17. Critical Care, Fluids, and Electrolytes - G. Christopher Wood, PharmD, FCCP, BCPS with Added Qualifications in Infectious Diseases

17-1. Sedation, Analgesia, and Neuromuscular Blockade

Definition and Classifications

• Pain: Critically ill patients may experience acute pain, chronic pain, or both.

• Anxiety or agitation: Patients may experience psychophysiological response to real or imagined danger. The term agitation is used in this chapter.

• ICU delirium: Delirium presented in the intensive care unit (ICU). See discussion of clinical presentation. The term delirium is used in this chapter.

Clinical Presentation

• Pain, agitation, or both in patients with impaired consciousness: pulling of tubes or lines, writhing, kicking, restlessness, hypertension, tachycardia, tachypnea, diaphoresis, moaning

• Delirium: fluctuating, disorganized thinking or inattentiveness not caused by an obviously reversible cause; with or without agitation


• Injuries

• Medical procedures and equipment (e.g., mechanical ventilation equipment or catheters)

• Mental status changes (e.g., fear, infection, hypoxia, sleep deprivation, or adverse drug effects or withdrawal)

• Preexisting medical conditions (e.g., chronic pain)

Diagnostic Criteria

• Pain: Use a verbal or visual scale to assess severity. For unconscious patients, use physical signs and symptoms.

• Agitation: Use a validated scale to assess (e.g., Riker Sedation-Agitation Scale).

• Delirium: Use Confusion Assessment Method for the ICU (CAM-ICU) scale.

Treatment Goals

• Find and remove the cause of pain, agitation, and delirium.

• Achieve a balance between patient comfort, adverse effects, and ability to provide care.

• Reserve neuromuscular blocking (NMB) agents for patients who are not controlled with maximum doses of sedation and analgesia.

Drug Therapy

Selected drug therapy is described in

Table 17-1.

Mechanism of action

• Opiates, nonsteroidal anti-inflammatory drugs (NSAIDs): See Chapter 23 on pain management.

• Benzodiazepines, haloperidol: See Chapter 25 on psychiatric disease.

• Propofol: Mechanism of action is unknown—possibly γ-aminobutyric acid (GABA)-related activity.

• NMB agents: These are postsynaptic cholinergic receptor antagonists; they do not provide analgesia or sedation.

[Table 17-1. Selected Drug Therapy Based on Guidelines for Use in ICU Patients]

Patient instructions

When patient-controlled analgesia pumps are used, make sure the patient understands how to activate the device.

Adverse drug events

• Opiates, NSAIDs: See Chapter 23 on pain management.

• Benzodiazepines, haloperidol: See Chapter 25 on psychiatric disease.

• Propofol: Adverse events include respiratory depression, hypotension, and hypertriglyceridemia. The maximum dose is 5 mg/kg/h.

• NMB agents: Adverse events include respiratory depression, prolonged weakness or paralysis after discontinuation, and tachycardia with pancuronium.

Drug interactions

• Opiates, NSAIDs: See Chapter 23 on pain management.

• Benzodiazepines, haloperidol: See Chapter 25 on psychiatric disease.

• Propofol: Actions are potentiated by other sedatives.

• NMB agents: Actions are potentiated by corticosteroids, aminoglycosides, clindamycin, calcium channel blockers, anesthetics; actions are inhibited by anticholinesterase inhibitors (e.g., neostigmine).

Parameters to monitor

• Opiates, NSAIDs: Use a visual or verbal scale to assess efficacy. Also monitor heart rate (HR), blood pressure (BP), and respiratory rate (RR). See also Chapter 23 on pain management.

• Benzodiazepines, haloperidol: Use a validated scale. Also monitor HR, BP, and RR. See also Chapter 25 on psychiatric disease.

• Propofol: Use a validated scale. Also monitor BP, HR, RR, intracranial pressure (ICP), and serum triglycerides at baseline and 1-2 times a week during long-term use.

• NMB agents: Monitor movement and spontaneous breathing. Also monitor BP, HR, and ICP (acute increases may indicate suboptimal sedation or analgesia). Peripheral nerve stimulation monitoring ("train of four") is highly recommended.

• Note: In patients with continuous sedation, a daily wakening and assessment period results in decreased sedative use and a shorter length of stay in ICU.


• Opiates, NSAIDs: See Chapter 23 on pain management.

• Benzodiazepines, haloperidol: See Chapter 25 on psychiatric disease.

• Propofol: Medication is highly lipophilic (may accumulate long term), has a rapid onset (1 minute), and has a short duration (about 10 minutes).

• NMB agents: Onset for all NMB agents is < 5 minutes. Duration is 60-90 minutes for pancuronium and 30-60 minutes for vecuronium and cisatracurium. Excretion of pancuronium is mostly renal; for vecuronium, it is about 50:50, hepatic:renal. Excretion of cisatracurium is not organ dependent.

Other aspects


Propofol is in a lipid vehicle (provides 1 kcal/mL). It should be used with caution in patients with egg allergy. It is a potential growth medium for bacteria; the maximum hang time for a bottle is 12 hours.


A newer agent (not discussed in depth in current guidelines), dexmedetomidine (Precedex), is available. It is a central alpha-2 agonist administered as a continuous IV infusion for up to 24 hours.

The potential advantage of dexmedetomidine is less respiratory depression than found with other agents. Adverse events include hypotension and bradycardia.

Newer data suggest the agent is safe for use longer than 24 hours and results in less delirium and shorter ICU stay than midazolam.

17-2. Traumatic Brain Injury


Traumatic brain injury is defined as neurologic deficit secondary to brain trauma.


• Severe

• Mild or moderate

Clinical Presentation

• Use the Glasgow Coma Scale (GCS) for assessment: sum of eye, motor, and verbal scores (range 3-15).

• Traumatic brain injury has a wide range of presentation from mild confusion to totally nonresponsive coma.


• Traumatic brain injury results from motor vehicle accidents (most common), falls and accidents, assaults, and gunshot wounds.

• It is most common in 15- to 24-year age group.

• Every year 375,000 cases and 75,000 deaths occur.

• Traumatic brain injury consists of direct neuronal damage ± edema ± secondary ischemia-related neuronal death.

Diagnostic Criteria

• Computed tomography (CT) scan


• ICP monitoring in severe patients (GCS score 3-8)

Treatment Goals

• Keep ICP < 20 mm Hg and cerebral perfusion pressure (CPP) > 50 mm Hg (CPP = mean arterial pressure - ICP).

• Prevent seizures.

Strategies to decrease ICP

• Osmotic agents and diuretics

• Mannitol 0.25-1.0 g/kg intravenous (IV) q4h

• Loop diuretics IV (e.g., furosemide)

• Hypertonic NaCl IV (e.g., 3.0%, 7.5%)

• Sedation

• Short-acting agents are preferred to allow frequent patient assessment (e.g., propofol, fentanyl).

• Pentobarbital (1-3 mg/kg/h IV) is a long-acting agent for refractory intracranial hypertension.

• NMB agents:

• A short-acting agent is preferred (vecuronium).

• Such agents are used for refractory intracranial hypertension.

Nondrug interventions

• Raising of the head of the bed (30 degrees)

• Ventricular drainage of cerebrospinal fluid via ventriculostomy

• Mild or moderate hyperventilation (pCO2 30-35 mm Hg)

• Surgery

Strategies to increase mean arterial pressure

• Maximize fluid status. The overall goal is euvolemia.

• Vasopressors and inotropes may be used in shock after fluid status is optimized.

Seizure prevention

• Seizure prevention may be started on the basis of severity and type of injury.

• Phenytoin (Dilantin, generic) can be used: 20 mg/kg IV loading dose plus 4-8 mg/kg/d for 7 days.

• Continue beyond 7 days if the patient has a seizure.

• An alternative agent is carbamazepine.

• See Chapter 24 on seizure control for the mechanism of action, adverse drug events, drug interactions, and kinetics.

Parameters to monitor

The overall goal is CPP > 50 mm Hg and ICP < 20 mm Hg. Drug classes are covered elsewhere.

Other Aspects

Nimodipine (Nimotop) is a calcium channel blocker given for 21 days. It is indicated for treating aneurysmal subarachnoid hemorrhage. It may also provide some benefit in traumatic subarachnoid hemorrhage.

17-3. Acute Spinal Cord Injury


Acute spinal cord injury is traumatic spinal cord injury with neurologic impairment.


• Complete: Total loss of motor and sensory function occurs in affected areas.

• Incomplete: Some motor or sensory function is retained in affected areas.

• Paraplegia: Neurologic deficit occurs in the lower extremities.

• Quadriplegia: Neurologic deficit occurs in the upper and lower extremities.

• Central cord syndrome: Symptoms are atypical.

Clinical Presentation

• Loss of motor function, loss of sensory function, or both, from nerves distal to level of vertebral injury

• Usually bilaterally symmetrical symptoms


See discussion of traumatic brain injury in Section 17-2.

Diagnostic Criteria

• Physical examination consistent with spinal cord injury

• CT or radiographic evidence of injury

Treatment Goals

Treatment goals are the reservation or restoration of motor and sensory function.

Drug Therapy

Drug therapy is considered optional in current treatment guidelines:

• A loading dose of methylprednisolone 30 mg/kg IV is given.

• If the loading dose is given within 3 hours of the injury, a 5.4 mg/kg/h IV infusion is continued for a total of 24 hours.

• If the loading dose is given within 3 hours of the injury, a 5.4 mg/kg/h IV infusion is continued for a total of 48 hours.

• No methylprednisolone is if > 8 hours have passed from the injury or in the case of penetrating injuries.

Mechanism of action

The mechanism of action is unknown. The medication is thought to protect neurons by inhibiting lipid peroxidation.

Adverse drug effects

• Increased infections (48 hours worse than 24 hours)

• Hyperglycemia

Parameters to monitor

• Neurologic status

• Serum glucose

17-4. Venous Thromboembolism Prophylaxis


Venous thromboembolism (VTE) is pathogenic blood clot formation.


• Deep venous thrombosis (DVT): VTE in a large vein, generally in a lower extremity

• Pulmonary embolism (PE): DVT that has embolized to the pulmonary vasculature (much less common)

Clinical Presentations

• DVT is often asymptomatic:

• Unilateral leg symptoms such as swelling, pain, tenderness, erythema, warmth, ± palpable cord

• Pain behind the knee upon dorsiflexion (Homans' sign)

• PE is often asymptomatic:

• Pulmonary symptoms such as chest pain, cough, dyspnea, tachypnea, hemoptysis

• May proceed rapidly to life-threatening shock and hypoxia


Three general risk factors can be identified:

• Hypercoagulable states:

• Clotting factor deficiencies or abnormalities (e.g., protein C or S deficiency)

• Malignancy, pregnancy, estrogen use

• Direct vessel trauma

• Venous stasis (i.e., poor blood flow allows clot formation)

Specific Risk Factors

• Risk increases with age (see

Table 17-2).

• Immobility, previous VTE, cancer, obesity, congestive heart failure, pregnancy, estrogen therapy, and smoking are risk factors.

• Major surgery or trauma are risk factors, particularly in the case of lower extremities or the pelvis, genito-urinary injury, and neurologic injury.


• About 600,000 hospitalizations take place in the United States yearly with about 60,000 deaths (10% mortality).

• Incidence of DVT ranges from 2% to 80% depending on risk factors.

Diagnostic Criteria

• Radiocontrast dye studies: Such studies (venography for DVT, pulmonary angiography for PE) are invasive, are expensive, and require expertise, and adverse events common (e.g., nephropathy). A ventilation/perfusion scan (for PE) is less invasive, but inconclusive results are common.

• Ultrasonography: Used for DVT, ultrasonography is noninvasive, is inexpensive, is performed at the bedside, but is less sensitive.

• Serum D-dimer concentrations: Normal levels may rule out VTE.

Treatment Goals

• Goals are to decrease morbidity (VTE recurrence, progression to PE); mortality; and costs of VTE.

• VTE prophylaxis is underused: only 35% to 50% of at-risk patients receive it.

Drug Therapy to Treat VTE


Therapy consists of full-dose IV heparin (80 units/kg load + 18 units/kg/h) or full-dose low molecular weight heparin (LMWH) subcutaneous (SC) (e.g., enoxaparin 1 mg/kg q12h or 1.5 mg/kg qd). LMWH may be used on an outpatient basis in stable DVT patients. Full-dose heparin may be given SC bid, but this is rarely done.


Begin warfarin concurrently. Discontinue heparin or LMWH when the international normalized ratio (INR) is therapeutic (usually 2-3) and stable. Duration is as follows:

• Reversible, 3 months

• Idiopathic, 6-12 months (consider longer)

• High risk, 12 months to indefinite

Direct thrombin inhibitors

Use direct thrombin inhibitors in place of heparin for heparin-induced thrombocytopenia.

Thrombolytic therapy

Reserve thrombolytic therapy for very severe cases. Therapy is highly individualized.

Inferior vena cava filter

Reserve this treatment for selected patients with contraindication to anticoagulation.

Drug Therapy to Prevent VTE

Drug therapy for prevention of VTE is described in Table 17-2.

Mechanism of action

• Heparin binds to antithrombin and potentiates its anticoagulation (anti-IIa activity > anti-Xa activity).

[Table 17-2. Drug and Nondrug Therapy for Prevention of Venous Thromboembolism]

• LMWHs are the same as heparin but anti-Xa activity is > anti-IIa activity. Some controversy exists over the interchangeability of these drugs because of differences in Xa:IIa activity ratios.

• Fondaparinux is a factor Xa inhibitor.

• For warfarin, see Chapter 10 on cardiac arrhythmias.

• Direct thrombin inhibitors (lepirudin [Refludan], bivalirudin [Angiomax], argatroban) directly inhibit thrombin.

Patient instructions and counseling

• For heparin, fondaparinux, thrombin inhibitors, and thrombolytics, patient instructions and counseling are not necessary.

• For LMWHs and fondaparinux, patients can be taught to self-inject after hospital discharge:

• Monitor for signs and symptoms of bleeding or VTE recurrence.

• Avoid NSAIDs.

• For warfarin, see Chapter 10 on cardiac arrhythmias.

Adverse drug events

• Bleeding: Occurs with all agents:

• Low-dose unfractionated heparin (LDUH) and low-dose LMWH have similar bleeding risks.

• Protamine sulfate reverses heparin and LMWH.

• Heparin-induced thrombocytopenia (HIT): Occurs with heparin, LMWH:

• Early onset occurs around the first week of therapy. It is transient, and no therapy is needed.

• Late onset (> 50% decrease from baseline) is immune mediated. If the event is severe, heparin or LMWH must be discontinued:

• Switch to direct thrombin inhibitor until platelets > 150,000/mcL, then possibly short-term warfarin (4 weeks).

• Adverse events are less frequent with LMWH.

• HIT may result in severe thrombosis or limb amputation.

• HIT may happen immediately upon rechallenge with heparin or LMWH.

• Spinal hematoma can occur with epidural catheters. LMWH or full anticoagulation is worse than LDUH; do not use LMWH.

• Osteoporosis can occur with long-term therapy. Heparin is worse than LMWH.

• Hypersensitivity (reexposure): Occurs with lepirudin.

Drug interactions

• NSAIDs may increase bleeding risk with all agents.

• For warfarin, see Chapter 10 on cardiac arrhythmias.

Parameters to monitor

• Heparin (full-dose IV) and thrombin inhibitors:

• Goal is partial thromboplastin time (PTT) that corresponds to an anti-Xa level of 0.3-0.7 units/mL (check with each lab for therapeutic range).

• Monitor q6h until therapeutic; then once or twice daily.

• LDUH does not affect PTT.

• LMWHs:

• Goal is an anti-Xa level of 0.6-1 units/mL.

• No routine monitoring is needed, but monitoring may be necessary in cases of renal impairment, obesity, prolonged use, and pregnancy.

• Fondaparinux:

• No monitoring is necessary.

• Fondaparinux affects anti-Xa levels.

• Direct thrombin inhibitors:

• Argatroban: Goal is PTT that is 1.5-3.0 times control. Argatroban falsely elevates INR.

• Bivalirudin: There are no recommendations in HIT. Bivalirudin elevates PTT and INR.

• Lepirudin: Goal PTT is 1.5-2.5 times control.

• Warfarin (see Chapter 10 on cardiac arrhythmias).


• Heparin: Cleared by endothelial cell enzymes (half-life about 90 minutes); higher doses also renally cleared.

• LMWHs: Renally cleared; half-life 2-4 times longer than heparin.

• Fondaparinux: Renally cleared; longer half-life (about 24 hours).

• Direct thrombin inhibitors: Half-life 30-90 minutes; lepirudin renally cleared; others hepatically cleared.

17-5. Stress Ulcer Prophylaxis


Stress ulcer prophylaxis refers to gastrointestinal (GI) mucosal damage related to metabolic stress in the ICU.

Clinical Presentation

Presentation is similar to that of peptic ulcer disease (see Chapter 21 on gastrointestinal disorders).


Shunting of blood from the GI tract to vital organs during critical illness results in breakdown of gastric mucosal defenses (e.g., bicarbonate production, epithelial cell turnover).

Risk Factors

• Mechanical ventilation > 48 hours

• Coagulopathy

• Other disease states or organ dysfunction where GI perfusion may be compromised (e.g., sepsis, burns, traumatic brain injury)

Diagnostic Criteria

Diagnosis is based on signs and symptoms and can be confirmed with endoscopy.

Treatment Goals

The goal is to prevent stress ulcers.

Drug Therapy

• See Chapter 21 on GI disorders for full drug information.

• Histamine-2 (H2) antagonists or sucralfate are traditional standards of therapy; H2 antagonists may be more effective. Sucralfate administration can be difficult in ICU patients.

• Proton pump inhibitors are equivalent to H2 antagonists.

• Optimal duration of therapy is unknown (usually until risk factors have resolved or transfer from ICU).

• Antacids are less effective and are not recommended. They have higher aspiration risk and require frequent dosing.

17-6. Severe Sepsis and Septic Shock

Definition and Classifications

Severe sepsis is sepsis (see Chapter 29 on infectious disease) plus dysfunction of one or more major organs (e.g., hypotension responsive to fluids, oliguria, acute mental status change, lactic acidosis, respiratory insufficiency, coagulopathy).

Septic shock is severe sepsis plus hypotension that is not fully responsive to fluids (i.e., requires vasopressor therapy).

Clinical Presentation

See sepsis criteria (in Chapter 29) and the definitions of severe sepsis and septic shock.


Progression is seen in the systemic manifestations of sepsis. Imbalances in the inflammatory, immune, and coagulation systems lead to organ hypoperfusion and organ dysfunction with or without refractory hypotension.

Causative organisms vary by institution, but broad patterns are known:

• Common community-acquired organisms include Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Escherichia coli, and "atypicals" (Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella spp.).

• Common nosocomial or health care-associated organisms include Pseudomonas aeruginosa, S. aureus (methicillin resistance more common), Enterobacter spp., Klebsiella spp., Proteus spp., Citrobacter spp., Serratia spp., and Candida spp.

Diagnostic Criteria

See sepsis criteria (in Chapter 29) and the definitions of severe sepsis and septic shock.

Treatment Goals

• Rapidly stabilize hemodynamic parameters and organ dysfunction within 6 hours.

• Identify causative organism or organisms, start appropriate antimicrobial therapy within 1 hour, and eliminate the source of infection, if applicable (e.g., vascular or urinary catheter, abscess). Duration of antimicrobial therapy is typically 7-14 days.

• Modulate inflammatory, coagulating, and hormonal derangements, if applicable.

Drug and Nondrug Therapy

See Chapter 29 on infectious disease for antimicrobial information (mechanism of action, dosing, adverse effects, etc.). Empiric antimicrobial selection is also covered in Chapter 29. Definitive therapy should be streamlined to a narrower spectrum agent, if possible, on the basis of the final culture and sensitivity reports.

See Section 17-7 for details on fluid therapy. Fluid therapy for severe sepsis and septic shock can be colloids, isotonic crystalloids, or both. Vasopressors should be used only after appropriate fluid therapy fails to adequately normalize BP (

Table 17-3).

Mechanism of action

• Vasopressors and inotropes are adrenergic-receptor agonists.

• Drotrecogin alfa is recombinant human-activated protein C (an endogenous anticoagulant). The exact method of action is unknown, but it modulates coagulation and inflammatory cascades.

Adverse drug events

• Vasopressors and inotropes: Tachycardia, arrhythmias, organ and extremity ischemia, hypertension

• Drotrecogin alfa: Bleeding (contraindicated in active internal bleeding, recent trauma, stroke, or other clinical condition at high bleeding risk or presence of epidural catheter)

Drug-drug interactions

• Vasopressors and inotropes: None

• Drotrecogin alfa: Increased bleeding risk with concomitant anticoagulation or antiplatelet therapy

Parameters to monitor

• Vasopressors and inotropes: Monitor BP, HR, cardiac output, urine output, and extremity perfusion on physical exam.

• Drotrecogin alfa: Note signs and symptoms of bleeding on physical exam and monitor BP and HR. Monitor improvement in signs and symptoms of infection, temperature, white blood count (WBC), and organ dysfunction. Drotecogin alfa may prolong activated PTT.

[Table 17-3. Vasopressors and Inotropes Used in Severe Sepsis and Septic Shock]


For drotrecogin alfa, dose adjustment is not required in renal or hepatic dysfunction.

Other aspects

Low-dose hydrocortisone (200-300 mg × 7 days ± fludrocortisone 50 mcg/d) is recommended for patients with septic shock who are not responsive to fluids and vasopressors. Patients with a poor response to cosyntropin stimulation testing (serum cortisol increase of < 9 mcg/dL) may respond better to corticosteroid supplementation.

Vasopressin infusion (0.03 units/min) may be used to increase BP in patients refractory to high doses of traditional pressors. Doses > 0.04 units/min are associated with severe adverse events (e.g., cardiac arrest). New data suggest that patients receiving lower doses of catecholamine vasopressors (i.e., < 15 mcg/min of norepinephrine) benefit more from vasopressin than do patients on higher doses of norepinephrine.

17-7. Fluid and Electrolyte Abnormalities in Critically Ill Patients


See also Chapter 16 on kidney disorders (for hyperphosphatemia), Chapter 18 on nutrition, and chapter 19 on oncology (for hypercalcemia).


Fluid and electrolyte abnormalities are pathologic alterations in fluid and electrolyte homeostasis.


Fluid and electrolyte abnormalities are classified by electrolyte (see the discussion on clinical presentation).

Clinical Presentation

In all cases, mild to moderate abnormalities are usually asymptomatic.

Sodium (normal range: 135-145 mEq/L)

In cases of hyponatremia or hypernatremia, lethargy, nausea, headache, dry mucous membranes, poor skin turgor (depends on hydration status), and confusion may occur.

Coma, seizures, or central pontine myelinolysis may occur in severe hyponatremia or if sodium increases or decreases rapidly (> 12 mEq/L/d).

Chloride (normal range: 96-106 mEq/L)

Symptoms are related to acid-base or fluid abnormalities, not chloride itself.

Water (moves osmotically with sodium)

In cases of dehydration, dry mucous membranes, poor skin turgor, lethargy, nausea, headache, hypotension, and tachycardia occur. Seizures, coma, or death can occur if dehydration is severe. Decreased urine output, metabolic acidosis, and hypotension are also found.

For edema or fluid overload, see Chapter 9 on heart failure.

Potassium (normal range: 3.5-5.0 mEq/L)

In cases of hypokalemia, confusion, muscle cramps, weakness, and cardiac arrhythmias occur.

In cases of hyperkalemia, muscle cramps, weakness, and cardiac arrhythmias occur.

Magnesium (normal range: 1.5-2.2 mEq/L)

With hypomagnesemia, presentation is similar to that of hypocalcemia.

In cases of hypermagnesemia, lethargy, weakness, and cardiac arrhythmias occur. Coma is possible in severe cases.

Phosphorus (normal range: 2.6-4.5 mg/dL)

In cases of hypophosphatemia, confusion, anxiety, weakness, respiratory depression, paresthesias, and lethargy occur. Seizures and coma are possible if hypophosphatemia is severe.

For hyperphosphatemia, see Chapter 16 on kidney disorders.

Calcium (normal range: 8.5-10.5 mg/dL)

In cases of hypocalcemia, confusion, anxiety, paresthesias, muscle cramps, and tetany occur. Coma and cardiac arrhythmias may occur in severe cases.

For hypercalcemia, see Chapter 19 on oncology.


Normal distribution of fluids and electrolytes

• Electrolytes with high serum concentrations are primarily extracellular (Na, Cl); those with low serum concentrations are mostly intracellular or in bone (K, P, Mg, Ca).

• Total body water is approximately 60-70% of total body weight (differs by age, gender, disease states).

• Of all water, intracellular is approximately two-thirds; extracellular is approximately one-third.

• Of extracellular water, approximately three-fourths is interstitial; approximately one-fourth is intravascular (plasma).

• Typical fluid requirements for adults are approximately 35 mL/kg/d; they can be much higher in critical illness because of extrarenal losses (GI tract, wounds) and fluid shifts (trauma, sepsis).

• Primary hormonal controls are aldosterone (sodium retention) and antidiuretic hormone (water retention).


The first three forms of hyponatremia listed below are hypotonic:

• Hypovolemic (sodium and water loss): This condition is characterized by high urine osmolality. It is related to extrarenal fluid losses (GI, wounds); diuretics; and adrenal insufficiency.

• Euvolemic (moderate water retention): This condition occurs with syndrome of inappropriate antidiuretic hormone (SIADH) release, renal failure, carbamazepine, NSAIDs, chlorpropamide.

• Hypervolemic (sodium and water retention): This condition occurs with congestive heart failure, cirrhosis, nephrotic syndrome, and glucocorticoids.

• Hypertonic: This condition is the dilutional effect of abnormal osmotic agents in the vasculature (severe hyperglycemia).


Hypernatremia occurs in cases of water loss or excessive sodium intake (e.g., from IV fluids). It is related to extrarenal fluid losses (GI, wounds) and diabetes insipidus.


Hypochloremia occurs with GI losses.


Hypokalemia is related to diuretics, β2-agonists, amphotericin B, glucocorticoids, cisplatin, and GI losses.


Hyperkalemia is related to renal dysfunction, acidosis, angiotensin-converting enzyme (ACE) inhibitors, potassium-sparing diuretics, trimethoprim, orally taken salt substitutes, and adrenal insufficiency.


Hypomagnesemia occurs with GI losses, diuretics, amphotericin B, alcohol, and cisplatin. It should be treated prior to treating hypokalemia; Na/K-ATPase pumps require magnesium to work.


Hypermagnesemia is related to renal dysfunction, magnesium-containing antacids, adrenal insufficiency, and hyperparathyroidism.


Hypophosphatemia is related to refeeding syndrome, phosphate binders, diuretics, hypercalcemia, vitamin D deficiency, and glucocorticoids.


Hypocalcemia occurs with hypoparathyroidism, hypomagnesemia, vitamin D deficiency, and loop diuretics. Total calcium is artificially low in hypoalbuminemia (calcium is highly albumin bound).

Diagnostic Criteria

• Criteria include serum concentration, signs, and symptoms.

• Sodium analysis may use urine sodium and urine osmolality.

Treatment Goals

• Find and treat the underlying cause of abnormality.

• Treat abnormality to avoid sequelae.

Drug and Nondrug Therapy

Fluid replacement

Administer fluids as follows:

• Crystalloids: Salt solutions — 1/2 or 1/4 normal saline (NS) ± dextrose 5% ± KCl 20 mEq/L (approximates urine electrolytes), NS (154 mEq/L of Na), lactated Ringer's (LR), 1/4 NS, or dextrose 5%—are chosen on the basis of sodium and fluid needs. NS or LR are typically used for fluid resuscitation (sodium is the major osmotic cation in plasma).

• Colloids: Osmotic agents—albumin 5-25% or hetastarch—are used for fluid resuscitation or to raise oncotic pressure (e.g., cirrhosis).

• Vasopressors ± isotropic activity: After fluids are optimized, vasopressors ± isotropic activity may be used (see Chapter 9 on heart failure).


Fluid restriction ± diuretics may be used. See Chapter 9 on heart failure and and Chapter 16 on kidney disorders.


If the case is severe, titrate 3% NaCl to maximum serum sodium increase of 12 mEq/d. Treat specific forms as follows:

• Hypovolemic: Replace fluid losses with IV NS (0.9% NaCl, 154 mEq/L).

• Euvolemic (SIADH): Use fluid restriction ± demeclocycline.

• Hypervolemic: Use fluid restriction ± diuretics.

• Hypertonic: Correct hyperglycemia.


Titrate low-sodium fluids (e.g., dextrose 5%, 1/4NS) to a normal serum sodium. In cases of diabetes insipidus, use DDAVP (desmopressin).


Give sodium acetate or LR instead of NS, especially if acidemic (acetate is converted to bicarbonate by the liver).


Administer IV (KCl) or po (KCl, K phosphate, or K acetate). Each 10 mEq dose increases serum potassium by about 0.1 mEq/L. IV administration faster than 10 mEq/h requires electrocardiogram (ECG) monitoring for arrhythmias.


Treat hyperkalemia as follows:

• Potassium removal (slower onset of action): Use Na polystyrene sulfonate (Kayexalate) po or PR (per rectum), loop diuretics, or hemodialysis (if severe).

• Intracellular potassium shifting (rapid onset of action): Administer regular insulin + dextrose IV, albuterol, or Na bicarbonate.

• Potassium antagonism of cardiac effects (rapid onset of action): Administer IV calcium.


Dosages are described below. A large percentage of the dose is renally wasted. Repletion requires 3-days of treatment.

• IV: 0.5-1 mEq/kg/d (8 mEq = 1 g); administration rate = 8 mEq/h

• IM: Can give IM but painful

• po: Magnesium-containing antacid or laxative tid-qid as tolerated or magnesium oxide 300-600 mg bid-qid


Treat with diuretics, IV calcium, or hemodialysis (similar to hyperkalemia).


If the case is severe, use IV sodium or potassium phosphate 0.16-0.64 mmol/kg at 7.5 mmol/h to avoid potassium overdose (if potassium phosphate is used), calcium precipitation, or both.

Administer po 1-2 g/d (5-60 mmol/d), for example, Neutra-Phos, Neutra-Phos-K, or Fleet Phospho-soda.


See Chapter 16 on kidney disorders for information about hyperphosphatemia.


If patient is symptomatic, administer IV calcium gluconate (2-3 g) or IV calcium chloride (1 g) over 10 minutes. In addition, the following may be administered:

• IV infusion of 0.5-2.0 mg/kg/h of elemental calcium

• Calcium salts such as calcium carbonate (po 1-3 g elemental calcium/d ± vitamin D)

Patient counseling

In cases of po administration, advise patient about potential adverse events.

Adverse drug events

• Sodium: Edema or central pontine myelinolysis can occur if serum Na changes rapidly (> 12 mEq/d).

• Crystalloids: Vein irritation is possible with hypotonic (1/4 NS, 1/2 NS) or hypertonic fluids (3% NaCl). Dextrose 5% is approximately isotonic and is often added to low-sodium fluids.

• Potassium: Events include cardiac arrhythmias (> 10 mEq/h), vein irritation (IV), GI upset (po; worse with wax matrix controlled-release tablets), and bad taste (po liquid). With sodium polystyrene sulfonate, constipation may occur (medication is usually mixed with sorbitol).

• Magnesium: Events include diarrhea (po), flushing, sweating (IV), and vein irritation (IV).

• Phosphorus: Events include diarrhea (po) and calcium phosphate precipitation (IV).

• Calcium: IV calcium gluconate is less irritating than calcium chloride. Cardiac dysfunction can occur if medication is administered > 60 mg/min (elemental calcium). Events also include calcium phosphate precipitation (IV) and constipation (po).

Drug interactions

• Hypokalemia and hypomagnesemia can predispose the patient to digoxin toxicity.

• Binding of drugs in the GI tract by calcium or magnesium is possible (see Chapter 18 on nutrition).

Parameters to monitor

• Serum concentrations

• Resolution of signs and symptoms

• With fluid replacement, normalization of the following: BP, HR, urine output (goal > 0.5 mL/kg/h), skin turgor, mucous membrane hydration, edema, cardiac output, pulmonary artery wedge pressure (see Chapter 9 on heart failure), and serum lactate/base deficit

Other aspects

Glucose control in critically ill patients

Tight glucose control (80-110 mg/dL) with insulin infusion was originally shown to reduce mortality in one large trial; however, recent large trials have not seen such a benefit. Hypoglycemia is common with intensive glucose control.

Anemia of critical illness

This common complication is caused by blood loss, bone marrow dysfunction (e.g., erythropoietin resistance), and hemodilution. Red blood count (RBC) transfusion is not recommended until hemoglobin is < 7.0 g/dL (unless patient is symptomatic). No benefit is gained from transfusing sooner, and transfusions are associated with increased infections and higher mortality.

Recombinant erythropoietin (40,000 units SC per week) has been shown to decrease the need for RBC transfusions by about 20% in a large trial; however, this benefit was not seen in a large follow-up trial. Until further data are available, erythropoietin is not recommended for routine use in the ICU, but it may be used if the patient has another indication for it (e.g., renal failure).

17-8. Key Points

• Appropriate sedation and analgesia are essential because pain and agitation are common in critically ill patients. Drug selection should be based on clinical guidelines and patient parameters.

• Sedation and analgesia should be monitored using a validated assessment tool.

• NMB agents should be used only after sedation and analgesia have been maximized.

• Neuromuscular blockade should be monitored using peripheral nerve stimulation in addition to observation of clinical signs and symptoms.

• Appropriate stress ulcer prophylaxis is recommended for patients at risk.

• Appropriate VTE prophylaxis is recommended for patients at risk. Optimal therapy is determined by clinical guidelines and patient risk factors.

• High-dose methylprednisolone therapy within 8 hours of injury may improve outcomes after acute spinal cord injury.

• ICP and CPP should be optimized after severe traumatic brain injury using drug and nondrug therapies. Phenytoin is effective at preventing early post-traumatic seizures.

• Severe sepsis and septic shock are progressions of sepsis. Therapy includes hemodynamic stabilization, appropriate antimicrobial agents, and removal of infectious foci, if possible.

• Drotrecogin alfa may decrease mortality as an adjunctive agent in patients with severe sepsis and a high severity of illness.

• Maintaining adequate fluid status is vital to maintaining tissue perfusion and organ function. However, many clinical factors can affect fluid and electrolyte status in critically ill patients. Finding and treating underlying causes of fluid and electrolyte abnormalities are essential.

• Fluid and electrolyte abnormalities are generally asymptomatic unless severe.

• Fluid and electrolyte therapy should be monitored closely because of patient instability and the risk of iatrogenic abnormalities (e.g., cardiac arrhythmias, fluid overload).

17-9. Questions


In most critically ill patients, the opiate of choice for analgesia is

A. morphine.

B. hydromorphone.

C. fentanyl.

D. acetaminophen.

E. ketorolac.



In which situations should hydromorphone or fentanyl be used for analgesia in critically ill patients?

I. Morphine allergy

II. Renal dysfunction

III. Hemodynamic instability

A. I only

B. III only

C. I and II only

D. II and III only

E. I, II, and III



What is the maximum duration of therapy for ketorolac?

A. 5 days

B. 7 days

C. 14 days

D. 30 days

E. There are no restrictions on length of use.



Which agent is recommended for general long-term sedation in the ICU (> 24-72 hours)?

A. Diazepam

B. Propofol

C. Midazolam

D. bentobarbital

E. Lorazepam



In most critically ill patients, which of the following is the NMB agent of choice?

A. Propofol

B. Vecuronium

C. Cisatracurium

D. Pancuronium

E. Any agent may be used first line.



The primary advantage of cisatracurium over pancuronium and vecuronium is that

A. elimination is not organ dependent.

B. it has a shorter duration of action.

C. it has a longer duration of action.

D. it is more effective.

E. it does not require monitoring.



Which of the following is preferred as a first-line sedative agent for ICP control in patients with traumatic brain injury?

A. Pentobarbital

B. Lorazepam

C. Propofol

D. Vecuronium

E. Sedation is not recommended.



The regimen of choice for post-traumatic seizure prophylaxis is

A. phenytoin indefinitely.

B. phenytoin × 7 days.

C. carbamazepine × 7 days.

D. benzodiazepines prn if seizures occur.

E. propofol × 7 days.



Which of the following best describes the use of high-dose methylprednisolone in acute spinal cord injury?

A. Duration of therapy is 24 hours if started within 12 hours of injury.

B. Duration of therapy is 48 hours if started within 8 hours of injury.

C. Duration of therapy is 24 hours if started 0-3 hours from injury and 48 hours if started 3-8 hours from injury.

D. High-dose methylprednisolone may be started at any time after injury.

E. Both blunt and penetrating spinal cord injuries should be treated with high-dose methylprednisolone.


Use Patient Profile 1 to answer questions 10 and 11.


Patient name: Dennis Green

Age: 24 years

Sex: M

Race: Caucasian


Injury from motor vehicle accident:

Multiple rib fractures

Moderate liver contusion

Lab/diagnostic tests: CT scan of liver shows no active bleeding

Address: 42 Spring Street

Height: 5´10″

Weight: 70 kg

Allergies: NKDA

Medication orders:

Cimetidine 300 mg IV q8h

Morphine 1-4 mg IV q1h prn pain

Dietary: N/A

Additional orders: Pharmacy consult for VTE prophylaxis

Pharmacist notes: N/A


Which of the following is the most appropriate VTE prophylaxis regimen for Mr. Green?

A. Low-dose LMWH

B. Heparin 5,000 units SC q12h

C. Full-dose IV heparin infusion

D. Warfarin to INR 2-3

E. Intermittent pneumatic compression and elastic stocking



The following day, Mr. Green requires placement of an epidural catheter for pain control for his rib fractures. Which of the following is true regarding VTE prophylaxis in Mr. Green?

A. LMWH should be started and monitored closely with anti-Xa levels.

B. LMWH should be avoided because of the risk of perispinal hematoma.

C. Full-dose IV heparin should be used for VTE prophylaxis.

D. Warfarin should be started.

E. A full-dose direct thrombin inhibitor should be started.


Use Patient Profile 2 to answer questions 12 and 13:


Patient name: Ann Collins

Age: 65 years

Sex: F

Race: Caucasian


Severe community-acquired pneumonia

Acute pain and swelling in left leg 7 days after admission

Lab/diagnostic tests: Bedside ultrasound shows acute DVT in left leg

Address: 34 Summer Street

Height: 5´4"

Weight: 60 kg

Allergies: Penicillin (rash)

Medication orders:

Ranitidine 50 mg IV q8h

Heparin 5,000 units SC q12h changed to IV heparin infusion 1,100 units/h after DVT is diagnosed

Gatifloxacin 400 mg IV qd

Dietary: N/A

Additional orders: N/A

Pharmacist notes: N/A

A comparison of Mrs. Collins's complete blood count (CBC) on admission and day 7 follows:



Day 7






% neutrophils/% bands




Hematocrit (%)









Which of Mrs. Collins's hematologic changes over time is most likely due to heparin?

A. Leukopenia

B. Leukocytosis

C. Increased hematocrit

D. Bandemia (left shift)

E. Thrombocytopenia



What should be done regarding heparin therapy in Mrs. Collins?

A. Switch to a direct thrombin inhibitor.

B. Continue heparin; monitor CBC closely.

C. Switch to high-dose LMWH.

D. Switch to aspirin.

E. Discontinue heparin; do not anticoagulate.



In most patients with an acute DVT who are hemodynamically stable, what is the initial treatment of choice?

A. Heparin 5,000 units SC q12h

B. Full-dose IV heparin or full-dose LMWH

C. Thrombolytic therapy (e.g., recombinant tissue plasminogen activator)

D. Aspirin

E. Low-dose LMWH



All of the following are risk factors for the development of stress ulcers except

A. sepsis.

B. coagulopathy.

C. mechanical ventilation.

D. age > 40 years.

E. burns.



Which of the following is correct regarding stress ulcer prophylaxis?

A. H2 antagonists or sucralfate are equally effective and considered drugs of choice.

B. Proton pump inhibitors are more effective than H2 antagonists or sucralfate.

C. Antacids have the most direct effect on gastric pH and are considered drugs of choice.

D. Sucralfate is more effective and causes less pneumonia than do H2 antagonists.

E. All agents (H2 antagonists, sucralfate, proton pump inhibitors, and antacids) are equally effective.



Which of the following is the most likely adverse event associated with drotrecogin alfa use in severe sepsis?

A. Renal dysfunction

B. Allergy and anaphylactic shock

C. Tachycardia

D. Bleeding

E. Rash



Which of the following will not increase blood pressure via α1-adrenergic activation?

A. Phenylephrine

B. Dopamine

C. Epinephrine

D. Norepinephrine

E. Dobutamine



M. W. is a 25-year-old pregnant female who is admitted to the medical ICU following several days of severe nausea and vomiting. She is hypotensive, tachycardic, and confused, and her urine output is very low. Her serum sodium is 128 mEq/L. Which of the following should be given to treat her fluid and sodium abnormality?

A. IV normal saline or lactated Ringer's

B. IV 5% dextrose in water

C. po water

D. IV furosemide

E. Desmopressin



Common fluid and electrolyte abnormalities associated with loop diuretics include all of the following except

A. hypokalemia.

B. hyperkalemia.

C. hypomagnesemia.

D. dehydration.

E. hypocalcemia.



R. T. is a 40-year-old male admitted to the medical ICU following a severe asthma exacerbation. RT's serum phosphorus is 0.9 mEq/L and his body weight is 70 kg (100% of ideal). Which of the following acute phosphorus supplementation regimens is most appropriate?

A. 45 mmol of sodium phosphate IV over 6 hours

B. 45 mmol of sodium phosphate IV over 10 minutes

C. 15 mmol of po phosphorus (e.g., Neutraphos) over the next 24 hours

D. 15 mmol of IV sodium phosphate over 2 hours

E. No acute phosphorus therapy is required.



The most common electrolyte abnormality associated with ACE inhibitors is

A. hypomagnesemia.

B. hypokalemia.

C. hyperkalemia.

D. hyperphosphatemia.

E. hypernatremia.



All of the following are useful in the rapid treatment of severe hyperkalemia except

A. potassium restriction.

B. IV calcium.

C. IV regular insulin and dextrose.

D. IV sodium bicarbonate.

E. Oral Kayexalate.



Which of the following electrolyte abnormalities are most commonly associated with amphotericin?

I. Hypokalemia

II. Hypomagnesemia

III. Hypocalcemia

A. I only

B. III only

C. I and II only

D. II and III only

E. I, II, and III



All of the following are side effects of potassium replacement therapy except

A. constipation (po).

B. GI upset (po).

C. cardiac arrhythmias (IV).

D. vein irritation (IV).

E. poor taste (po liquid).



Which of the following best describes GI side effects of antacids containing magnesium and calcium salts?

A. Mg causes constipation; Ca causes diarrhea.

B. Mg causes diarrhea; Ca causes constipation.

C. Both cause diarrhea.

D. Both cause constipation.

E. Neither has GI side effects.


17-10. Answers


A. Morphine is recommended by the current Society of Critical Care Medicine (SCCM) guidelines on sedation and analgesia as the opiate of choice for most critically ill patients. Morphine is inexpensive, relatively short acting, and well tolerated by many patients.



E. Under SCCM guidelines, hydromorphone or fentanyl is recommended for critically ill patients with any of the three conditions mentioned. Morphine may cause more hemodynamic instability than does hydromorphone or fentanyl because of more histamine release. In addition, morphine has a renally excreted, partially active metabolite that may accumulate in renal dysfunction. Hydromorphone and fentanyl do not have such a metabolite. The reason for using these agents in morphine allergy is self-explanatory.



A. According to the manufacturer, ketorolac should not be used longer than 5 days because of the high risk of GI bleeding with this drug.



E. According to SCCM guidelines, lorazepam is the sedative of choice in most critically ill patients requiring long-term sedation. Lorazepam is less expensive than propofol and has a longer duration of action than propofol or midazolam.



D. Under SCCM guidelines, pancuronium is the NMB agent of choice for most critically ill patients. Pancuronium is less expensive than the other agents.



A. Cisatracurium is metabolized by nonspecific plasma esterases, whereas pancuronium and vecuronium have varying degrees of hepatic and renal elimination. Thus, SCCM guidelines recommend cisatracurium for use in patients with renal and hepatic dysfunction.



C. According to SCCM guidelines, propofol is the sedative of choice for patients who require neurologic assessment often. Patients with traumatic brain injury may require multiple neurologic assessments daily. The short duration of action of propofol allows rapid wakening.



B. According to the Brain Trauma Foundation guidelines, phenytoin for 7 days postinjury is the regimen of choice for post-traumatic seizure prophylaxis in patients requiring such therapy.



C. This regimen is based on the results of the National Acute Spinal Cord Injury Study III trial. Some controversy exists regarding the study design of this trial and the actual efficacy of the drug for this indication; however, most clinicians treat acute spinal cord injury with high-dose methylprednisolone.



A. According to American College of Chest Physicians (ACCP) guidelines, low-dose LMWH is the drug of choice for VTE prophylaxis in a patient with multiple trauma. LMWH is acceptable in this patient because the organ injury is not actively bleeding. If the patient had active bleeding, then mechanical methods (intermittent pneumatic compression and elastic stocking) would be indicated instead of LMWH.



B. Manufacturers of LMWHs do not recommend using these agents in patients with epidural catheters because of case reports of clinically significant spinal hematomas. Full anticoagulation should also be avoided.



E. Thrombocytopenia is a common hematologic side effect of heparin. A severe drop in platelets during the first 7-14 days is a typical presentation.



A. According to ACCP guidelines, all forms of heparin must be discontinued. However, this patient requires acute, full anticoagulation for treatment of an active DVT. A direct thrombin inhibitor should be started. These agents do not cross react with heparin and potentiate thrombocytopenia.



B. According to ACCP guidelines, rapid, full anticoagulation with IV heparin or SC LMWH is recommended in most patients with uncomplicated DVT. Thrombolytic therapy is recommended only in selected patients with hemodynamic instability or a massive VTE.



D. Increased age is not an independent risk factor for stress ulcers.



A. According to American Society of Health-System Pharmacists guidelines, H2 antagonists and sucralfate are generally considered to be equally effective and are the drugs of choice. However, some controversy exists over the effect of H2 antagonists on pneumonia development. Therefore, some clinicians prefer sucralfate.



D. Drotrecogin alfa is a recombinant form of the endogenous anticoagulant activated protein C. The anticoagulant activity increases the risk of bleeding.



E. Dobutamine has no α1-adrenergic (vasoconstriction) activity.



A. M. W. is hyponatremic, and her clinical signs and symptoms indicate severe dehydration from GI losses of water and sodium. She requires rapid fluid resuscitation with a fluid that has an approximately physiologic amount of sodium (either NS 154 mEq/L or LR 130 mEq/L). This amount of sodium will increase her serum sodium into the normal range over time, and the osmotic effect will hold water in the extracellular compartment (the vasculature and interstitium) to help restore organ perfusion.



B. Loop diuretics enhance renal excretion of water, potassium, magnesium, and calcium.



A. R. T. is severely hypophosphatemic and requires high-dose IV therapy (0.64 mmol/kg × 70 kg = 44.8 mmol). The dose should be infused at 7.5 mmol/h (total time: 6 hours) to avoid precipitation with calcium.



C. ACE inhibitors cause hyperkalemia because of aldosterone inhibition.



E. Oral Kayexalate (sodium polystyrene sulfonate) does not act very quickly. It requires transit time through the intestines to bind potassium and create a gradient that pulls more potassium into the lumen of the GI tract.



C. Amphotericin B causes renal wasting of potassium and magnesium.



A. Oral potassium replacement therapy does not normally cause constipation. Cardiac arrhythmias are a concern if IV potassium is given faster than 10 mEq/h.



B. Magnesium salts (e.g., milk of magnesia) are often used as osmotic laxatives and may cause diarrhea. Calcium salts may cause constipation.


17-11. References

Allen ME, Kopp BJ, Erstad BL. Stress ulcer prophylaxis in the postoperative period. Am J Health Syst Pharm. 2004;61:588-96.

American Association of Neurological Surgeons and Congress of Neurological Surgeons. Pharmacological therapy after acute cervical spinal cord injury. Neurosurgery. 2002;50(3 suppl):S63-72.

American Society of Health-System Pharmacists Commission on Therapeutics. ASHP therapeutic guidelines on stress ulcer prophylaxis. Am J Health Syst Pharm. 1999;56:347-79.

Boucher BA, Clifton GD, Hanes SD. Critical care therapy. In: Helms RA, Quan DJ, Herfindal ET, Gourley DR, eds. Textbook of Therapeutics: Drug and Disease Management. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2006:655-73.

Boucher BA, Timmons SD. Acute management of the brain injury patient. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York: McGraw-Hill; 2008:965-76.

Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons. Guidelines for the Management of Severe Traumatic Brain Injury. New York: Brain Trauma Foundation; 2003.

Brophy DF, Gehr TWB. Disorders of potassium and magnesium homeostasis. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York: McGraw-Hill; 2008:877-88.

Corwin HL, Gettinger A, Fabian TC, et al. Efficacy and safety of epoetin alfa in critically ill patients. New Engl J Med. 2007;357:965-76.

Coyle JD, Joy MS. Disorders of sodium, water homeostasis. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York: McGraw-Hill; 2008: 845-60.

Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36:296-327.

Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133(suppl): 381S-453S.

Jacobi J, Fraser GL, Coursin DB, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med. 2002;30:119-41.

Kang-Birken SL, DiPiro JT. Sepsis and septic shock. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York: McGraw-Hill; 2008:1943-56.

Lau A, Chan LN. Electrolytes, other minerals, and trace elements. In: Lee M, ed. Basic Skills in Interpreting Laboratory Data. 3rd ed. Bethesda, Md.: American Society of Health-System Pharmacists; 2004:183-232.

Murray MJ, Cowen J, DeBlock H, et al. Clinical practice guidelines for sustained neuromuscular blockade in the critically ill patient. Crit Care Med. 2002;30:142-56.

Pai AB, Rohrscheib, Joy MS. Disorders of calcium and phosphorus homeostasis. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York: McGraw-Hill; 2008:861-76.