in a lateral decubitus position, with the bleeding side down to prevent aspiration into the unaffected lung, and given supplemental oxygen If large-volume bleeding continues or the airway is compromised, the patient should be intubated and undergo emergency bronchoscopy If the site of bleeding is detected, either the patient undergoes a definitive surgical procedure or the lesion is treated with a neodymium:yttrium-aluminum-garnet (Nd:YAG) laser, argon plasma coagulation, or electrocautery In stable 2/9/15 3:34 PM 1794 patients, multidetector CT angiography delineates bronchial and non- PART 12 bronchial systemic arteries and identifies the source of bleeding and underlying pathology with high sensitivity Massive hemoptysis usually originates from the high-pressure bronchial circulation Bronchial artery embolization is considered a first-line definite procedure for managing hemoptysis Bronchial artery embolization may control brisk bleeding in 75–90% of patients, permitting the definitive surgical procedure to be done more safely Embolization without definitive surgery is associated with rebleeding in 20–50% of patients Recurrent hemoptysis usually responds to a second embolization procedure A postembolization syndrome characterized by pleuritic pain, fever, dysphagia, and leukocytosis may occur; it lasts 5–7 days and resolves with symptomatic treatment Bronchial or esophageal wall necrosis, myocardial infarction, and spinal cord infarction are rare complications Surgery, as a salvage strategy, is indicated after failure of embolization and is associated with better survival when performed in a nonurgent setting Pulmonary hemorrhage with or without hemoptysis in hematologic malignancies is often associated with fungal infections, particularly Aspergillus sp After granulocytopenia resolves, the lung infiltrates in aspergillosis may cavitate and cause massive hemoptysis Thrombocytopenia and coagulation defects should be corrected, if possible Surgical evaluation is recommended in patients with aspergillosis-related cavitary lesions Bevacizumab, an antibody to vascular endothelial growth factor (VEGF) that inhibits angiogenesis, has been associated with lifethreatening hemoptysis in patients with non-small-cell lung cancer, particularly of squamous cell histology Non-small-cell lung cancer patients with cavitary lesions or previous hemoptysis (≥2.5 mL) within the past months have higher risk for pulmonary hemorrhage Critical Care Medicine AIRWAY OBSTRUCTION Airway obstruction refers to a blockage at the level of the mainstem bronchi or above It may result either from intraluminal tumor growth or from extrinsic compression of the airway The most common cause of malignant upper airway obstruction is invasion from an adjacent primary tumor, most commonly lung cancer, followed by esophageal, thyroid, and mediastinal malignancies including lymphomas Extrathoracic primary tumors such as renal, colon, or breast cancer can cause airway obstruction through endobronchial and/or mediastinal lymph node metastases Patients may present with dyspnea, hemoptysis, stridor, wheezing, intractable cough, postobstructive pneumonia, or hoarseness Chest radiographs usually demonstrate obstructing lesions CT scans reveal the extent of tumor Cool, humidified oxygen, glucocorticoids, and ventilation with a mixture of helium and oxygen (Heliox) may provide temporary relief If the obstruction is proximal to the larynx, a tracheostomy may be lifesaving For more distal obstructions, particularly intrinsic lesions incompletely obstructing the airway, bronchoscopy with mechanical debulking and dilatation or ablational treatments including laser treatment, photodynamic therapy, argon plasma coagulation, electrocautery, or stenting can produce immediate relief in most patients (Fig 331-3) However, radiation therapy (either external-beam irradiation or brachytherapy) given together with glucocorticoids may also open the airway Symptomatic extrinsic compression may be palliated by stenting Patients with primary airway tumors such as squamous cell carcinoma, carcinoid tumor, adenocystic carcinoma, or non-small-cell lung cancer, if resectable, should have surgery Figure 331-3  Airway obstruction A Computed tomography scan of a 62-year-old man with tracheal obstruction caused by renal carcinoma showing paratracheal mass with tracheal invasion/obstruction (arrow) B Chest x-ray of same patient after stent (arrows) placement HYPERCALCEMIA Hypercalcemia is the most common paraneoplastic syndrome Its pathogenesis and management are discussed fully in Chaps 121 and 424 LACTIC ACIDOSIS Lactic acidosis is a rare and potentially fatal metabolic complication of cancer Lactic acidosis associated with sepsis and circulatory failure is a common preterminal event in many malignancies Lactic acidosis in the absence of hypoxemia may occur in patients with leukemia, lymphoma, or solid tumors In some cases, hypoglycemia also is present Extensive involvement of the liver by tumor is often present In most cases, decreased metabolism and increased production by the tumor both contribute to lactate accumulation Tumor cell overexpression of certain glycolytic enzymes and mitochondrial dysfunction can contribute to its increased lactate production HIV-infected patients have an increased risk of aggressive lymphoma; lactic acidosis that occurs in such patients may be related either to the rapid growth of the tumor or from toxicity of nucleoside reverse transcriptase inhibitors Symptoms of lactic acidosis include tachypnea, tachycardia, change of mental status, and hepatomegaly The serum level of lactic acid may reach 10–20 mmol/L (90–180 mg/dL) Treatment is aimed at the underlying disease The danger from lactic acidosis is from the acidosis, not the lactate Sodium bicarbonate should be added if acidosis is very severe or if hydrogen ion production is very rapid and uncontrolled Other treatment options include renal replacement therapy, such as hemodialysis, and thiamine replacement The prognosis is poor regardless of the treatment offered SYNDROME OF INAPPROPRIATE SECRETION OF ANTIDIURETIC HORMONE (SIADH) Hyponatremia is a common electrolyte abnormality in cancer patients, and SIADH is the most common cause among patients with cancer SIADH is discussed fully in Chaps 121 and 401e HYPOGLYCEMIA Persistent hypoglycemia is occasionally associated with tumors other than pancreatic islet cell tumors Usually these tumors are large; tumors of mesenchymal origin, hepatomas, or adrenocortical tumors METABOLIC EMERGENCIES HPIM19_Part12_p1729-p1798.indd 1794 2/9/15 3:34 PM may cause hypoglycemia Mesenchymal tumors are usually located in the retroperitoneum or thorax Obtundation, confusion, and behavioral aberrations occur in the postabsorptive period and may precede the diagnosis of the tumor These tumors often secrete incompletely processed insulin-like growth factor II (IGF-II), a hormone capable of activating insulin receptors and causing hypoglycemia Tumors secreting incompletely processed big IGF-II are characterized by an increased IGF-II to IGF-I ratio, suppressed insulin and C-peptide level, and inappropriately low growth hormone and β-hydroxybutyrate concentrations Rarely, hypoglycemia is due to insulin secretion by a non-islet cell carcinoma The development of hepatic dysfunction from liver metastases and increased glucose consumption by the tumor can contribute to hypoglycemia If the tumor cannot be resected, hypoglycemia symptoms may be relieved by the administration of glucose, glucocorticoids, or glucagon Hypoglycemia can be artifactual; hyperleukocytosis from leukemia, myeloproliferative diseases, leukemoid reactions, or colony-stimulating factor treatment can increase glucose consumption in the test tube after blood is drawn, leading to pseudohypoglycemia TREATMENT-RELATED EMERGENCIES TUMOR LYSIS SYNDROME Tumor lysis syndrome (TLS) is characterized by hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia and is caused by the destruction of a large number of rapidly proliferating neoplastic cells Acidosis may also develop Acute renal failure occurs frequently HPIM19_Part12_p1729-p1798.indd 1795 CHAPTER 331 Oncologic Emergencies ADRENAL INSUFFICIENCY In patients with cancer, adrenal insufficiency may go unrecognized because the symptoms, such as nausea, vomiting, anorexia, and orthostatic hypotension, are nonspecific and may be mistakenly attributed to progressive cancer or to therapy Primary adrenal insufficiency may develop owing to replacement of both glands by metastases (lung, breast, colon, or kidney cancer; lymphoma), to removal of both glands, or to hemorrhagic necrosis in association with sepsis or anticoagulation Impaired adrenal steroid synthesis occurs in patients being treated for cancer with mitotane, ketoconazole, or aminoglutethimide or undergoing rapid reduction in glucocorticoid therapy Rarely, metastatic replacement causes primary adrenal insufficiency as the first manifestation of an occult malignancy Metastasis to the pituitary or hypothalamus is found at autopsy in up to 5% of patients with cancer, but associated secondary adrenal insufficiency is rare On the other hand, ipilimumab, an anti-CTLA-4 antibody used for treatment of malignant melanoma, may cause autoimmunity including autoimmune-like enterocolitis, hypophysitis, and hepatitis Autoimmune hypophysitis may present with headache, visual field defects, and pituitary hormone deficiencies manifesting as hypopituitarism, adrenal insufficiency (including adrenal crisis), or hypothyroidism Anti-CTLA-4-associated hypophysitis symptoms occur at an average of 6–12 weeks after initiation of therapy The treatment of severe autoimmune toxicity is glucocorticoids Almost all patients with hypophysitis respond to withdrawal of ipilimumab and glucocorticoid therapy in several days However, pituitary dysfunction may resolve or may be permanent, requiring longterm therapy and thyroid and testosterone replacement Peripheral Addison’s disease can also be observed with anti-CTLA-4 antibodies Megestrol acetate, used to manage cancer and HIV-related cachexia, may suppress plasma levels of cortisol and adrenocorticotropic hormone (ACTH) Patients taking megestrol may develop adrenal insufficiency, and even those whose adrenal dysfunction is not symptomatic may have inadequate adrenal reserve if they become seriously ill Paradoxically, some patients may develop Cushing’s syndrome and/or hyperglycemia because of the glucocorticoid-like activity of megestrol acetate Cranial irradiation for childhood brain tumors may affect the hypothalamus-pituitary-adrenal axis, resulting in secondary adrenal insufficiency Acute adrenal insufficiency is potentially lethal Treatment of suspected adrenal crisis is initiated after the sampling of serum cortisol and ACTH levels (Chap 406) TLS is most often associated with the treatment of Burkitt’s lym- 1795 phoma, acute lymphoblastic leukemia, and other rapidly proliferating lymphomas, but it also may be seen with chronic leukemias and, rarely, with solid tumors This syndrome has been seen in patients with chronic lymphocytic leukemia after treatment with nucleosides like fludarabine TLS has been observed with administration of glucocorticoids, hormonal agents such as letrozole and tamoxifen, and monoclonal antibodies such as rituximab and gemtuzumab TLS usually occurs during or shortly (1–5 days) after chemotherapy Rarely, spontaneous necrosis of malignancies causes TLS Hyperuricemia may be present at the time of chemotherapy Effective treatment kills malignant cells and leads to increased serum uric acid levels from the turnover of nucleic acids Owing to the acidic local environment, uric acid can precipitate in the tubules, medulla, and collecting ducts of the kidney, leading to renal failure Lactic acidosis and dehydration may contribute to the precipitation of uric acid in the renal tubules The finding of uric acid crystals in the urine is strong evidence for uric acid nephropathy The ratio of urinary uric acid to urinary creatinine is >1 in patients with acute hyperuricemic nephropathy and 1500 U/L), both of which correlate with total tumor burden, also correlate with the risk of TLS In patients at risk for TLS, pretreatment evaluations should include a complete blood count, serum chemistry evaluation, and urine analysis High leukocyte and platelet counts may artificially elevate potassium levels (“pseudohyperkalemia”) due to lysis of these cells after the blood is drawn In these cases, plasma potassium instead of serum potassium should be followed In pseudohyperkalemia, no electrocardiographic abnormalities are present In patients with abnormal baseline renal function, the kidneys and retroperitoneal area should be evaluated by sonography and/or CT to rule out obstructive uropathy Urine output should be watched closely TREATMENT Tumor Lysis Syndrome Recognition of risk and prevention are the most important steps in the management of this syndrome (Fig 331-4) The standard preventive approach consists of allopurinol, urinary alkalinization, and aggressive hydration Urinary alkalization with sodium bicarbonate is controversial It increases uric acid solubility, but decreases calcium phosphate solubility If it is used, it should be discontinued when hyperphosphatemia develops Intravenous allopurinol may be given in patients who cannot tolerate oral therapy In some cases, uric acid levels cannot be lowered sufficiently with the standard preventive approach Rasburicase (recombinant urate oxidase) can be effective in these instances, particularly when renal failure is present Urate oxidase is missing from primates and catalyzes the conversion of poorly soluble uric acid to readily soluble allantoin Rasburicase acts rapidly, decreasing uric acid levels within hours; however, it may cause hypersensitivity reactions such as bronchospasm, hypoxemia, and hypotension Rasburicase should also be administered to high-risk patients for TLS prophylaxis Rasburicase is contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency who are unable to break down hydrogen peroxide, an end product of the urate oxidase reaction Rasburicase is known to cause ex vivo enzymatic degradation of uric acid in test tube at room temperature This leads to spuriously low uric acid levels 2/9/15 3:34 PM 1796 PREVENTION AND TREATMENT OF TUMOR LYSIS SYNDROME Maintain hydration by administration of normal or 1/2 normal saline at 3000 mL/m2 per day –/+ Keep urine pH at 7.0 or greater by administration of sodium bicarbonate* Administer allopurinol at 300 mg/m2 per day Monitor serum chemistry If, after 24–48 h Serum uric acid >8 mg/dL Serum creatinine >1.6 mg/dL Correct treatable renal failure (obstruction) Start rasburicase 0.2 mg/kg daily Serum uric acid ≤8.0 mg/dL Serum creatinine ≤1.6 mg/dL Urine pH ≥7.0 monocytes/macrophages and T and B lymphocytes Severe reactions from rituximab have occurred with high numbers (>50 × 109 lymphocytes) of circulating cells bearing the target antigen (CD20) and have been associated with a rapid fall in circulating tumor cells, mild electrolyte evidence of TLS, and very rarely, death In addition, increased liver enzymes, D-dimer, and LDH and prolongation of the prothrombin time may occur Diphenhydramine, hydrocortisone, and acetaminophen can often prevent or suppress the infusion-related symptoms If they occur, the infusion is stopped and restarted at half the initial infusion rate after the symptoms have abated Severe CRS may require intensive support for acute respiratory distress syndrome (ARDS) and resistant hypotension PART 12 Critical Care Medicine HEMOLYTIC-UREMIC SYNDROME Hemolytic-uremic syndrome (HUS) and, less commonly, thrombotic thrombocytopenic purpura (TTP) Serum uric acid >8 mg/dL (Chap 341) may rarely occur after treatment with Serum creatinine >1.6 mg/dL antineoplastic drugs, including mitomycin, gemcitabine, cisplatin, and bleomycin, and with VEGF inhibitors It occurs most often in patients with Delay chemotherapy if Start chemotherapy feasible or start hemodialysis gastric, lung, colorectal, pancreatic, and breast carDiscontinue bicarbonate administration* ± chemotherapy Monitor serum chemistry every 6–12 h cinoma In one series, 35% of patients were without evident cancer at the time this syndrome appeared Secondary HUS/TTP has also been reported as a rare but sometimes fatal complication of bone marrow If serum potassium >6 meq/L transplantation Serum uric acid >10 mg/dL HUS usually has its onset 4–8 weeks after the last Serum creatinine >10 mg/dL dose of chemotherapy, but it is not rare to detect it Serum phosphate >10 mg/dL or increasing Symptomatic hypocalcemia present several months later HUS is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal failure Dyspnea, weakness, fatigue, oliguBegin hemodialysis ria, and purpura are also common initial symptoms and findings Systemic hypertension and pulmonary edema frequently occur Severe hypertension, pulFigure 331-4  Management of patients at high risk for the tumor lysis syndrome monary edema, and rapid worsening of hemoly*See text sis and renal function may occur after a blood or blood product transfusion Cardiac findings include during laboratory monitoring of the patient with TLS Samples atrial arrhythmias, pericardial friction rub, and pericardial effusion must be cooled immediately to deactivate the urate oxidase Despite Raynaud’s phenomenon is part of the syndrome in patients treated aggressive prophylaxis, TLS and/or oliguric or anuric renal failure with bleomycin may occur Care should be taken to prevent worsening of symptomLaboratory findings include severe to moderate anemia associatic hypocalcemia by induction of alkalosis during bicarbonate infu- ated with red blood cell fragmentation and numerous schistocytes sion Administration of sodium bicarbonate may also lead to urinary on peripheral smear Reticulocytosis, decreased plasma haptoglobin, precipitation of calcium phosphate, which is less soluble at alkaline and an LDH level document hemolysis The serum bilirubin level is pH Dialysis is often necessary and should be considered early in the usually normal or slightly elevated The Coombs’ test is negative The course Hemodialysis is preferred Hemofiltration offers a gradual, white cell count is usually normal, and thrombocytopenia (10 mm on ultrasonogram have higher mortality rates However, bowel wall thickening is significantly more prominent in patients with C difficile colitis Pneumatosis intestinalis is a more specific finding, seen only in those with neutropenic enterocolitis and ischemia The combined involvement of the small and large bowel suggests a diagnosis of neutropenic enterocolitis HPIM19_Part12_p1729-p1798.indd 1798 HEMORRHAGIC CYSTITIS Hemorrhagic cystitis can develop in patients receiving cyclophosphamide or ifosfamide Both drugs are metabolized to acrolein, which is a strong chemical irritant that is excreted in the urine Prolonged contact or high concentrations may lead to bladder irritation and hemorrhage Symptoms include gross hematuria, frequency, dysuria, burning, urgency, incontinence, and nocturia The best management is prevention Maintaining a high rate of urine flow minimizes exposure In addition, 2-mercaptoethanesulfonate (mesna) detoxifies the metabolites and can be coadministered with the instigating drugs Mesna usually is given three times on the day of ifosfamide administration in doses that are each 20% of the total ifosfamide dose If hemorrhagic cystitis develops, the maintenance of a high urine flow may be sufficient supportive care If conservative management is not effective, irrigation of the bladder with a 0.37–0.74% formalin solution for 10 stops the bleeding in most cases N-Acetylcysteine may also be an effective irrigant Prostaglandin (carboprost) can inhibit the process In extreme cases, ligation of the hypogastric arteries, urinary diversion, or cystectomy may be necessary Hemorrhagic cystitis also occurs in patients who undergo bone marrow transplantation (BMT) In the BMT setting, early-onset hemorrhagic cystitis is related to drugs in the treatment regimen (e.g., cyclophosphamide), and late-onset hemorrhagic cystitis is usually due to the polyoma virus BKV or adenovirus type 11 BKV load in urine alone or in combination with acute graft-versus-host disease correlates with development of hemorrhagic cystitis Viral causes are usually detected by PCR-based diagnostic tests Treatment of viral hemorrhagic cystitis is largely supportive, with reduction in doses of immunosuppressive agents, if possible No antiviral therapy is approved, although cidofovir is reported to be effective in a small series Hyperbaric oxygen therapy has been used successfully in patients with BKV-associated and cyclophosphamide-induced hemorrhagic cystitis during hematopoietic stem cell transplantation, as well as in hemorrhagic radiation cystitis HYPERSENSITIVITY REACTIONS TO ANTINEOPLASTIC DRUGS Many antineoplastic drugs may cause hypersensitivity reaction These reactions are unpredictable and potentially life-threatening Most reactions occur during or within hours of parenteral drug administration Taxanes, platinum compounds, asparaginase, etoposide, procarbazine, and biologic agents, including rituximab, bevacizumab, trastuzumab, gemtuzumab, cetuximab, and alemtuzumab, are more commonly associated with acute hypersensitivity reactions than are other agents Acute hypersensitivity reactions to some drugs, such as taxanes, occur during the first or second dose administered Hypersensitivity to platinum compounds occurs after prolonged exposure Skin testing may identify patients with high risk for hypersensitivity after carboplatin exposure Premedication with histamine H1 and H2 receptor antagonists and glucocorticoids reduces the incidence of hypersensitivity reaction to taxanes, particularly paclitaxel Despite premedication, hypersensitivity reactions may still occur In these cases, rapid desensitization in the intensive care unit setting or re-treatment may be attempted with care, but the use of alternative agents may be required Candidate patients for desensitization include those who have mild to severe hypersensitivity type I, with mast cell–mediated and IgE-dependent reactions occurring during a chemotherapy infusion or shortly thereafter 2/9/15 3:34 PM ... WITHHOLDING OR WITHDRAWING CARE (See also Chap 10) Withholding or withdrawal of care occurs commonly in the ICU setting The Task Force on Ethics of the Society of Critical Care Medicine reported that... CRITICAL ILLNESS SEPSIS IN THE CRITICAL CARE UNIT (See also Chap 325) Sepsis, defined as the presence of SIRS in the setting of known or suspected infection, is a significant problem in the care. .. not Critical care providers should meet regularly with patients and/or surrogates to discuss prognosis when the withholding or withdrawal of care is being considered After a consensus among caregivers