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Surgery_Schwartz. in the first few days of an uncomplicated post-operative course. However, postoperative diuresis may require attention to replacement of urinary potassium loss. All measured losses, including losses through vomiting, nasogastric suction-ing, drains, and urine output, as well as insensible losses, are replaced with the appropriate parenteral solutions as previously reviewed.Fluid Management in Enhanced Recovery After Surgery (ERAS) PathwaysAs pioneered by the Danish surgeon Henrik Kehlet, ERAS path-ways have been designed to guide the perioperative management Brunicardi_Ch03_p0083-p0102.indd 9708/12/18 10:07 AM 98BASIC CONSIDERATIONSPART Iof various types of surgical procedures. ERAS consists of a mul-timodal strategy to maximize and maintain preoperative organ function, and implementation of ERAS protocols has resulted in a decrease in length of stay, improved patient satisfaction, cost savings, and a reduction in complications. A full discussion of ERAS is outside the scope of


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Surgery_Schwartz. of ERAS protocols has resulted in a decrease in length of stay, improved patient satisfaction, cost savings, and a reduction in complications. A full discussion of ERAS is outside the scope of this chapter; however, it is impor-tant to note that perioperative fluid management is a major tenet of ERAS protocols. The 2011 European Society of Anaesthesi-ology guidelines were among the first formal recommendations to alter standard recommendations for preoperative enteral intake. These recommendations include allowance of clear liq-uids up to 2 hours prior to surgery.36 Many ERAS protocols include the use of carbohydrate and electrolyte-rich fluids to enhance hydration and metabolic response to surgery. In addi-tion to preoperative enteral hydration, a major focus of ERAS protocols is the restriction of intraand postoperative sodium and intravenous fluids. Fluid overload has been associated with prolonged ileus and coagulation abnormalities.37 Goal-directed fluid therapy has been shown to


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Surgery_Schwartz. of intraand postoperative sodium and intravenous fluids. Fluid overload has been associated with prolonged ileus and coagulation abnormalities.37 Goal-directed fluid therapy has been shown to reduce postoperative morbidity and length of stay independent of the other multimodal compo-nents of ERAS, making minimizing fluids a major target of intervention.38 Postoperatively, early enteral intake is advised, with prompt discontinuation of intravenous fluids. These strate-gies targeting euvolemia have been shown to be safe and improve outcomes, making ERAS a rapidly evolving strat-egy that will continue to influence the perioperative fluid and electrolyte management of surgical patients.39,40Special Considerations for the Postoperative PatientVolume excess is a common disorder in the postoperative period. The administration of isotonic fluids in excess of actual needs may result in excess volume expansion. This may be due to the overestimation of third-space losses or to ongoing GI losses


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Surgery_Schwartz. period. The administration of isotonic fluids in excess of actual needs may result in excess volume expansion. This may be due to the overestimation of third-space losses or to ongoing GI losses that are difficult to measure accurately. The earliest sign of volume overload is weight gain. The average postopera-tive patient who is not receiving nutritional support should lose approximately 0.25 to 0.5 lb/d (0.11 to 0.23 kg/d) from catabo-lism. Additional signs of volume excess may also be present as listed in Table 3-2. Peripheral edema may not necessarily be associated with intravascular volume overload because overex-pansion of total ECF may exist in association with a deficit in the circulating plasma volume.Volume deficits also can be encountered in surgical patients if preoperative losses were not completely corrected, intraoperative losses were underestimated, or postoperative losses were greater than appreciated. The clinical manifestations are described in Table 3-2 and include


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Surgery_Schwartz. were not completely corrected, intraoperative losses were underestimated, or postoperative losses were greater than appreciated. The clinical manifestations are described in Table 3-2 and include tachycardia, orthostasis, and oliguria. Hemoconcentration also may be present. Treat-ment will depend on the amount and composition of fluid lost. In most cases of volume depletion, replacement with an isotonic fluid will be sufficient while alterations in concentration and composition are being evaluated.ELECTROLYTE ABNORMALITIES IN SPECIFIC SURGICAL PATIENTSNeurologic PatientsSyndrome of Inappropriate Secretion of Antidiuretic Hormone. The syndrome of inappropriate secretion of antidi-uretic hormone (SIADH) can occur after head injury or surgery to the central nervous system, but it also is seen in association with administration of drugs such as morphine, nonsteroidals, and oxytocin, and in a number of pulmonary and endocrine dis-eases, including hypothyroidism and glucocorticoid


Surgery_Schwartz

Surgery_Schwartz. is seen in association with administration of drugs such as morphine, nonsteroidals, and oxytocin, and in a number of pulmonary and endocrine dis-eases, including hypothyroidism and glucocorticoid deficiency. Additionally, it can be seen in association with a number of malignancies, most often small cell cancer of the lung but also pancreatic carcinoma, thymoma, and Hodgkin’s disease.41 SIADH should be considered in patients who are euvolemic and hyponatremic with elevated urine sodium levels and urine osmolality. ADH secretion is considered inap-propriate when it is not in response to osmotic or volume-related conditions. Correction of the underlying problem should be attempted when possible. In most cases, restriction of free water will improve the hyponatremia. The goal is to achieve net water balance while avoiding volume depletion that may compromise renal function. Furosemide also can be used to induce free water loss. If hyponatremia persists after fluid restriction, the


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Surgery_Schwartz. net water balance while avoiding volume depletion that may compromise renal function. Furosemide also can be used to induce free water loss. If hyponatremia persists after fluid restriction, the addition of isotonic or hypertonic fluids may be effective. The adminis-tration of isotonic saline may sometimes worsen the problem if the urinary sodium concentration is higher than the infused sodium concentration. The use of loop diuretics may be helpful in this situation by preventing further urine concentration. In chronic SIADH, when long-term fluid restriction is difficult to maintain or is ineffective, demeclocycline and lithium can be used to induce free water loss.Diabetes Insipidus. Diabetes insipidus (DI) is a disorder of ADH stimulation and is manifested by dilute urine in the case of hypernatremia. Central DI results from a defect in ADH secre-tion, and nephrogenic DI results from a defect in end-organ responsiveness to ADH. Central DI is frequently seen in asso-ciation with


Surgery_Schwartz

Surgery_Schwartz. of hypernatremia. Central DI results from a defect in ADH secre-tion, and nephrogenic DI results from a defect in end-organ responsiveness to ADH. Central DI is frequently seen in asso-ciation with pituitary surgery, closed head injury, and anoxic encephalopathy.42 Nephrogenic DI occurs in association with hypokalemia, administration of radiocontrast dye, and use of certain drugs such as aminoglycosides and amphotericin B. In patients tolerating oral intake, volume status usually is normal because thirst stimulates increased intake. However, volume depletion can occur rapidly in patients who are incapable of oral intake. The diagnosis can be confirmed by documenting a paradoxical increase in urine osmolality in response to a period of water deprivation. In mild cases, free water replacement may be adequate therapy. In more severe cases, vasopressin can be added. The usual dosage of vasopressin is 5 U subcutaneously every 6 to 8 hours. However, serum electrolytes and osmolality should


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Surgery_Schwartz. may be adequate therapy. In more severe cases, vasopressin can be added. The usual dosage of vasopressin is 5 U subcutaneously every 6 to 8 hours. However, serum electrolytes and osmolality should be monitored to avoid excess vasopressin administration with resulting iatrogenic SIADH.Cerebral Salt Wasting. Cerebral salt wasting is a diagnosis of exclusion that occurs in patients with a cerebral lesion and renal wasting of sodium and chloride with no other identifiable cause.43 Natriuresis in a patient with a contracted extracellular volume should prompt the possible diagnosis of cerebral salt wasting. Hyponatremia is frequently observed but is nonspecific and occurs as a secondary event, which differentiates it from SIADH.Malnourished Patients: Refeeding SyndromeRefeeding syndrome is a potentially lethal condition that can occur with rapid and excessive feeding of patients with severe underlying malnutrition due to starvation, alcoholism, delayed nutritional support, anorexia nervosa,


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Surgery_Schwartz. lethal condition that can occur with rapid and excessive feeding of patients with severe underlying malnutrition due to starvation, alcoholism, delayed nutritional support, anorexia nervosa, or massive weight loss in obese patients.44 With refeeding, a shift in metabolism from fat to carbohydrate substrate stimulates insulin release, which 678Brunicardi_Ch03_p0083-p0102.indd 9808/12/18 10:07 AM 99FLUID AND ELECTROLYTE MANAGEMENT OF THE SURGICAL PATIENTCHAPTER 3results in the cellular uptake of electrolytes, particularly phos-phate, magnesium, potassium, and calcium. However, severe hyperglycemia may result from blunted basal insulin secretion. The refeeding syndrome can be associated with enteral or par-enteral refeeding, and symptoms from electrolyte abnormalities include cardiac arrhythmias, confusion, respiratory failure, and even death. To prevent the development of refeeding syndrome, underlying electrolyte and volume deficits should be corrected. Additionally, thiamine


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Surgery_Schwartz. arrhythmias, confusion, respiratory failure, and even death. To prevent the development of refeeding syndrome, underlying electrolyte and volume deficits should be corrected. Additionally, thiamine should be administered before the initia-tion of feeding. Caloric repletion should be instituted slowly and should gradually increase over the first week.45 Vital signs, fluid balance, and electrolytes should be closely monitored and any deficits corrected as they evolve.Acute Renal Failure PatientsA number of fluid and electrolyte abnormalities are specific to patients with acute renal failure. With the onset of renal failure, an accurate assessment of volume status must be made. If prerenal azotemia is present, prompt correction of the underlying volume deficit is mandatory. Once acute tubular necrosis is established, measures should be taken to restrict daily fluid intake to match urine output and insensible and GI losses. Oliguric renal failure requires close monitoring of serum


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Surgery_Schwartz. tubular necrosis is established, measures should be taken to restrict daily fluid intake to match urine output and insensible and GI losses. Oliguric renal failure requires close monitoring of serum potassium levels. Measures to correct hyperkalemia as reviewed in Table 3-14 should be instituted early, including consideration of early hemodialysis. Hyponatremia is common in established renal failure as a result of the breakdown of proteins, carbohydrates, and fats, as well as the administration of free water. Dialysis may be required for severe hyponatremia. Hypocalcemia, hypermagnesemia, and hyperphosphatemia also are associated with acute renal failure. Hypocalcemia should be verified by measuring ionized calcium, because many patients also are hypoalbuminemic. Phosphate binders can be used to control hyperphosphatemia, but dialy-sis may be required in more severe cases. Metabolic acidosis is commonly seen with renal failure, as the kidneys lose their ability to clear acid


Surgery_Schwartz

Surgery_Schwartz. can be used to control hyperphosphatemia, but dialy-sis may be required in more severe cases. Metabolic acidosis is commonly seen with renal failure, as the kidneys lose their ability to clear acid by-products. Bicarbonate can be useful, but dialysis often is needed. Although dialysis may be either intermittent or continuous, renal recovery may be improved by continuous renal replacement.46Cancer PatientsFluid and electrolyte abnormalities are common in patients with cancer. The causes may be common to all patient populations or may be specific to cancer patients and their treatment.47 Hypo-natremia is frequently hypovolemic due to renal loss of sodium caused by diuretics or salt-wasting nephropathy as seen with some chemotherapeutic agents such as cisplatin. Cerebral salt wasting also can occur in patients with intracerebral lesions. Normovolemic hyponatremia may occur in association with SIADH from cervical cancer, lymphoma, and leukemia, or from certain chemotherapeutic agents.


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Surgery_Schwartz. can occur in patients with intracerebral lesions. Normovolemic hyponatremia may occur in association with SIADH from cervical cancer, lymphoma, and leukemia, or from certain chemotherapeutic agents. Hypernatremia in can-cer patients most often is due to poor oral intake or GI volume losses, which are common side effects of chemotherapy. Central DI also can lead to hypernatremia in patients with central ner-vous system lesions.Hypokalemia can develop from GI losses associated with diarrhea caused by radiation enteritis or chemotherapy, or from tumors such as villous adenomas of the colon. Tumor lysis syn-drome can precipitate severe hyperkalemia from massive tumor cell destruction.Hypocalcemia can be seen after removal of a thyroid or parathyroid tumor or after a central neck dissection, which can damage the parathyroid glands. Hungry bone syndrome produces acute and profound hypocalcemia after parathyroid surgery for secondary or tertiary hyperparathyroidism because calcium is rapidly


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Surgery_Schwartz. can damage the parathyroid glands. Hungry bone syndrome produces acute and profound hypocalcemia after parathyroid surgery for secondary or tertiary hyperparathyroidism because calcium is rapidly taken up by bones. Prostate and breast cancer can result in increased osteoblastic activity, which decreases serum calcium by increasing bone formation. Acute hypocalce-mia also can occur with hyperphosphatemia because phospho-rus complexes with calcium. Hypomagnesemia is a side effect of ifosfamide and cisplatin therapy. Hypophosphatemia can be seen in hyperparathyroidism, due to decreased phosphorus reabsorption, and in oncogenic osteomalacia, which increases the urinary excretion of phosphorus. Other causes of hypophos-phatemia in cancer patients include renal tubular dysfunction from multiple myeloma, Bence Jones proteins, and certain che-motherapeutic agents. Acute hypophosphatemia can occur as rapidly proliferating malignant cells take up phosphorus in acute leukemia. Tumor lysis


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Surgery_Schwartz. myeloma, Bence Jones proteins, and certain che-motherapeutic agents. Acute hypophosphatemia can occur as rapidly proliferating malignant cells take up phosphorus in acute leukemia. Tumor lysis syndrome or the use of bisphosphonates to treat hypercalcemia also can result in hyperphosphatemia.Malignancy is the most common cause of hypercalcemia in hospitalized patients and is due to increased bone resorption or decreased renal excretion. Bone destruction occurs from bony metastasis as seen in breast or renal cell cancer but also can occur in multiple myeloma. With Hodgkin’s and non-Hodgkin’s lymphoma, hypercalcemia results from increased calcitriol for-mation, which increases both absorption of calcium from the GI tract and mobilization from bone. Humoral hypercalcemia of malignancy is a common cause of hypercalcemia in cancer patients. As in primary hyperparathyroidism, a parathyroid-related protein is secreted that binds to parathyroid receptors, stimulating calcium resorption from


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Surgery_Schwartz. common cause of hypercalcemia in cancer patients. As in primary hyperparathyroidism, a parathyroid-related protein is secreted that binds to parathyroid receptors, stimulating calcium resorption from bone and decreasing renal excretion of calcium. The treatment of hypercalcemia of malig-nancy should begin with saline volume expansion, which will decrease renal reabsorption of calcium as the associated volume deficit is corrected. Once an adequate volume status has been achieved, a loop diuretic may be added. Unfortunately, these measures are only temporary, and additional treatment is often necessary. A variety of drugs are available with varying times of onset, durations of action, and side effects.48 The bisphos-phonates etidronate and pamidronate inhibit bone resorption and osteoclastic activity. They have a slow onset of action, but effects can last for 2 weeks. Calcitonin also is effective, inhibit-ing bone resorption and increasing renal excretion of calcium. It acts quickly,


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Surgery_Schwartz. activity. They have a slow onset of action, but effects can last for 2 weeks. Calcitonin also is effective, inhibit-ing bone resorption and increasing renal excretion of calcium. It acts quickly, within 2 to 4 hours, but its use is limited by the development of tachyphylaxis. Corticosteroids may decrease tachyphylaxis in response to calcitonin and can be used alone to treat hypercalcemia. Gallium nitrates are potent inhibitors of bone resorption. They display a long duration of action but can cause nephrotoxicity. Mithramycin is an antibiotic that blocks osteoclastic activity, but it can be associated with liver, renal, and hematologic abnormalities, which limits its use to the treatment of Paget’s disease of bone. For patients with severe, refractory hypercalcemia who are unable to tolerate volume expansion due to pulmonary edema or congestive heart failure, dialysis is an option.Tumor lysis syndrome results when the release of intracel-lular metabolites overwhelms the kidneys’


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Surgery_Schwartz. tolerate volume expansion due to pulmonary edema or congestive heart failure, dialysis is an option.Tumor lysis syndrome results when the release of intracel-lular metabolites overwhelms the kidneys’ excretory capacity. This rapid release of uric acid, potassium, and phosphorus can result in marked hyperuricemia, hyperkalemia, hyperphospha-temia, hypocalcemia, and acute renal failure. It is typically seen with poorly differentiated lymphomas and leukemias but also can occur with a number of solid tumor malignancies. Tumor lysis syndrome most commonly develops during treatment Brunicardi_Ch03_p0083-p0102.indd 9908/12/18 10:07 AM 100BASIC CONSIDERATIONSPART Iwith chemotherapy or radiotherapy. Once it develops, volume expansion should be undertaken and any associated electrolyte abnormalities corrected. In this setting, hypocalcemia should not be treated unless it is symptomatic to avoid metastatic calci-fications. Dialysis may be required for management of impaired renal function


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Surgery_Schwartz. corrected. In this setting, hypocalcemia should not be treated unless it is symptomatic to avoid metastatic calci-fications. Dialysis may be required for management of impaired renal function or correction of electrolyte abnormalities.REFERENCESEntries highlighted in bright blue are key references. 1. Aloia JF, Vaswani A, Flaster E, et al. Relationship of body water compartment to age, race and fat-free mass. J Lab Clin Med. 1998;132:483. 2. Bourque CW, Oliet SHR. Osmoreceptors in the central nervous system. Annu Rev Physiol. 1997;59:601. 3. Verbalis JG. How does the brain sense osmolality? J Am Soc Nephrol. 2007;18(12):3056. 4. Stauss HM. Baroreceptor reflex function. Am J Physiol Regul Integr Comp Physiol. 2002;283:R284. 5. Miller M. Syndromes of excess antidiuretic hormone release. Crit Care Clin. 2001;17:11. 6. Kapoor M, Chan G. Fluid and electrolyte abnormalities. Crit Care Clin. 2001;17:571. 7. Adrogue HJ, Lederer ED, Suki WN, et al. Determinants of plasma potassium in diabetic


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Surgery_Schwartz. Care Clin. 2001;17:11. 6. Kapoor M, Chan G. Fluid and electrolyte abnormalities. Crit Care Clin. 2001;17:571. 7. Adrogue HJ, Lederer ED, Suki WN, et al. Determinants of plasma potassium in diabetic ketoacidosis. Medicine. 1986;65:163. 8. Zietse R, Zuotendijk R, Hoorn EJ. Fluid, electrolyte and acid-base disorders associated with antibiotic therapy. Nat Rev Nephrol. 2009;5(4):193. 9. Cobos E, Hall RR. Effects of chemotherapy on the kidney. Semin Nephrol. 1993;13:297. 10. Gennari FJ. Hypokalemia. N Engl J Med. 1998;339:451. 11. French S, Subauste J, Geraci S. Calcium abnormalities in hos-pitalized patients. South Med J. 2012;105(4):231. 12. Witteveen JE, van Theil S, Romijn JA. Therapy of endo-crine disease: hungry bone syndrome. Eur J Endocrinol. 2013;168(3):R45. 13. Bushinsky DA, Monk RD. Calcium. Lancet. 1998;352:306. 14. Dunlay RW, Camp MA, Allon M, et al. Calcitriol in prolonged hypocalcemia due to tumor lysis syndrome. Ann Intern Med. 1989;110:162. 15. Reber PM, Heath H.


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Surgery_Schwartz. Monk RD. Calcium. Lancet. 1998;352:306. 14. Dunlay RW, Camp MA, Allon M, et al. Calcitriol in prolonged hypocalcemia due to tumor lysis syndrome. Ann Intern Med. 1989;110:162. 15. Reber PM, Heath H. Hypocalcemic emergencies. Med Clin North Am. 1995;19:93. 16. Tong GM, Rude RK. Magnesium deficiency in critical illness. J Intensive Care Med. 2005;20(1):3. 17. Quamme GA. Renal magnesium handling: new insights in understanding old problems. Kidney Int. 1997;52:1180. 18. Marino PL. Acid-base interpretations. In: Marino PL, ed. The ICU Book. 2nd ed. Baltimore: Williams & Wilkins; 1998:581. 19. Gluck SL. Acid-base. Lancet. 1998;352:474. 20. Kraut JA, Madias NE. Treatment of acute metabolic acidosis: a pathophysiologic approach. Nat Rev Nephrol. 2012;8(10):589. 21. Pal JD, Victorino GP, Twomey P, et al. Admission serum lactate levels do not predict mortality in the acutely injured patient. J Trauma. 2006;60:583. 22. Rizoli S. PlasmaLyte. J Trauma. 2011 May;70(5 Suppl):S17-8. 23. Roberts JS,


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Surgery_Schwartz. et al. Admission serum lactate levels do not predict mortality in the acutely injured patient. J Trauma. 2006;60:583. 22. Rizoli S. PlasmaLyte. J Trauma. 2011 May;70(5 Suppl):S17-8. 23. Roberts JS, Bratton SL. Colloid volume expanders: problems, pitfalls, and possibilities. Drugs. 1998;55:621. 24. Cottenceau V, Masson F, Mahamid E, et al. Comparison effects of equiosmolar doses of mannitol and hypertonic saline on cerebral blood flow and metabolism in traumatic brain injury. J Neurotrauma. 2011;28(10):2003. 25. Berger-Pelleiter E, Emond M, Lauzier F, et al. Hypertonic saline in severe traumatic brain injury: a systematic review and meta-analysis of randomized controlled trials. CJEM. 2016 Mar;18(2):112-120. This meta-analysis demonstrated no mortality benefit or effect on intracranial pressure control utilizing hypertonic saline and was a key summary of eleven major trials in the field. 26. Annane D, Siami S, Jaber S, et al. Effects of fluid resuscita-tion with colloids vs


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Surgery_Schwartz. pressure control utilizing hypertonic saline and was a key summary of eleven major trials in the field. 26. Annane D, Siami S, Jaber S, et al. Effects of fluid resuscita-tion with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial. JAMA. 2013 Nov 6;310(17):1809-1817. This multi-center randomized trial found no difference in mor-tality at 28 days in a mixed ICU population of patients with hypovolemia when comparing colloid to crystalloid resuscita-tion. The authors observed a reduction in 90-day mortality in the group receiving colloids; however, they cautioned that this observation was exploratory and required further analysis. 27. Perel P, Roberts I, Ker K. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Data-base Syst Rev. 2013 Feb 28;(2):CD000567. This Cochrane review of 70 trials including mortality data found no benefit to colloid resuscitation for reduction


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Surgery_Schwartz. in critically ill patients. Cochrane Data-base Syst Rev. 2013 Feb 28;(2):CD000567. This Cochrane review of 70 trials including mortality data found no benefit to colloid resuscitation for reduction of risk of mor-tality, while the use of hydroxyethyl starch (HES) was found to have a possible association with increased mortality. The recom-mendation of the review was that colloid use in the ICU could not be supported due to increased cost and no mortality benefit. 28. Myburgh JA, Finfer S, Bellomo R, et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012 Nov 15;367(20):1901-1911. In a randomized trial designed to address a primary outcome of 90-day mortality, the use of HES revealed no mortality benefit over saline with a statistically significant increase in the rate of renal replacement therapy after HES use. 29. Overgaard-Steensen C, Ring T. Clinical review: practical approach to hyponatremia and hypernatremia in critically ill


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Surgery_Schwartz. significant increase in the rate of renal replacement therapy after HES use. 29. Overgaard-Steensen C, Ring T. Clinical review: practical approach to hyponatremia and hypernatremia in critically ill patients. Crit Care. 2013;17(1):206. 30. Norenberg MD. Central pontine myelinolysis: historical and mechanistic considerations. Metab Brain Dis. 2010;25(1):97. 31. Graff-Radford J, Fugate JE, Kauffmann TJ. Clinical and radio-logic correlations of central pontine myelinolysis syndrome. Mayo Clin Proc. 2011;86(11):1063. 32. American College of Surgeons. Shock. In: American College of Surgeons Advanced Trauma Life Support Manual. 9th ed. Chicago: American College of Surgeons; 2012. 33. Shires GT, Williams J, Brown F. Acute changes in extracel-lular fluids associated with major surgical procedures. Ann Surg. 1961;154:803. This early paper by Shires and colleagues produced important early observations of fluid shifts and resuscitation strategies fol-lowing surgery and shaped some of the early


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Surgery_Schwartz. Ann Surg. 1961;154:803. This early paper by Shires and colleagues produced important early observations of fluid shifts and resuscitation strategies fol-lowing surgery and shaped some of the early questions in the field of resuscitation science after surgery. 34. Shires GT, Jackson DE. Postoperative salt tolerance. Arch Surg. 1962;84:703. 35. Shires GT III, Peitzman AB, Albert SA, et al. Response of extravascular lung water to intraoperative fluids. Ann Surg. 1983;197:515. 36. Smith I, Kranke P, Murat I, et al. Perioperative fasting in adults and children: guidelines from the European Society of Anaesthesiology. Eur J Anaesthesiol. 2011;28:556-569. Index guidelines published by the European Society of Anaes-thesiology were among the first to support the use of ERAS principles and provided a template for the design of the rapidly evolving practice of ERAS worldwide. 37. Horosz B, Nawrocka K, Malec-Milewska M. Anaesthetic peri-operative management according to the ERAS protocol.


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Surgery_Schwartz. a template for the design of the rapidly evolving practice of ERAS worldwide. 37. Horosz B, Nawrocka K, Malec-Milewska M. Anaesthetic peri-operative management according to the ERAS protocol. Anaes-thesiol Intensive Ther. 2016;48(1):49-54. 38. Rollins KE, Lobo DN. Intraoperative goal-directed fluid therapy in elective major abdominal surgery: a meta-analysis of randomized controlled trials. Ann Surg. 2016 Mar;263(3):465-476. Meta-analysis of randomized controlled trials demonstrated a marked reduction in morbidity, hospital length of stay (LOS), Brunicardi_Ch03_p0083-p0102.indd 10008/12/18 10:07 AM 101FLUID AND ELECTROLYTE MANAGEMENT OF THE SURGICAL PATIENTCHAPTER 3ICU LOS, and time to passage of feces utilizing goal-directed fluid therapy (GDFT) for intraoperative fluid management. Of note, in those studies where a multimodal ERAS pathway was utilized, the benefits of GDFT were reduced, although reduc-tion in major morbidities remained. These data suggest that the multimodal


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Surgery_Schwartz. Of note, in those studies where a multimodal ERAS pathway was utilized, the benefits of GDFT were reduced, although reduc-tion in major morbidities remained. These data suggest that the multimodal benefits of ERAS may extend beyond just fluid management. 39. Miller TE, Roche AM, Mythen M. Fluid management and goal-directed therapy as an adjunct to enhanced recovery after sur-gery (ERAS). Can J Anaesth. 2015 Feb;62(2):158-168. 40. Liu VX, Rosas E, Hwang J, et al. Enhanced recovery after surgery program implementation in 2 surgical populations in an integrated health care delivery system. JAMA Surg. 2017 Jul 19;152(7):e171032. 41. Ellison DH, Burl T. Clinical practice. The syndrome of inap-propriate antidiuresis. N Engl J Med. 2007;356(20):2064. 42. Tisdall M, Crocker M, Watkiss J, et al. Disturbances of sodium in critically ill adult neurologic patients: a clinical review. J Neurosurg Anesthesiol. 2006;18(1):57. 43. Yee AH, Burns JD, Wijdicks EF. Cerebral salt wasting:


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Surgery_Schwartz. J, et al. Disturbances of sodium in critically ill adult neurologic patients: a clinical review. J Neurosurg Anesthesiol. 2006;18(1):57. 43. Yee AH, Burns JD, Wijdicks EF. Cerebral salt wasting: patho-physiology, diagnosis, and treatment. Neurosurg Clin N Am. 2010;21(2):339. 44. Kozar RA, McQuiggan MM, Moore FA. Nutritional support in trauma patients. In: Shikora SA, Martindale RG, Schwaitzberg SD, eds. Nutritional Considerations in the Intensive Care Unit. 1st ed. Dubuque, IA: Kendall/Hunt Publishing; 2002:229. 45. Boateng AA, Sriram K, Mequid MM, et al. Refeeding syn-drome: treatment considerations based on collective analysis of literature case reports. Nutrition. 2010;26(2):156. 46. Glassford NJ, Bellomo R. Acute kidney injury: how can we facilitate recovery? Curr Opin Crit Care. 2011;17(6):562. 47. Kapoor M, Chan GZ. Fluid and electrolyte abnormalities. Crit Care Clin. 2002;17:503. 48. Clines GA. Mechanisms and treatment of hypercalce-mia of malignancy. Curr Opin Endocrinol


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Surgery_Schwartz. 2011;17(6):562. 47. Kapoor M, Chan GZ. Fluid and electrolyte abnormalities. Crit Care Clin. 2002;17:503. 48. Clines GA. Mechanisms and treatment of hypercalce-mia of malignancy. Curr Opin Endocrinol Diabetes Obes. 2011;18(6):339.Brunicardi_Ch03_p0083-p0102.indd 10108/12/18 10:07 AM


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Surgery_Schwartz. Hemostasis, Surgical Bleeding, and TransfusionRonald Chang, John B. Holcomb, Evan Leibner, Matthew Pommerening, and Rosemary A. Kozar 4chapterBIOLOGY OF HEMOSTASISHemostasis is a complex process whose function is to limit blood loss from an injured vessel. Four major physiologic events participate in the hemostatic process: vascular constric-tion, platelet plug formation, fibrin formation, and fibrinolysis. Although each tends to be activated in order, the four processes are interrelated so that there is a continuum and multiple rein-forcements. The process is shown schematically in Fig. 4-1.Vascular ConstrictionVascular constriction is the initial response to vessel injury. It is more pronounced in vessels with medial smooth muscles and is dependent on local contraction of smooth muscle. Vasoconstric-tion is subsequently linked to platelet plug formation. Throm-boxane A2 (TXA2) is produced locally at the site if injury via the release of arachidonic acid from platelet membranes and


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Surgery_Schwartz. Vasoconstric-tion is subsequently linked to platelet plug formation. Throm-boxane A2 (TXA2) is produced locally at the site if injury via the release of arachidonic acid from platelet membranes and is a potent constrictor of smooth muscle. Similarly, endothelin synthesized by injured endothelium and serotonin (5-hydroxy-tryptamine [5-HT]) released during platelet aggregation are potent vasoconstrictors. Lastly, bradykinin and fibrinopeptides, which are involved in the coagulation schema, are also capable of contracting vascular smooth muscle.The extent of vasoconstriction varies with the degree of vessel injury. A small artery with a lateral incision may remain open due to physical forces, whereas a similarly sized vessel that is completely transected may contract to the extent that bleeding ceases spontaneously.Platelet FunctionPlatelets are anucleate fragments of megakaryocytes. The nor-mal circulating number of platelets ranges between 150,000 and 400,000/μL. Up to 30% of


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Surgery_Schwartz. bleeding ceases spontaneously.Platelet FunctionPlatelets are anucleate fragments of megakaryocytes. The nor-mal circulating number of platelets ranges between 150,000 and 400,000/μL. Up to 30% of circulating platelets may be sequestered in the spleen. If not consumed in a clotting reaction, platelets are normally removed by the spleen and have an aver-age life span of 7 to 10 days.Platelets play an integral role in hemostasis by forming a hemostatic plug and by contributing to thrombin formation (Fig. 4-2). Platelets do not normally adhere to each other or to the vessel wall but can form a plug that aids in cessation of bleeding when vascular disruption occurs. Injury to the intimal layer in the vascular wall exposes subendothelial collagen to which platelets adhere. This process requires von Willebrand factor (vWF), a protein in the subendothelium that is lacking in patients with von Willebrand’s disease. vWF binds to glycopro-tein (GP) I/IX/V on the platelet membrane. Following


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Surgery_Schwartz. von Willebrand factor (vWF), a protein in the subendothelium that is lacking in patients with von Willebrand’s disease. vWF binds to glycopro-tein (GP) I/IX/V on the platelet membrane. Following adhesion, platelets initiate a release reaction that recruits other platelets from the circulating blood to seal the disrupted vessel. Up to this point, this process is known as primary hemostasis. Platelet aggregation is reversible and is not associated with secretion. Additionally, heparin does not interfere with this reaction, and thus, hemostasis can occur in the heparinized patient. Adenosine diphosphate (ADP) and serotonin are the principal mediators in platelet aggregation.Arachidonic acid released from the platelet membranes is converted by cyclooxygenase to prostaglandin G2 (PGG2) and then to prostaglandin H2 (PGH2), which, in turn, is converted to TXA2. TXA2 has potent vasoconstriction and platelet aggrega-tion effects. Arachidonic acid may also be shuttled to adjacent endothelial


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Surgery_Schwartz. to prostaglandin H2 (PGH2), which, in turn, is converted to TXA2. TXA2 has potent vasoconstriction and platelet aggrega-tion effects. Arachidonic acid may also be shuttled to adjacent endothelial cells and converted to prostacyclin (PGI2), which is a vasodilator and acts to inhibit platelet aggregation. Platelet cyclooxygenase is irreversibly inhibited by aspirin and revers-ibly blocked by nonsteroidal anti-inflammatory agents but is not affected by cyclooxygenase-2 (COX-2) inhibitors.In the second wave of platelet aggregation, a release reaction occurs in which several substances including ADP, Ca2+, serotonin, TXA2, and α-granule proteins are discharged. Biology of Hemostasis 103Vascular Constriction / 103Platelet Function / 103Coagulation / 104Fibrinolysis / 106Congenital Factor Deficiencies 106Coagulation Factor Deficiencies / 106Platelet Functional Defects / 107Acquired Hemostatic Defects 108Platelet Abnormalities / 108Acquired Hypofibrinogenemia / 110Myeloproliferative Diseases


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Surgery_Schwartz. Factor Deficiencies / 106Platelet Functional Defects / 107Acquired Hemostatic Defects 108Platelet Abnormalities / 108Acquired Hypofibrinogenemia / 110Myeloproliferative Diseases / 110Coagulopathy of Liver Disease / 110Coagulopathy of Trauma / 111Acquired Coagulation Inhibitors / 112Anticoagulation and Bleeding / 112Topical Hemostatic Agents / 115Transfusion 115Background / 115Replacement Therapy/ 115Indications for Replacement of Blood and Its Elements / 117Volume Replacement / 117New Concepts in Resuscitation / 117Prehospital Transfusion / 119Whole Blood Resuscitation / 121Fibrinogen Replacement / 121Complications of Transfusion (Table 4-9) / 121Tests of Hemostasis and Blood Coagulation 123Evaluation of Excessive Intraoperative or Postoperative Bleeding 124Brunicardi_Ch04_p0103-p0130.indd 10329/01/19 11:05 AM 104Figure 4-1. Biology of hemostasis. The four phys-iologic processes that interrelate to limit blood loss from an injured vessel are illustrated and include vascular


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Surgery_Schwartz. 10329/01/19 11:05 AM 104Figure 4-1. Biology of hemostasis. The four phys-iologic processes that interrelate to limit blood loss from an injured vessel are illustrated and include vascular constriction, platelet plug formation, fibrin clot formation, and fibrinolysis.Key Points1 The life span of platelets ranges from 7 to 10 days. Drugs that interfere with platelet function include aspirin, clopido-grel, prasugrel, dipyridamole, and the glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors. Approximately 5 to 7 days should pass from the time the drug is stopped until an elective pro-cedure is performed.2 Laboratory evidence of trauma-induced coagulopathy is found in up to one-third of severely injured patients at admission. It is distinct from disseminated intravascular coagulopathy and iatrogenic causes of coagulopathy such as hemodilution. Several non–mutually exclusive mechanisms have been proposed. However, the relationship between laboratory coagulation abnormalities and clinically


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Surgery_Schwartz. causes of coagulopathy such as hemodilution. Several non–mutually exclusive mechanisms have been proposed. However, the relationship between laboratory coagulation abnormalities and clinically evident coagulopathic bleeding is unclear.3 Direct oral anticoagulants have no readily available method for monitoring anticoagulation. A new monoclonal antibody has been approved to reverse coagulopathy due to dabiga-tran, and agents are currently in clinical trials for the reversal of direct factor Xa oral anticoagulants.4 When determining the need for bridging of therapeutic anti-coagulation in the preoperative and postoperative setting, the patient’s risk of bleeding should be carefully considered against the risk of thromboembolism and used to guide the need for reversal of anticoagulation therapy preoperatively and the timing of its reinstatement postoperatively.5 Damage control resuscitation has three basic components: permissive hypotension, minimizing crystalloid-based resus-citation,


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Surgery_Schwartz. preoperatively and the timing of its reinstatement postoperatively.5 Damage control resuscitation has three basic components: permissive hypotension, minimizing crystalloid-based resus-citation, and the administration of balanced ratios of blood products.6 The need for massive transfusion should be anticipated, and guidelines should be in place to provide early and balanced amounts of red blood cells, plasma, and platelets.Fibrinogen is a required cofactor for this process, acting as a bridge for the GP IIb/IIIa receptor on the activated platelets. The release reaction results in compaction of the platelets into a plug, a process that is no longer reversible. Thrombospondin, another protein secreted by the α-granule, stabilizes fibrino-gen binding to the activated platelet surface and strengthens the platelet-platelet interactions. Platelet factor 4 (PF4) and α-thromboglobulin are also secreted during the release reac-tion. PF4 is a potent heparin antagonist. The second wave of


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Surgery_Schwartz. strengthens the platelet-platelet interactions. Platelet factor 4 (PF4) and α-thromboglobulin are also secreted during the release reac-tion. PF4 is a potent heparin antagonist. The second wave of platelet aggregation is inhibited by aspirin and nonsteroidal anti-inflammatory drugs, by cyclic adenosine monophosphate (cAMP), and by nitric oxide. As a consequence of the release reaction, alterations occur in the phospholipids of the platelet membrane that allow calcium and clotting factors to bind to the platelet surface, forming enzymatically active complexes. The altered lipoprotein surface (sometimes referred to as platelet factor 3) catalyzes reactions that are involved in the conversion of prothrombin (factor II) to thrombin (factor IIa) by activated factor X (Xa) in the presence of factor V and calcium, and it is involved in the reaction by which activated factor IX (IXa), fac-tor VIII, and calcium activated factor X. Platelets may also play a role in the initial activation of


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Surgery_Schwartz. factor V and calcium, and it is involved in the reaction by which activated factor IX (IXa), fac-tor VIII, and calcium activated factor X. Platelets may also play a role in the initial activation of factors XI and XII.CoagulationHemostasis involves a complex interplay and combination of interactions between platelets, the endothelium, and multiple circulating or membrane-bound coagulation factors. While overly simplistic and not reflective of the depth or complexity of these interactions, the coagulation cascade has traditionally been depicted as two possible pathways converging into a single Common pathwayIntrinsic pathwayClotting factorsVIII, IX, X, XI, XIIFibrin1. Vascular phase(Vasoconstriction)2. Platelet phase(Platelets aggregate)3. Coagulation phase (Clot formation)(Clot retraction)4. Fibrinolysis(Clot destruction)Extrinsic pathwayClotting factorsVIIProthrombinThrombinCA2+vCA2+Brunicardi_Ch04_p0103-p0130.indd 10429/01/19 11:05 AM 105HEMOSTASIS, SURGICAL BLEEDING, AND


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Surgery_Schwartz. Fibrinolysis(Clot destruction)Extrinsic pathwayClotting factorsVIIProthrombinThrombinCA2+vCA2+Brunicardi_Ch04_p0103-p0130.indd 10429/01/19 11:05 AM 105HEMOSTASIS, SURGICAL BLEEDING, AND TRANSFUSIONCHAPTER 4common pathway (Fig. 4-3). While this pathway reflects the basic process and sequences that lead to the formation of a clot, the numerous feedback loops, endothelial interplay, and platelet functions are not included. The intrinsic pathway begins with the activation of factor XII that subsequently activates factors XI, IX, and VIII. In this pathway, each of the primary factors is “intrinsic” to the circulating plasma, whereby no surface is required to initi-ate the process. In the extrinsic pathway, tissue factor (TF) is released or exposed on the surface of the endothelium, binding to circulating factor VII, facilitating its activation to VIIa. Each of these pathways continues on to a common sequence that begins with the activation of factor X to Xa (in the presence of VIIIa).


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Surgery_Schwartz. to circulating factor VII, facilitating its activation to VIIa. Each of these pathways continues on to a common sequence that begins with the activation of factor X to Xa (in the presence of VIIIa). Subsequently, Xa (with the help of factor Va) converts factor II (prothrombin) to thrombin and then factor I (fibrinogen) to fibrin. Clot formation occurs after fibrin monomers are cross-linked to polymers with the assistance of factor XIII.One convenient feature of depicting the coagulation cas-cade with two merging arms is that commonly used laboratory tests segregate abnormalities of clotting to one of the two arms. An elevated activated partial thromboplastin time (aPTT) is associated with abnormal function of the intrinsic arm of the cascade (II, IX, X, XI, XII), while the prothrombin time (PT) is associated with the extrinsic arm (II, VII, X). Vitamin K defi-ciency or warfarin use affects factors II, VII, IX, and X.Expanding from the basic concept of Fig. 4-3, the cell-based model of


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Surgery_Schwartz. (PT) is associated with the extrinsic arm (II, VII, X). Vitamin K defi-ciency or warfarin use affects factors II, VII, IX, and X.Expanding from the basic concept of Fig. 4-3, the cell-based model of hemostasis, divided into the initiation, ampli-fication, and propagation phases, provides a more complete picture of clot formation. During initiation, the primary pathway for coagulation is initiated by TF exposure following suben-dothelial injury. TF binds to VIIa, and this complex catalyzes the activation of factor X to Xa and IX to IXa, which in turn activates factor V to Va. This “prothrombinase” complex gener-ates small amounts of thrombin from prothrombin in a calcium-dependent process. During amplification, platelets adhere to extracellular matrix components at the site of injury and become activated upon exposure to thrombin and other stimuli. Finally, during the propagation phase, “tenase” (factor VIIIa/IXa) and prothrombinase (factor Va/Xa) complexes are assembled on the


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Surgery_Schwartz. and become activated upon exposure to thrombin and other stimuli. Finally, during the propagation phase, “tenase” (factor VIIIa/IXa) and prothrombinase (factor Va/Xa) complexes are assembled on the surfaces of activated platelets. This results in large-scale genera-tion of thrombin (“thrombin burst”) and fibrin.In building on the redundancy inherent in the coagulation system, factor VIIIa combines with IXa to form the intrinsic factor complex. Factor IXa is responsible for the bulk of the conversion of factor X to Xa. This complex (VIIIa-IXa) is 50 times more effective at catalyzing factor X activation than is the extrinsic (TF-VIIa) complex and five to six orders of mag-nitude more effective than factor IXa alone.Once formed, thrombin leaves the membrane surface and converts fibrinogen by two cleavage steps into fibrin and two small peptides termed fibrinopeptides A and B. Removal of fibrinopeptide A permits end-to-end polymerization of the fibrin molecules, whereas cleavage of


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Surgery_Schwartz. by two cleavage steps into fibrin and two small peptides termed fibrinopeptides A and B. Removal of fibrinopeptide A permits end-to-end polymerization of the fibrin molecules, whereas cleavage of fibrinopeptide B allows side-to-side polymerization of the fibrin clot. This latter step is Platelet hemostaticfunctionVasoconstrictionADP, serotonin,Ca2+, fibrinogenADP, serotonin,Ca2+, fibrinogenSubendothelial collagenPlatelet adhesion secretionPlatelet aggregation secretionPlatelet aggregationPlatelet-fibrinthrombus(Reversible)(Irreversible)Coagulation activationvia tissue factor-factor VIIaIXa, XaComplexes onactivated plateletsThrombin+FibrinogenVascular endothelialinjuryFigure 4-2. Schematic of platelet activation and thrombus function.Figure 4-3. Schematic of the coagulation system. HMW = high molecular weight.Tissue factor-Factor VIIaInflammationComplement activationFibrinolysisPhysiologicFactor VFactor VaCa2+PhospholipidCa2+Ca2+Prothrombin(factor II) Thrombin(factor


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Surgery_Schwartz. system. HMW = high molecular weight.Tissue factor-Factor VIIaInflammationComplement activationFibrinolysisPhysiologicFactor VFactor VaCa2+PhospholipidCa2+Ca2+Prothrombin(factor II) Thrombin(factor IIa)IntrinsicSurfaceFactor XIIFactor XIIa KallikreinPrekallikreinHMW kininogenSurfaceFactor XIaFactor IXaFactor XIFactor IXExtrinsicVascular injuryTissue factor +factor VIIFactor XaFactor XCa2+FibrinFactor XIIIFibrinFactor XIIIaX-Linked fibrinFibrinogenFactor VIIIaCa2+PhospholipidFactor VIIIBrunicardi_Ch04_p0103-p0130.indd 10529/01/19 11:05 AM 106BASIC CONSIDERATIONSPART Ifacilitated by thrombin-activatable fibrinolysis inhibitor (TAFI), which acts to stabilize the resultant clot.In seeking to balance profound bleeding with overwhelm-ing clot burden, several related processes exist to prevent prop-agation of the clot beyond the site of injury.1 First, feedback inhibition on the coagulation cascade deactivates the enzyme complexes leading to thrombin formation. Thrombomodulin (TM)


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Surgery_Schwartz. prevent prop-agation of the clot beyond the site of injury.1 First, feedback inhibition on the coagulation cascade deactivates the enzyme complexes leading to thrombin formation. Thrombomodulin (TM) presented by the endothelium serves as a “thrombin sink” by forming a complex with thrombin, rendering it no longer available to cleave fibrinogen. This then activates protein C (APC) and reduces further thrombin generation by inhibiting factors V and VIII. Second, tissue plasminogen activator (tPA) is released from the endothelium following injury, cleaving plasminogen to initiate fibrinolysis. APC then consumes plas-minogen activator inhibitor-1 (PAI-1), leading to increased tPA activity and fibrinolysis. Building on the anticoagulant response to inhibit thrombin formation, tissue factor pathway inhibitor (TFPI) is released, blocking the TF-VIIa complex and reducing the production of factors Xa and IXa. Antithrombin III (AT-III) then neutralizes all of the procoagulant serine proteases


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Surgery_Schwartz. inhibitor (TFPI) is released, blocking the TF-VIIa complex and reducing the production of factors Xa and IXa. Antithrombin III (AT-III) then neutralizes all of the procoagulant serine proteases and also inhibits the TF-VIIa complex. The most potent mechanism of thrombin inhibition involves the APC system. APC forms a complex with its cofactor, protein S, on a phospholipid surface. This complex then cleaves factors Va and VIIIa so that they are no longer able to participate in the formation of TF-VIIa or pro-thrombinase complexes. This is of interest clinically in the form of a genetic mutation, called factor V Leiden. In this setting, factor V is resistant to cleavage by APC, thereby remaining active as a procoagulant. Patients with factor V Leiden are pre-disposed to venous thromboembolic events.Degradation of fibrin clot is accomplished by plasmin, a serine protease derived from the proenzyme plasminogen. Plas-min formation occurs as a result of one of several plasminogen


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Surgery_Schwartz. events.Degradation of fibrin clot is accomplished by plasmin, a serine protease derived from the proenzyme plasminogen. Plas-min formation occurs as a result of one of several plasminogen activators. tPA is made by the endothelium and other cells of the vascular wall and is the main circulating form of this family of enzymes. tPA is selective for fibrin-bound plasminogen so that endogenous fibrinolytic activity occurs predominately at the site of clot formation. The other major plasminogen activa-tor, urokinase plasminogen activator (uPA), also produced by endothelial cells as well as by urothelium, is not selective for fibrin-bound plasminogen. Of note, the thrombin-TM complex activates TAFI, leading to a mixed effect on clot stability. In addition to inhibiting fibrinolysis directly, removal of the termi-nal lysine on the fibrin molecule by TAFI renders the clot more susceptible to lysis by plasmin.FibrinolysisFibrin clot breakdown (lysis) allows restoration of blood flow during the


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Surgery_Schwartz. of the termi-nal lysine on the fibrin molecule by TAFI renders the clot more susceptible to lysis by plasmin.FibrinolysisFibrin clot breakdown (lysis) allows restoration of blood flow during the healing process following injury and begins at the same time clot formation is initiated. Fibrin polymers are degraded by plasmin, a serine protease derived from the pro-enzyme plasminogen. Plasminogen is converted to plasmin by one of several plasminogen activators, including tPA. Plasmin then degrades the fibrin mesh at various places, leading to the production of circulating fragments, termed fibrin degradation products (FDPs), cleared by other proteases or by the kidney and liver (Fig. 4-4). Fibrinolysis is directed by circulating kinases, tissue activators, and kallikrein present in vascular endothelium. tPA is synthesized by endothelial cells and released by the cells on thrombin stimulation. Bradykinin, a potent endothelial-dependent vasodilator, is cleaved from high molecular weight


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Surgery_Schwartz. endothelium. tPA is synthesized by endothelial cells and released by the cells on thrombin stimulation. Bradykinin, a potent endothelial-dependent vasodilator, is cleaved from high molecular weight kininogen by kallikrein and enhances the release of tPA. Both tPA and plasminogen bind to fibrin as it forms, and this trimo-lecular complex cleaves fibrin very efficiently. After plasmin is generated, however, it cleaves fibrin somewhat less efficiently.As with clot formation, fibrinolysis is also kept in check through several robust mechanisms. tPA activates plasmino-gen more efficiently when it is bound to fibrin, so that plasmin is formed selectively on the clot. Plasmin is inhibited by α2-antiplasmin, a protein that is cross-linked to fibrin by factor XIII, which helps to ensure that clot lysis does not occur too quickly. Any circulating plasmin is also inhibited by α2-antiplasmin and circulating tPA or urokinase. Clot lysis yields FDPs including E-nodules and D-dimers. These smaller


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Surgery_Schwartz. lysis does not occur too quickly. Any circulating plasmin is also inhibited by α2-antiplasmin and circulating tPA or urokinase. Clot lysis yields FDPs including E-nodules and D-dimers. These smaller fragments interfere with normal platelet aggregation, and the larger fragments may be incorporated into the clot in lieu of normal fibrin monomers. This may result in an unstable clot as seen in cases of severe coagu-lopathy such as hyperfibrinolysis associated with trauma-induced coagulopathy or disseminated intravascular coagulopathy. The presence of D-dimers in the circulation may serve as a marker of thrombosis or other conditions in which a significant activa-tion of the fibrinolytic system is present. Another inhibitor of the fibrinolytic system is TAFI, which removes lysine residues from fibrin that are essential for binding plasminogen.CONGENITAL FACTOR DEFICIENCIESCoagulation Factor DeficienciesInherited deficiencies of all of the coagulation factors are seen. However, the three


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Surgery_Schwartz. fibrin that are essential for binding plasminogen.CONGENITAL FACTOR DEFICIENCIESCoagulation Factor DeficienciesInherited deficiencies of all of the coagulation factors are seen. However, the three most frequent are factor VIII deficiency (hemophilia A or von Willebrand’s disease), factor IX defi-ciency (hemophilia B or Christmas disease), and factor XI deficiency. Hemophilia A and hemophilia B are inherited as sex-linked recessive disorders with males being affected almost exclusively. The clinical severity of hemophilia A and hemo-philia B depends on the measurable level of factor VIII or factor IX in the patient’s plasma. Plasma factor levels less than 1% of normal are considered severe disease, factor levels between 1% and 5% moderately severe disease, and levels between 5% and 30% mild disease. Patients with severe hemophilia have spontaneous bleeds, frequently into joints, leading to crippling arthropathies. Intracranial bleeding, intramuscular hematomas, retroperitoneal


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Surgery_Schwartz. 30% mild disease. Patients with severe hemophilia have spontaneous bleeds, frequently into joints, leading to crippling arthropathies. Intracranial bleeding, intramuscular hematomas, retroperitoneal hematomas, and gastrointestinal, genitourinary, and retropharyngeal bleeding are added clinical sequelae seen with severe disease. Patients with moderately severe hemophilia have less spontaneous bleeding but are likely to bleed severely EndotheliumPlateletThrombinPlasminogentPAPlasminFibrinFDPFigure 4-4. Formation of fibrin degradation products (FDPs). tPA = tissue plasminogen activator.Brunicardi_Ch04_p0103-p0130.indd 10629/01/19 11:05 AM 107HEMOSTASIS, SURGICAL BLEEDING, AND TRANSFUSIONCHAPTER 4after trauma or surgery. Mild hemophiliacs do not bleed sponta-neously and have only minor bleeding after major trauma or sur-gery. Since platelet function is normal in hemophiliacs, patients may not bleed immediately after an injury or minor surgery as they have a normal response with


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Surgery_Schwartz. bleeding after major trauma or sur-gery. Since platelet function is normal in hemophiliacs, patients may not bleed immediately after an injury or minor surgery as they have a normal response with platelet activation and forma-tion of a platelet plug. At times, the diagnosis of hemophilia is not made in these patients until after their first minor procedure (e.g., tooth extraction or tonsillectomy).Patients with hemophilia A or B are treated with factor VIII or factor IX concentrate, respectively. Recombinant factor VIII is strongly recommended for patients not treated previously and is generally recommended for patients who are both human immunodeficiency virus (HIV) and hepatitis C virus (HCV) seronegative. For factor IX replacement, the preferred products are recombinant or high-purity factor IX. In general, activity levels should be restored to 30% to 40% for mild hemorrhage, 50% for severe bleeding, and 80% to 100% for life-threatening bleeding. Up to 20% of hemophiliacs with


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Surgery_Schwartz. factor IX. In general, activity levels should be restored to 30% to 40% for mild hemorrhage, 50% for severe bleeding, and 80% to 100% for life-threatening bleeding. Up to 20% of hemophiliacs with factor VIII defi-ciency develop inhibitors that can neutralize FVIII. For patients with low titers, inhibitors can be overcome with higher doses of factor VIII. For patients with high titer inhibitors, alternate treat-ments should be used and may include porcine factor VIII, pro-thrombin complex concentrates, activated prothrombin complex concentrates, or recombinant factor VIIa. For patients undergo-ing elective surgical procedures, a multidisciplinary approach with preoperative planning and replacement is recommended.2von Willebrand’s Disease. von Willebrand’s disease (vWD), the most common congenital bleeding disorder, is characterized by a quantitative or qualitative defect in vWF, a large glycopro-tein responsible for carrying factor VIII and platelet adhesion. The latter is important


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Surgery_Schwartz. bleeding disorder, is characterized by a quantitative or qualitative defect in vWF, a large glycopro-tein responsible for carrying factor VIII and platelet adhesion. The latter is important for normal platelet adhesion to exposed subendothelium and for aggregation under high shear condi-tions. Patients with vWD have bleeding that is characteristic of platelet disorders such as easy bruising and mucosal bleed-ing. Menorrhagia is common in women. vWD is classified into three types. Type I is a partial quantitative deficiency; type II is a qualitative defect; type III is total deficiency. For bleeding, type I patients usually respond well to desmopressin (DDAVP). Type II patients may respond, depending on the particular defect. Type III patients are usually unresponsive. These patients may require vWF concentrates.3Factor XI Deficiency. Factor XI deficiency, an autosomal recessive inherited condition sometimes referred to as hemo-philia C, is more prevalent in the Ashkenazi Jewish


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Surgery_Schwartz. may require vWF concentrates.3Factor XI Deficiency. Factor XI deficiency, an autosomal recessive inherited condition sometimes referred to as hemo-philia C, is more prevalent in the Ashkenazi Jewish population but found in all races. Spontaneous bleeding is rare, but bleeding may occur after surgery, trauma, or invasive procedures. Treat-ment of patients with factor XI deficiency who present with bleeding or in whom surgery is planned and who are known to have bled previously is with fresh frozen plasma (FFP). Each milliliter of plasma contains 1 unit of factor XI activity, so the volume needed depends on the patient’s baseline level, the desired level, and the plasma volume. Antifibrinolytics may be useful in patients with menorrhagia. Factor VIIa is recom-mended for patients with anti-factor XI antibodies, although thrombosis has been reported.4 There has been renewed interest in factor XI inhibitors as antithrombotic agents because patients with factor XI deficiency generally have


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Surgery_Schwartz. XI antibodies, although thrombosis has been reported.4 There has been renewed interest in factor XI inhibitors as antithrombotic agents because patients with factor XI deficiency generally have only minimal bleeding risk unless a severe deficiency is present and seem to be pro-tected from thrombosis.5Deficiency of Factors II (Prothrombin), V, and X. Inher-ited deficiencies of factors II, V, and X are rare. These deficiencies are inherited as autosomal recessive. Significant bleeding in homozygotes with less than 1% of normal activ-ity is encountered. Bleeding with any of these deficiencies is treated with FFP. Similar to factor XI, FFP contains one unit of activity of each per milliliter. However, factor V activity is decreased because of its inherent instability. The half-life of prothrombin (factor II) is long (approximately 72 hours), and only about 25% of a normal level is needed for hemostasis. Prothrombin complex concentrates can be used to treat defi-ciencies of prothrombin or


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Surgery_Schwartz. (factor II) is long (approximately 72 hours), and only about 25% of a normal level is needed for hemostasis. Prothrombin complex concentrates can be used to treat defi-ciencies of prothrombin or factor X. Daily infusions of FFP are used to treat bleeding in factor V deficiency, with a goal of 20% to 25% activity. Factor V deficiency may be coinherited with factor VIII deficiency. Treatment of bleeding in individuals with the combined deficiency requires factor VIII concentrate and FFP. Some patients with factor V deficiency are also lacking the factor V normally present in platelets and may need platelet transfusions as well as FFP.Factor VII Deficiency. Inherited factor VII deficiency is a rare autosomal recessive disorder. Clinical bleeding can vary widely and does not always correlate with the level of FVII coagulant activity in plasma. Bleeding is uncommon unless the level is less than 3%. The most common bleeding manifesta-tions involve easy bruising and mucosal bleeding,


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Surgery_Schwartz. with the level of FVII coagulant activity in plasma. Bleeding is uncommon unless the level is less than 3%. The most common bleeding manifesta-tions involve easy bruising and mucosal bleeding, particularly epistaxis or oral mucosal bleeding. Postoperative bleeding is also common, reported in 30% of surgical procedures.6 Treat-ment is with FFP or recombinant factor VIIa. The half-life of recombinant factor VIIa is only approximately 2 hours, but excellent hemostasis can be achieved with frequent infusions. The half-life of factor VII in FFP is up to 4 hours.Factor XIII Deficiency. Congenital factor XIII (FXIII) defi-ciency, originally recognized by Duckert in 1960, is a rare autosomal recessive disease usually associated with a severe bleeding diathesis.7 The male-to-female ratio is 1:1. Although acquired FXIII deficiency has been described in association with hepatic failure, inflammatory bowel disease, and myeloid leukemia, the only significant association with bleeding in chil-dren


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Surgery_Schwartz. acquired FXIII deficiency has been described in association with hepatic failure, inflammatory bowel disease, and myeloid leukemia, the only significant association with bleeding in chil-dren is the inherited deficiency.8 Bleeding is typically delayed because clots form normally but are susceptible to fibrinolysis. Umbilical stump bleeding is characteristic, and there is a high risk of intracranial bleeding. Spontaneous abortion is usual in women with factor XIII deficiency unless they receive replace-ment therapy. Replacement can be accomplished with FFP, cryoprecipitate, or a factor XIII concentrate. Levels of 1% to 2% are usually adequate for hemostasis.Platelet Functional DefectsInherited platelet functional defects include abnormalities of platelet surface proteins, abnormalities of platelet granules, and enzyme defects. The major surface protein abnormalities are thrombasthenia and Bernard-Soulier syndrome. Thrombasthe-nia, or Glanzmann thrombasthenia, is a rare genetic platelet


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Surgery_Schwartz. granules, and enzyme defects. The major surface protein abnormalities are thrombasthenia and Bernard-Soulier syndrome. Thrombasthe-nia, or Glanzmann thrombasthenia, is a rare genetic platelet disorder, inherited in an autosomal recessive pattern, in which the platelet glycoprotein IIb/IIIa (GP IIb/IIIa) complex is either lacking or present but dysfunctional. This defect leads to faulty platelet aggregation and subsequent bleeding. The disorder was first described by Dr. Eduard Glanzmann in 1918.9 Bleeding in thrombasthenic patients must be treated with platelet transfu-sions. Bernard-Soulier syndrome is caused by a defect in the GP Ib/IX/V receptor for vWF, which is necessary for platelet adhesion to the subendothelium. Transfusion of normal platelets is required for bleeding in these patients.Brunicardi_Ch04_p0103-p0130.indd 10729/01/19 11:05 AM 108BASIC CONSIDERATIONSPART IThe most common intrinsic platelet defect is storage pool disease. It involves loss of dense granules


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Surgery_Schwartz. patients.Brunicardi_Ch04_p0103-p0130.indd 10729/01/19 11:05 AM 108BASIC CONSIDERATIONSPART IThe most common intrinsic platelet defect is storage pool disease. It involves loss of dense granules (storage sites for ADP, adenosine triphosphate [ATP], Ca2+, and inorganic phosphate) and α-granules. Dense granule deficiency is the most prevalent of these. It may be an isolated defect or occur with partial albinism in Hermansky-Pudlak syndrome. Bleed-ing is variable, depending on the severity of the granule defect. Bleeding is caused by the decreased release of ADP from these platelets. A few patients have been reported who have decreased numbers of both dense and α-granules. They have a more severe bleeding disorder. Patients with mild bleeding as a consequence of a form of storage pool disease can be treated with DDAVP. It is likely that the high levels of vWF in the plasma after DDAVP somehow compensate for the intrinsic platelet defect. With more severe bleeding, platelet transfusion


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Surgery_Schwartz. can be treated with DDAVP. It is likely that the high levels of vWF in the plasma after DDAVP somehow compensate for the intrinsic platelet defect. With more severe bleeding, platelet transfusion is required.ACQUIRED HEMOSTATIC DEFECTSPlatelet AbnormalitiesAcquired congenital abnormalities of platelets are much more common than acquired defects and may be quantitative or quali-tative, although some patients have both types of defects. Quan-titative defects may be a result of failure of production, shortened survival, or sequestration. Failure of production is generally a result of bone marrow disorders such as leukemia, myelodys-plastic syndrome, severe vitamin B12 or folate deficiency, che-motherapeutic drugs, radiation, acute ethanol intoxication, or viral infection. If a quantitative abnormality exists and treatment is indicated either due to symptoms or the need for an invasive procedure, platelet transfusion is utilized. The etiologies of both qualitative and quantitative defects


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Surgery_Schwartz. exists and treatment is indicated either due to symptoms or the need for an invasive procedure, platelet transfusion is utilized. The etiologies of both qualitative and quantitative defects are reviewed in Table 4-1.Quantitative Defects. Shortened platelet survival is seen in immune thrombocytopenia, disseminated intravascular coagu-lation, or disorders characterized by platelet thrombi such as thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Immune thrombocytopenia may be idiopathic or associated with other autoimmune disorders or low-grade B-cell malignancies, and it may also be secondary to viral infections (including HIV) or drugs. Secondary immune thrombocytopenia often presents with a very low platelet count, petechiae and pur-pura, and epistaxis. Large platelets are seen on peripheral smear. Initial treatment consists of corticosteroids, intravenous gamma globulin, or anti-D immunoglobulin in patients who are Rh posi-tive. Both gamma globulin and anti-D


Surgery_Schwartz

Surgery_Schwartz. are seen on peripheral smear. Initial treatment consists of corticosteroids, intravenous gamma globulin, or anti-D immunoglobulin in patients who are Rh posi-tive. Both gamma globulin and anti-D immunoglobulin are rapid in onset. Platelet transfusions are not usually needed unless cen-tral nervous system bleeding or active bleeding from other sites occurs. Survival of the transfused platelets is usually short.Primary immune thrombocytopenia is also known as idio-pathic thrombocytopenic purpura (ITP). In children, it is usually acute in onset, short lived, and typically follows a viral illness. In contrast, ITP in adults is gradual in onset, chronic in nature, and has no identifiable cause. Because the circulating platelets in ITP are young and functional, bleeding is less for a given platelet count than when there is failure of platelet production. The patho-physiology of ITP is believed to involve both impaired platelet production and T cell–mediated platelet destruction.10


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Surgery_Schwartz. platelet count than when there is failure of platelet production. The patho-physiology of ITP is believed to involve both impaired platelet production and T cell–mediated platelet destruction.10 Manage-ment options are summarized in Table 4-2.11 Treatment of drug-induced immune thrombocytopenia may simply entail withdrawal of the offending drug, but corticosteroids, gamma globulin, and anti-D immunoglobulin may hasten recovery of the count.12,13Table 4-1Etiology of acquired platelet disordersA. Quantitative Disorders1. Failure of production: related to impairment in bone marrow functiona. Leukemiab. Myeloproliferative disordersc. B12 or folate deficienciesd. Chemotherapy or radiation therapye. Acute alcohol intoxicationf. Viral infections2. Decreased survivala. Immune-mediated1) Idiopathic thrombocytopenia (ITP)2) Heparin-induced thrombocytopenia3) Autoimmune disorders or B-cell malignancies4) Secondary thrombocytopeniab. Disseminated intravascular coagulation (DIC)c. Related to


Surgery_Schwartz

Surgery_Schwartz. thrombocytopenia (ITP)2) Heparin-induced thrombocytopenia3) Autoimmune disorders or B-cell malignancies4) Secondary thrombocytopeniab. Disseminated intravascular coagulation (DIC)c. Related to platelet thrombi1) Thrombocytopenic purpura (TTP)2) Hemolytic uremic syndrome (HUS)3. Sequestrationa. Portal hypertensionb. Sarcoidc. Lymphomad. Gaucher’s DiseaseB. Qualitative Disorders1. Massive transfusion2. Therapeutic platelet inhibitors3. Disease statesa. Myeloproliferative disordersb. Monoclonal gammopathiesc. Liver diseaseTable 4-2Management of idiopathic thrombocytopenic purpura (ITP) in adultsFirst line: a. Corticosteroids: Longer courses of corticosteroids are preferred over shorter courses of corticosteroids b. Intravenous immunoglobulin (IVIG) or anti-D immunoglobulin: the dose should initially be 1 g/kg as a one-time dose. This dosage may be repeated if necessarySecond line: a. Splenectomy b. Rituximab, an anti-CD 20 monoclonal antibody c. Thrombopoietin (TPO) receptor


Surgery_Schwartz

Surgery_Schwartz. should initially be 1 g/kg as a one-time dose. This dosage may be repeated if necessarySecond line: a. Splenectomy b. Rituximab, an anti-CD 20 monoclonal antibody c. Thrombopoietin (TPO) receptor agonists d. Immunosuppressive agentsThird line: (failing first and second line therapy) a. Thrombopoietin (TPO) receptor agonists b. Combination of first and second line therapies c. Combination chemotherapyBrunicardi_Ch04_p0103-p0130.indd 10829/01/19 11:05 AM 109HEMOSTASIS, SURGICAL BLEEDING, AND TRANSFUSIONCHAPTER 4Heparin-induced thrombocytopenia (HIT) is a form of drug-induced immune thrombocytopenia. It is an immunologic event during which antibodies against platelet factor 4 (PF4) formed during exposure to heparin affect platelet activation and endothelial function with resultant thrombocytopenia and intravascular thrombosis.14 The platelet count typically begins to fall 5 to 7 days after heparin has been started, but if it is a reexposure, the decrease in count may occur within 1


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Surgery_Schwartz. and intravascular thrombosis.14 The platelet count typically begins to fall 5 to 7 days after heparin has been started, but if it is a reexposure, the decrease in count may occur within 1 to 2 days. HIT should be suspected if the platelet count falls to less than 100,000 or if it drops by 50% from baseline in a patient receiv-ing heparin. While HIT is more common with full-dose unfrac-tionated heparin (1% to 3%), it can also occur with prophylactic doses or with low molecular weight heparins. Interestingly, approximately 17% of patients receiving unfractionated hepa-rin and 8% receiving low molecular weight heparin develop antibodies against PF4, yet a much smaller percentage develop thrombocytopenia, and even fewer develop clinical HIT.15 In addition to mild to moderate thrombocytopenia, this disorder is characterized by a high incidence of thrombosis that may be arterial or venous. Importantly, the absence of thrombo-cytopenia in these patients does not preclude the diagnosis of


Surgery_Schwartz

Surgery_Schwartz. this disorder is characterized by a high incidence of thrombosis that may be arterial or venous. Importantly, the absence of thrombo-cytopenia in these patients does not preclude the diagnosis of HIT. The 4Ts scoring system by Lo et al can be used to assess the pretest probability of HIT and incorporates the timing and magnitude of the platelet count fall, new thrombosis, and the likelihood of other reasons for thrombocytopenia.16 A low probability 4Ts score is quite accurate in excluding HIT, but patients with intermediate or high probability scores require further evaluation.Laboratory testing should include an anti–platelet fac-tor 4–heparin enzyme-linked immunosorbent assay (ELISA). Unfortunately, this test, like the 4Ts, has a high negative predic-tive value but a low positive predictive value. While a negative ELISA essentially rules out HIT, a positive ELISA does not confirm HIT. To increase the specificity of this assay, it can be restricted to IgG antibodies or obtained in


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Surgery_Schwartz. value. While a negative ELISA essentially rules out HIT, a positive ELISA does not confirm HIT. To increase the specificity of this assay, it can be restricted to IgG antibodies or obtained in conjunction with a functional assay such as the serotonin release assay and the heparin-induced platelet activation test. Both of these are avail-able only at specialized laboratories and should only be used as second-line diagnostic assays.l7The initial treatment of suspected HIT is to stop heparin and begin an alternative anticoagulant. Stopping heparin with-out addition of another anticoagulant is not adequate to prevent thrombosis in this setting. Alternative anticoagulants are pri-marily thrombin inhibitors. The most recent guideline by the American College of Chest Physicians recommends lepiru-din, argatroban, or danaparoid for patients with normal renal function and argatroban for patients with renal insufficiency.18 Because of warfarin’s early induction of a hypercoagulable state,


Surgery_Schwartz

Surgery_Schwartz. lepiru-din, argatroban, or danaparoid for patients with normal renal function and argatroban for patients with renal insufficiency.18 Because of warfarin’s early induction of a hypercoagulable state, warfarin should be instituted only once full anticoagula-tion with an alternative agent has been accomplished and the platelet count has begun to recover.These are also disorders in which thrombocytopenia is a result of platelet activation and formation of platelet thrombi. In thrombotic thrombocytopenic purpura (TTP), large vWF mol-ecules interact with platelets, leading to activation. These large molecules result from inhibition of a metalloproteinase enzyme, ADAM-S13, which cleaves the large vWF molecules.19 TTP is classically characterized by thrombocytopenia, microangio-pathic hemolytic anemia, fever, and renal and neurologic signs or symptoms. The finding of schistocytes on a peripheral blood smear aids in the diagnosis. Plasma exchange with replacement of FFP is the treatment for


Surgery_Schwartz

Surgery_Schwartz. anemia, fever, and renal and neurologic signs or symptoms. The finding of schistocytes on a peripheral blood smear aids in the diagnosis. Plasma exchange with replacement of FFP is the treatment for acute TTP.20 Additionally, rituximab, a monoclonal antibody against the CD20 protein on B lympho-cytes, is indicated in relapsing and/or refractory TTP.21Hemolytic uremic syndrome (HUS) often occurs second-ary to infection by Escherichia coli 0157:H7 or other Shiga toxin-producing bacteria. The metalloproteinase is normal in these cases. HUS is usually associated with some degree of renal failure, with many patients requiring renal replacement therapy. Neurologic symptoms are less frequent. A number of patients develop features of both TTP and HUS. This may occur with autoimmune diseases, especially systemic lupus erythematosus and HIV infection, or in association with certain drugs (such as ticlopidine, mitomycin C, gemcitabine) or immunosuppressive agents (such as cyclosporine and


Surgery_Schwartz

Surgery_Schwartz. especially systemic lupus erythematosus and HIV infection, or in association with certain drugs (such as ticlopidine, mitomycin C, gemcitabine) or immunosuppressive agents (such as cyclosporine and tacrolimus). Discontinuation of the involved drug is the mainstay of therapy. Plasmapheresis is frequently used, but it is not clear what etiologic factor is being removed by the pheresis.Sequestration is another important cause of thrombocyto-penia and usually involves trapping of platelets in an enlarged spleen typically related to portal hypertension, sarcoid, lym-phoma, or Gaucher’s disease. The total body platelet mass is essentially normal in patients with hypersplenism, but a much larger fraction of the platelets are in the enlarged spleen. Platelet survival is mildly decreased. Bleeding is less than anticipated from the count because sequestered platelets can be mobilized to some extent and enter the circulation. Platelet transfusion does not increase the platelet count as much as


Surgery_Schwartz

Surgery_Schwartz. is less than anticipated from the count because sequestered platelets can be mobilized to some extent and enter the circulation. Platelet transfusion does not increase the platelet count as much as it would in a normal person because the transfused platelets are similarly sequestered in the spleen. Splenectomy is not indicated to correct the throm-bocytopenia of hypersplenism caused by portal hypertension.Thrombocytopenia and platelet dysfunction are the most common abnormalities of hemostasis that result in bleeding in the surgical patient. The patient may have a reduced platelet count as a result of a variety of disease processes, as discussed earlier. In these circumstances, the marrow usually demon-strates a normal or increased number of megakaryocytes. By contrast, when thrombocytopenia occurs in patients with leu-kemia or uremia and in patients on cytotoxic therapy, there are generally a reduced number of megakaryocytes in the marrow. Thrombocytopenia also occurs in surgical


Surgery_Schwartz

Surgery_Schwartz. occurs in patients with leu-kemia or uremia and in patients on cytotoxic therapy, there are generally a reduced number of megakaryocytes in the marrow. Thrombocytopenia also occurs in surgical patients as a result of massive blood loss with product replacement deficient in platelets. Thrombocytopenia may also be induced by heparin administration during cardiac and vascular cases, as in the case of HIT, or may be associated with thrombotic and hemorrhagic complications. When thrombocytopenia is present in a patient for whom an elective operation is being considered, manage-ment is contingent upon the extent and cause of platelet reduc-tion and extent of platelet dysfunction.Early platelet administration has now become part of mas-sive transfusion protocols.22,23 Platelets are also administered preoperatively to rapidly increase the platelet count in surgical patients with underlying thrombocytopenia or platelet dysfunc-tion. One unit of platelet concentrate contains approximately 5.5 ×


Surgery_Schwartz

Surgery_Schwartz. preoperatively to rapidly increase the platelet count in surgical patients with underlying thrombocytopenia or platelet dysfunc-tion. One unit of platelet concentrate contains approximately 5.5 × 1010 platelets and would be expected to increase the cir-culating platelet count by about 10,000/μL in the average 70-kg person. Fever, infection, hepatosplenomegaly, and the pres-ence of antiplatelet alloantibodies decrease the effectiveness of platelet transfusions. In patients who are refractory to standard platelet transfusion, the use of human leukocyte antigen (HLA)-compatible platelets coupled with special processors has proved effective.Brunicardi_Ch04_p0103-p0130.indd 10929/01/19 11:05 AM 110BASIC CONSIDERATIONSPART IQualitative Platelet Defects. Impaired platelet function often accompanies thrombocytopenia but may also occur in the presence of a normal platelet count. The importance of this is obvious when one considers that 80% of overall clot strength is related to platelet


Surgery_Schwartz

Surgery_Schwartz. thrombocytopenia but may also occur in the presence of a normal platelet count. The importance of this is obvious when one considers that 80% of overall clot strength is related to platelet function. The life span of platelets ranges from 7 to 10 days, placing them at increased risk for impairment by medical disorders and prescription and over-the-counter medications. Impairment of ADP-stimulated aggregation occurs with massive transfusion of blood products. Ure-mia may be associated with increased bleeding time and impaired aggregation. Defective aggregation and platelet dys-function are also seen in patients with severe trauma, thrombo-cythemia, polycythemia vera, and myelofibrosis.Drugs that interfere with platelet function include aspirin, clopidogrel, prasugrel, dipyridamole, and GP IIb/IIIa inhibitors. Aspirin, clopidogrel, and prasugrel all irreversibly inhibit plate-let function. Clopidogrel and prasugrel do so through selective irreversible inhibition of ADP-induced platelet


Surgery_Schwartz

Surgery_Schwartz. IIb/IIIa inhibitors. Aspirin, clopidogrel, and prasugrel all irreversibly inhibit plate-let function. Clopidogrel and prasugrel do so through selective irreversible inhibition of ADP-induced platelet aggregation.24 Aspirin works through irreversible acetylation of platelet pros-taglandin synthase.There are no prospective randomized trials in general sur-gical patients to guide the timing of surgery in patients on aspi-rin, clopidogrel, or prasugrel.25 The general recommendation is that approximately 5 to 7 days should pass from the time the drug is stopped until an elective procedure is performed.26 Tim-ing of urgent and emergent surgeries is even more unclear. Pre-operative platelet transfusions may be beneficial, but there are no good data to guide their administration. However, functional tests such as thromboelastography (TEG) with platelet mapping are becoming available that may better demonstrate defects in platelet function and may serve to guide the timing of operation or when


Surgery_Schwartz

Surgery_Schwartz. tests such as thromboelastography (TEG) with platelet mapping are becoming available that may better demonstrate defects in platelet function and may serve to guide the timing of operation or when platelet transfusions might be indicated.Other disorders associated with abnormal platelet func-tion include uremia, myeloproliferative disorders, monoclonal gammopathies, and liver disease. In the surgical patient, plate-let dysfunction of uremia can often be corrected by dialysis or the administration of DDAVP. Platelet transfusion may not be helpful if the patient is uremic when the platelets are given and only serve to increase antibodies. Platelet dysfunction in myelo-proliferative disorders is intrinsic to the platelets and usually improves if the platelet count can be reduced to normal with chemotherapy. If possible, surgery should be delayed until the count has been decreased. These patients are at risk for both bleeding and thrombosis. Platelet dysfunction in patients with


Surgery_Schwartz

Surgery_Schwartz. normal with chemotherapy. If possible, surgery should be delayed until the count has been decreased. These patients are at risk for both bleeding and thrombosis. Platelet dysfunction in patients with monoclonal gammopathies is a result of interaction of the mono-clonal protein with platelets. Treatment with chemotherapy or, occasionally, plasmapheresis to lower the amount of monoclo-nal protein improves hemostasis.Acquired HypofibrinogenemiaDisseminated Intravascular Coagulation (DIC). DIC is an acquired syndrome characterized by systemic activation of coagulation pathways that result in excessive thrombin genera-tion and the diffuse formation of microthrombi. This distur-bance ultimately leads to consumption and depletion of platelets and coagulation factors with the resultant classic picture of dif-fuse bleeding. Fibrin thrombi developing in the microcirculation may cause microvascular ischemia and subsequent end-organ failure if severe. There are many different conditions that


Surgery_Schwartz

Surgery_Schwartz. picture of dif-fuse bleeding. Fibrin thrombi developing in the microcirculation may cause microvascular ischemia and subsequent end-organ failure if severe. There are many different conditions that pre-dispose a patient to DIC, and the presence of an underlying condition is required for the diagnosis. For example, injuries resulting in embolization of materials such as brain matter, bone marrow, or amniotic fluid can act as potent thromboplastins that activate the DIC cascade.27 Additional etiologies include malig-nancy, organ injury (such as severe pancreatitis), liver failure, certain vascular abnormalities (such as large aneurysms), snake bites, illicit drugs, transfusion reactions, transplant rejection, and sepsis.28 In fact, DIC frequently accompanies sepsis and may be associated with multiple organ failure. The important interplay between sepsis and coagulation abnormalities was demonstrated by Dhainaut et al who showed that activated protein C was effective in septic patients


Surgery_Schwartz

Surgery_Schwartz. multiple organ failure. The important interplay between sepsis and coagulation abnormalities was demonstrated by Dhainaut et al who showed that activated protein C was effective in septic patients with DIC, though this has subsequently been disproven.29 The diagnosis of DIC is made based on an inciting etiology with associated thrombo-cytopenia, prolongation of the prothrombin time, a low fibrino-gen level, and elevated fibrin markers (FDPs, D-dimer, soluble fibrin monomers). A scoring system developed by the Interna-tional Society for Thrombosis and Hemostasis has been shown to have high sensitivity and specificity for diagnosing DIC as well as a strong correlation between an increasing DIC score and mortality, especially in patients with infections.30The most important facets of treatment are relieving the patient’s causative primary medical or surgical problem and maintaining adequate perfusion. If there is active bleeding, hemostatic factors should be replaced with FFP, which is


Surgery_Schwartz

Surgery_Schwartz. are relieving the patient’s causative primary medical or surgical problem and maintaining adequate perfusion. If there is active bleeding, hemostatic factors should be replaced with FFP, which is usually sufficient to correct the hypofibrinogenemia, although cryopre-cipitate, fibrinogen concentrates, or platelet concentrates may also be needed. Given the formation of microthrombi in DIC, heparin therapy has also been proposed. Heparin may be indi-cated in cases where thrombosis predominates, such as arterial or venous thromboembolism and severe purpura fulminans.31Primary Fibrinolysis. Other than due to trauma, an acquired hypofibrinogenic state in the surgical patient can be a result of pathologic fibrinolysis. This may occur in patients following prostate resection when urokinase is released during surgical manipulation of the prostate or in patients undergoing extracor-poreal bypass. The severity of fibrinolytic bleeding is dependent on the concentration of breakdown products in


Surgery_Schwartz

Surgery_Schwartz. during surgical manipulation of the prostate or in patients undergoing extracor-poreal bypass. The severity of fibrinolytic bleeding is dependent on the concentration of breakdown products in the circula-tion. Antifibrinolytic agents, such as ε-aminocaproic acid and tranexamic acid, interfere with fibrinolysis by inhibiting plas-minogen activation.Myeloproliferative DiseasesPolycythemia, or an excess of red blood cells, places surgical patients at risk. Spontaneous thrombosis is a complication of polycythemia vera, a myeloproliferative neoplasm, and can be explained in part by increased blood viscosity, increased plate-let count, and an increased tendency toward stasis. Paradoxi-cally, a significant tendency toward spontaneous hemorrhage also is noted in these patients. Thrombocytosis can be reduced by the administration of low-dose aspirin, phlebotomy, and hydroxyurea.32Coagulopathy of Liver DiseaseThe liver plays a key role in hemostasis because it is responsible for the synthesis


Surgery_Schwartz

Surgery_Schwartz. be reduced by the administration of low-dose aspirin, phlebotomy, and hydroxyurea.32Coagulopathy of Liver DiseaseThe liver plays a key role in hemostasis because it is responsible for the synthesis of many of the coagulation factors (Table 4-3). Patients with liver disease, therefore, have decreased production of several key nonendothelial cell-derived coagulation factors as well as natural anticoagulant proteins, causing a disturbance in the balance between procoagulant and anticoagulant path-ways. This disturbance in coagulation mechanisms causes a complex paradigm of both increased bleeding risk and increased 1Brunicardi_Ch04_p0103-p0130.indd 11029/01/19 11:05 AM 111HEMOSTASIS, SURGICAL BLEEDING, AND TRANSFUSIONCHAPTER 4thrombotic risk. The most common coagulation abnormalities associated with liver dysfunction are thrombocytopenia and impaired humoral coagulation function manifested as prolonga-tion of the prothrombin time and international normalized ratio (INR). The etiology


Surgery_Schwartz

Surgery_Schwartz. with liver dysfunction are thrombocytopenia and impaired humoral coagulation function manifested as prolonga-tion of the prothrombin time and international normalized ratio (INR). The etiology of thrombocytopenia in patients with liver disease is typically related to hypersplenism, reduced produc-tion of thrombopoietin, and immune-mediated destruction of platelets. The total body platelet mass is often normal in patients with hypersplenism, but a much larger fraction of the platelets is sequestered in the enlarged spleen. Bleeding may be less than anticipated because sequestered platelets can be mobilized to some extent and enter the circulation. Thrombopoietin, the pri-mary stimulus for thrombopoiesis, may be responsible for some cases of thrombocytopenia in cirrhotic patients, although its role is not well delineated. Finally, immune-mediated thrombocyto-penia may also occur in cirrhotics, especially those with hepatitis C and primary biliary cirrhosis.33 In addition to


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Surgery_Schwartz. although its role is not well delineated. Finally, immune-mediated thrombocyto-penia may also occur in cirrhotics, especially those with hepatitis C and primary biliary cirrhosis.33 In addition to thrombocytope-nia, these patients also exhibit platelet dysfunction via defective interactions between platelets and the endothelium, and possibly due to uremia and changes in endothelial function in the setting of concomitant renal insufficiency. Hypocoagulopathy is fur-ther exacerbated with low platelet counts because platelets help facilitate thrombin generation by assembling coagulation factors on their surfaces. In conditions mimicking intravascular flow, low hematocrit and low platelet counts contributed to decreased adhesion of platelets to endothelial cells, although increased vWF, a common finding in cirrhotic patients, may offset this change in patients with cirrhosis.34 Hypercoagulability of liver disease has recently gained increased attention, with more evi-dence demonstrating


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Surgery_Schwartz. finding in cirrhotic patients, may offset this change in patients with cirrhosis.34 Hypercoagulability of liver disease has recently gained increased attention, with more evi-dence demonstrating the increased incidence of thromboem-bolism despite thrombocytopenia and a hypocoagulable state on conventional blood tests.35,36 This is attributed to decreased production of liver-synthesized proteins C and S, antithrombin, and plasminogen levels, as well as elevated levels of endothe-lial-derived vWF and factor VIII, a potent driver of thrombin generation.37,38 Given the concomitant hypoand hypercoagu-lable features seen in patients with liver disease, conventional coagulation tests may be difficult to interpret, and whole blood functional tests such as thromboelastography (TEG) or ROTEM may be more informative of the status of clot formation and stability in cirrhotic patients. Small studies have indicated that TEG provides a better assessment of bleeding risk than standard tests of


Surgery_Schwartz

Surgery_Schwartz. may be more informative of the status of clot formation and stability in cirrhotic patients. Small studies have indicated that TEG provides a better assessment of bleeding risk than standard tests of hemostasis in patients with liver disease; however, no large studies have directly tested this, and future larger trials are needed.39Before instituting any therapy to ameliorate thrombocy-topenia, the actual need for correction should be strongly con-sidered. In general, correction based solely on a low platelet count should be discouraged. Most often, treatment should be withheld for invasive procedures and surgery. When required, platelet transfusions are the mainstay of therapy; however, the effect typically lasts only several hours. Risks associated with transfusions in general and the development of antiplate-let antibodies in a patient population likely to need recurrent correction should be considered. A less well-accepted option is splenectomy or splenic embolization to reduce


Surgery_Schwartz

Surgery_Schwartz. development of antiplate-let antibodies in a patient population likely to need recurrent correction should be considered. A less well-accepted option is splenectomy or splenic embolization to reduce hypersplenism. In addition to the risks associated with these techniques, reduced splenic blood flow can reduce portal vein flow with subsequent portal vein thrombosis. Results are mixed following insertion of a transjugular intrahepatic portosystemic shunt (TIPS). There-fore, treatment of thrombocytopenia should not be the primary indication for a TIPS procedure.Decreased production or increased destruction of coagula-tion factors as well as vitamin K deficiency can all contribute to a prolonged PT and INR in patients with liver disease. As liver dysfunction worsens, so does the liver’s synthetic func-tion, which results in decreased production of coagulation fac-tors. Additionally, laboratory abnormalities may mimic those of DIC. Elevated D-dimers have been reported to increase the risk


Surgery_Schwartz

Surgery_Schwartz. func-tion, which results in decreased production of coagulation fac-tors. Additionally, laboratory abnormalities may mimic those of DIC. Elevated D-dimers have been reported to increase the risk of variceal bleeding. The absorption of vitamin K is dependent on bile production. Therefore, liver patients with impaired bile production and cholestatic disease may be at risk for vitamin K deficiency.Similar to thrombocytopenia, correction of coagulopathy should be reserved for treatment of active bleeding and prophy-laxis for invasive procedures and surgery. Treatment of coagu-lopathy caused by liver disease is usually done with FFP, but because the coagulopathy is usually not a result of decreased levels of factor V, complete correction is not usually possible. If the fibrinogen is less than 200 mg/dL, administration of cryo-precipitate may be helpful. Cryoprecipitate is also a source of factor VIII for the rare patient with a low factor VIII level.Coagulopathy of TraumaTraditional


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Surgery_Schwartz. than 200 mg/dL, administration of cryo-precipitate may be helpful. Cryoprecipitate is also a source of factor VIII for the rare patient with a low factor VIII level.Coagulopathy of TraumaTraditional teaching regarding trauma-related coagulopathy attributed its development to acidosis, hypothermia, and dilution of coagulation factors. Recent data, however, have shown that over one-third of severely injured patients have laboratory-based evidence of coagulopathy at the time of admission,40 a phenotype called trauma-induced coagulopathy (TIC). TIC is independent of traditional (iatrogenic) causes of posttraumatic coagulopathy such as hemodilution, is precipitated by tissue injury and/or hemorrhagic shock, and is associated with signifi-cantly higher risk of mortality, especially in the first 24 hours after injury. Furthermore, TIC is a separate and distinct process from disseminated intravascular coagulopathy with its own specific components of hemostatic failure.As shown in Fig. 4-5,