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28-1 HYPOVOLEMIC SHOCK A Glass Half Full. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Level II Brian L. Erstad, PharmD, FCCP, MCCM, FASHP Yvonne C. Huckleberry, PharmD, BCPS CASE SUMMARY A 20-year-old man with a history of Crohn disease, ankylosing spondylitis, and pulmonary coccidioidomycosis is hospitalized because of vomiting, diarrhea, fatigue, decreased oral intake, and fever. The patient has clinical signs of hypotension (volume depletion) that indicate the early stages of hypovolemic shock. The hypovolemia was apparently caused by a flare-up of Crohn disease that contributed to the patient’s abdominal pain, vomiting, and diarrhea and resulted in lost plasma volume. The gastrointestinal problems precluded adequate fluid intake that ultimately led to extracellular depletion. When considering alternatives for intravascular volume repletion, the reader must weigh the benefits and limitations of crystalloids versus colloids. The potential need for adjunctive therapies, such as inotropic agents and vasopressors, should also be considered. Dosage adjustment of concomitant medications (eg, fluconazole) in the face of acute kidney injury would not be warranted unless the process continues to worsen or does not improve with fluid resuscitation alone. Monitoring parameters should be directed toward achieving successful fluid resuscitation while minimizing the likelihood of fluid overload. The use of a TNF-blocker such as infliximab in a patient with a history of pulmonary coccidioidomycosis is very controversial, and some would consider its use to be contraindicated in this patient. However, this scenario was based on an actual case where the benefits were thought to exceed the risks, given the small cocci lesion noted in one lung on CXR, the relative lack of pulmonary symptoms (only cough was present in this patient on initial presentation), and the rapid decrease in cocci titers. Given the cocci concern, it is important that the fluconazole not be discontinued; additionally, the dose should only be decreased if the acute kidney injury is sustained or worsens despite fluid resuscitation. QUESTIONS Problem Identification 1.a. Create a list of the patient’s drug-related problems. • This patient is in early stages of shock (as noted by physical examination, vital signs, decreased urine output, and elevated creatinine), which initially requires treatment with fluids. • The patient will need dosage adjustments of renally eliminated medications (fluconazole) if the renal dysfunction is not reversed within the next 24–48 hours. • Medication nonadherence. • Possible infectious disease (including reactivation of pulmonary coccidioidomycosis, but seems unlikely with negative • A possible acid-base disorder is suggested by the elevated serum CO2 and increasing serum creatinine in the setting of hypotension without tachypnea. The elevated serum CO2 would argue against metabolic acidosis with lactic acid production that would be expected in septic shock and/or metabolic acidosis associated with acute kidney injury. Instead, a loss of acidic gastric contents with vomiting in excess of alkaline loss with persistent diarrhea might explain this patient’s increase in serum CO2. • Anemia is apparent as this patient has a decreased hemoglobin and hematocrit, even in the setting of significant hypovolemia. This may be due to subtle blood loss with Crohn ulcerations, overall malnutrition, or specific nutrient deficiencies. A workup for anemia would be warranted as part of outpatient follow-up. • Active flare-up of Crohn disease as indicated by elevated CRP and ESR and abdominal pain; azathioprine may cause gastrointestinal adverse effects, but this seems much less likely to be the primary etiology of the patient’s abdominal symptoms, given the indicators of a Crohn’s flare-up and the patient’s admission that he has not been routinely taking the medication. • Ankylosing spondylitis (does not appear to be cause of elevated CRP and ESR given gastrointestinal complaints consistent with Crohn’s flare-up). 1.b.What information (signs, symptoms, laboratory values) indicates the presence or severity of hypovolemic shock? • The presence of the early stages of shock is determined from inadequate oral intake of fluids, vomiting and diarrhea, decreased blood pressure, skin pallor, tachycardia, weak pulse, and acute kidney injury leading to decreased urine output and impending renal failure. Also, sodium and chloride concentrations tend to increase and decrease together in fluid disorders, and their elevation is not unexpected in a patient with hypovolemia. • Acute kidney injury is evidenced by the elevated BUN/ creatinine and decreased urine output. The relatively normal creatinine value is likely to be misleadingly low in early stages of renal dysfunction and in patients with decreased lean tissue mass (this patient is 13 kg below his ideal body weight of 73 kg). Desired Outcome 2.What are the goals of pharmacotherapy in this case? • Prevent progression of shock to a potentially life-threatening situation. • Reverse organ dysfunction (eg, acute kidney injury) related to shock. • Eliminate the patient’s symptoms of volume depletion and shock. • Resolve infectious process, if found. Copyright © 2017 by McGraw-Hill Education. All rights reserved. Hypovolemic Shock Brian J. Kopp, PharmD, BCPS, FCCM • Malnutrition as reflected by low albumin actual, weight less than ideal weight, and physical examination. CHAPTER 28 28 CXR) as evidenced by increased temperature and white blood cell count. If an infectious process is suspected, broad spectrum antibiotics should be administered as soon as possible considering the patient’s immunosuppression. Delay in antibiotic therapy has been associated with increased mortality for patients with septic shock.1 28-2 SECTION 2 • Treat underlying Crohn disease flare and optimize maintenance therapy. • Maintain long-term control of ankylosing spondylitis. Therapeutic Alternatives 3.a. What nondrug therapies might be useful for this patient? Cardiovascular Disorders • Subacutely: Parenteral nutrition is not indicated at this time since oral feedings should resume once the acute disease state resolves. Once feedings have resumed, the patient’s protein requirements will need to be evaluated in light of his decreased albumin and weight. • Chronically: Dietary compliance. Calorie requirements are approximately 15–20% above basal energy expenditure with <30% of calories obtained from saturated fat. Protein requirements typically average 0.8 g/kg per day, but should be increased in this patient to at least 1 g/kg per day by insuring adherence to whey protein shakes. Although the patient is underweight, he should be questioned about physical activity as a way of increasing lean weight and to relieve stress that is likely aggravating the Crohn disease. Stretching exercises would also be beneficial for his ankylosing spondylitis since he was found to have some limited mobility of his hips and knees on physical examination. After evaluation of anemia, nutrient supplementation, such as ferrous sulfate, may be warranted. 3.b.What feasible pharmacotherapeutic alternatives are available for treatment of shock and the associated laboratory alterations? Treatment of shock: • Oral rehydration solutions are appropriate and usually adequate therapy for acute diarrhea since they contain sodium, potassium, and glucose in addition to the fluid needed to replace losses. However, IV fluids are needed in cases such as this when the patient cannot drink the required volume to replace losses or when shock occurs. • Ringer’s lactate and normal saline solution are crystalloids that are near-isotonic, salt-containing fluids given intravenously for the treatment of shock. These fluids fill the extracellular space (all 1,000 mL of 1,000 mL infused), which is more important than intracellular filling in symptomatic patients with obvious intravascular depletion. Ringer’s lactate does contain small amounts of potassium that could accumulate in patients with ongoing acute kidney injury; thus, serum potassium concentrations should be monitored. • Balanced salt solutions (eg, Plasmalyte) are crystalloids that are isotonic and have physiologic amounts of sodium and chloride. In recent years, multiple studies have evaluated differences in outcomes between those that received chlorideliberal (normal saline, 4% albumin) and those that received chloride-restrictive (Plasmalyte, Hartmann solution) fluid resuscitation strategies in various critically ill patient populations. In addition to causing hyperchloremia and metabolic acidosis, fluid resuscitation with chloride-liberal solutions appears to increase the risk of acute kidney injury and need for renal replacement therapy.2 A meta-analysis that included 21 trials and more than 6200 critically ill and perioperative patients found similar results.3 While these results are preliminary and directly applicable to critically ill and perioperative patient populations, balanced salt solutions are a reasonable fluid resuscitation strategy in this patient. • Dextrose solutions for patients with intravascular depletion are not appropriate because only a small amount of the solution is Copyright © 2017 by McGraw-Hill Education. All rights reserved. retained in the extracellular space (eg, one third of the amount infused for 5% dextrose in water). • Colloids (eg, 5% albumin) may be considered if at least 2 L of crystalloid solution has been administered without an adequate response in monitoring parameters, although this use is controversial. Albumin has been compared with normal saline in a randomized multicenter study involving 6,997 patients admitted to intensive care units for fluid resuscitation.4 In this landmark trial, there were no statistically significant differences in overall mortality, length of stay, days of mechanical ventilation, or days of renal replacement therapy between 4% albumin and normal saline solution used for acute intravascular volume repletion. In addition, while albumin infusion is initially restricted to the intravascular space, substantial differences in the ratio of albumin to saline administration (1:1.4) were not demonstrated likely as a result of substantial leakage into the interstitial space that occurs within hours, even in patients without altered capillary permeability. Although clinicians need to be cautious in extrapolating the results of this multicenter trial to other patient populations and settings, it is increasingly difficult to justify the use of colloid products for hypovolemia given their higher cost and lack of increased efficacy or safety compared with crystalloid solutions. Starch solutions have been studied as an initial resuscitative strategy, although concerns related to coagulation abnormalities and acute kidney injury have limited their use historically.5 In recent years, newer starch solutions with lower molecular weights and less starch substitution (eg, 130/0.4) have been developed with the hope that they would alleviate some of the concerns related to the development of acute kidney injury. However, large randomized trials conducted in critically ill patients with or without sepsis demonstrated that patients receiving 6% hydroxyethyl starch 130/0.4 were more likely to require renal replacement therapy compared with patients receiving crystalloid solutions. Mortality rates at 90 days were also higher in the starch groups, although the differences were only statistically significant in patients with sepsis.6,7 Therefore, resuscitation with starch solutions should generally be avoided unless subsequent data from large, randomized controlled trials demonstrate that these products are safe to administer. • Albumin therapy may also be considered (albeit with a lack of published data) if the patient develops dyspnea, rales, or radiographic evidence of substantial interstitial fluid accumulation, assuming such findings are consistent with interstitial fluid accumulation caused by crystalloid administration despite inadequate responses in monitoring parameters (eg, blood pressure, urine output). If such problems develop, oxygen therapy, titrated by arterial blood gas determinations and/or oximetric recordings, will also be indicated. • Vasopressors (eg, norepinephrine, epinephrine, vasopressin) are used when continued evidence of shock persists despite adequate fluid resuscitation, particularly in patients with septic shock.1 These agents increase systemic blood pressure through vasoconstriction in desired and undesired vessels and may lead to ischemic adverse events such as tissue necrosis of extremities especially if fluid resuscitation is inadequate. • Inotropic agents (eg, dobutamine) are occasionally considered if there is an inadequate response to plasma expanders and/or vasopressor, particularly in specific patient populations (eg, heart failure) as determined by vital signs, hemodynamic indices, urine output, and physical examination. 28-3 Treatment of laboratory alterations: Optimal Plan 4.What drug, dosage form, dose, schedule, and duration of therapy are best for this patient? • Plasma expansion using a crystalloid solution is necessary for preventing the progression of shock. Begin by infusing 15 mL/kg of crystalloid solution (such as 0.9% sodium chloride or Ringer’s lactate) over approximately 2 hours. Administration of additional fluids is based on physical examination findings, heart rate, blood pressure (arterial if not rapidly responding to fluid resuscitation), and urine output in patients with urinary catheters. • Because the patient does not have a history of renal failure, it is possible that the patient’s acute kidney injury will reverse relatively quickly with adequate fluid resuscitation. Therefore, rather than immediately adjusting doses of renally eliminated medications, it may be more appropriate to wait until adequate resuscitation has been performed (within the first 24–48 hours) and see whether renal function improves quickly. • No specific interventions for the laboratory alterations are needed at this time other than replacement doses of electrolytes for low values such as potassium. • Empiric antimicrobials are not needed on admission since the temperature elevation is not substantial and the hypotension is likely due to extracellular fluid depletion associated with diarrhea and inadequate oral intake. Furthermore, some infectious forms of diarrhea (eg, C. difficile) may be caused or aggravated by antimicrobial agents. The scheduled infliximab infusion will need to be held until an infectious process, including possible reactivation of the patient’s pulmonary coccidioidomycosis, has been ruled out (which appears to be the case given the negative CXR). • Assuming an infectious disease process is ruled out, consideration could be given to short-course corticosteroid therapy to get the patient’s Crohn disease under control. Outcome Evaluation 5.What clinical and laboratory parameters are necessary to evaluate the therapy for achievement of the desired therapeutic outcome and to detect or prevent adverse events? • Initially, physical examination findings (eg, skin turgor), heart rate, blood pressure (preferably arterial), urine output (by bladder catheterization), and mental status should be monitored every 10–15 minutes and then with decreasing frequency as compensation for fluid losses is achieved. In addition, monitoring for clearance of elevated lactate levels, performing passive leg raises and using bedside ultrasonography to look for indicators that the patient has been adequately • As successful resuscitation occurs, one would expect the skin to have normal turgor. The heart rate and blood pressure recordings should return to normal pretreatment values. Urine output in healthy adults should be at least 0.5 mL/kg/ hour (assuming the patient is catheterized). Other signs and symptoms related to volume depletion (eg, fatigue, dry oral mucosa) should abate with successful resuscitation. Note that blood pressure alone is not adequate to monitor the progression or regression of shock. Normal blood pressure recordings, particularly from cuff measurements, do not necessarily imply adequate tissue perfusion and oxygenation. • Basic laboratory parameters (electrolytes including calcium, phosphorus, and magnesium, BUN, and creatinine) should be monitored at least once daily until stable. Admission cultures and a titer for C. difficile were ordered on admission; subsequent testing should be based on the patient’s clinical course. • Fluid intake and output should be monitored at least every nursing shift until stable, and then decreased to daily. • The most likely adverse effects of crystalloid and colloid therapies are fluid overload as a result of interstitial space expansion such as increasing ascitic fluid accumulation, leg edema or pulmonary edema as noted by physical exam, auscultation, and/or radiographic evidence. Development of congestive heart failure is a concern in patients with poor left ventricular function. • All medications that are renally eliminated will need to be adjusted as acute kidney injury improves or worsens (as noted by changes primarily in serum creatinine concentrations and urine output). • For the Crohn disease, control would include lack of abdominal pain, vomiting, and diarrhea and ability to achieve adequate oral intake without reoccurrence of these problems. • Monitoring for ankylosing spondylitis disease control would include improved range of motion, normalization or reduction in CRP and ESR, and lack of pain or swelling. Patient Education 6.What information should be provided to the patient to enhance adherence, ensure successful therapy, and minimize adverse effects? • With your Crohn disease, it is essential that you maintain appropriate fluid and food intake. When you do not drink enough liquids, your body cannot work properly and it may be harmful to many organs including your kidneys. We will have a dietitian see you regarding a healthy diet for your Crohn disease and ankylosing spondylitis. • If you have problems such as vomiting, diarrhea, or fatigue in the future contact your healthcare provider or me for helpful advice, which may prevent you from having to be hospitalized. • Finally, it is very important that you take your medications exactly as ordered. If you feel you are having a problem related to a medication, contact your healthcare provider or me for further instructions. Do not take any other medication, even over-the-counter products such as aspirin or antacids, without consulting one of us first. Copyright © 2017 by McGraw-Hill Education. All rights reserved. Hypovolemic Shock • Treatment of the underlying problems (shock, malnutrition, Crohn’s, and possibly infection) will lead to a normalization of the laboratory parameters, so no other interventions are needed other than replacement of electrolytes if low values are present. Arterial blood gases have been ordered, since the vomiting could have led to an acute metabolic alkalosis due to loss of stomach acid. The single episode of diarrhea would be unlikely to lead to substantial changes in the blood gases. fluid resuscitated can be useful, particularly in more critically ill patients where it may be difficult to determine when the end point of resuscitation has occurred. Daily weights and intake/ output should be monitored as other indicators of fluid status. In general, an adult patient will require 30–35 mL/kg per day of fluids to maintain euvolemia, so even larger amounts are required for patients with hypovolemia. CHAPTER 28 • Antimotility agents should not be considered for the diarrhea until an infectious cause has been ruled out, which would take approximately 2–3 days for the cultures and Clostridium difficile titer results to be reported by the clinical laboratory. In this case, the C. difficile titer result was negative. 28-4 ■■ FOLLOW-UP QUESTION SECTION 2 1.Explain why hypotonic IV fluids such as 5% dextrose are not indicated in a patient with overt hypovolemia who is going into shock. Cardiovascular Disorders • Hypovolemia is associated with extracellular, not intracellular, fluid depletion. For each 1 L of 5% dextrose administered by the IV route, only 333 mL is retained in the extracellular space. Furthermore, just over 80 mL is retained in the intravascular space where it is most needed for maintaining blood pressure and perfusion of organs. REFERENCES 1. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013;41:580–631. Copyright © 2017 by McGraw-Hill Education. All rights reserved. 2. Yunos NM, Bellomo R, Hegarty C, et al. Association between chlorideliberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA 2012;308:1566–1572. 3. Krajewski ML, Raghunathan K, Paluszkiewicz SM, et al. Meta-analysis of high- versus low-chloride content in perioperative and critical care fluid resuscitation. BJS 2015;102:24–36. 4. Finfer S, Bellomo R, Boyce N, et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004;350:2247–2256. 5.Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008;358:125–139. 6. Myburgh JA, Finfer S, Bellomo R, et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 2012;367:1901–1911. 7.Perner A, Haase N, Guttormsen AB, et al. Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med 2012;367:124–134.