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In reply: Iron therapy and infection
In Reply: We agree that iron therapy is different than iron stores, but iron therapy should be started on the basis of depleted iron stores; otherwise, it is unjustifiable. We also agree that elevated iron stores are dangerous in the setting of infection, more than iron therapy itself. This is really an unproven theory. Most studies that showed worse outcomes of iron therapy found that elevated ferritin is a risk factor.1 The problem, as we outlined in our paper, is that most serum markers of iron are unreliable in case of inflammation or infection or in the critically ill.2 Evaluation of bone marrow stores is probably the most accurate.3
- Cavill I. Intravenous iron as adjuvant therapy: a two-edged sword? Nephrol Dial Transplant 2003; 18(suppl 8):viii24–viii28.
- Pieracci FM, Barie PS. Diagnosis and management of iron-related anemias in critical illness. Crit Care Med 2006; 34:1898–1905.
- Wish JB. Assessing iron status: beyond serum ferritin and transferrin saturation. Clin J Am Soc Nephrol 2006; 1(suppl 1):S4–S8.
In Reply: We agree that iron therapy is different than iron stores, but iron therapy should be started on the basis of depleted iron stores; otherwise, it is unjustifiable. We also agree that elevated iron stores are dangerous in the setting of infection, more than iron therapy itself. This is really an unproven theory. Most studies that showed worse outcomes of iron therapy found that elevated ferritin is a risk factor.1 The problem, as we outlined in our paper, is that most serum markers of iron are unreliable in case of inflammation or infection or in the critically ill.2 Evaluation of bone marrow stores is probably the most accurate.3
In Reply: We agree that iron therapy is different than iron stores, but iron therapy should be started on the basis of depleted iron stores; otherwise, it is unjustifiable. We also agree that elevated iron stores are dangerous in the setting of infection, more than iron therapy itself. This is really an unproven theory. Most studies that showed worse outcomes of iron therapy found that elevated ferritin is a risk factor.1 The problem, as we outlined in our paper, is that most serum markers of iron are unreliable in case of inflammation or infection or in the critically ill.2 Evaluation of bone marrow stores is probably the most accurate.3
- Cavill I. Intravenous iron as adjuvant therapy: a two-edged sword? Nephrol Dial Transplant 2003; 18(suppl 8):viii24–viii28.
- Pieracci FM, Barie PS. Diagnosis and management of iron-related anemias in critical illness. Crit Care Med 2006; 34:1898–1905.
- Wish JB. Assessing iron status: beyond serum ferritin and transferrin saturation. Clin J Am Soc Nephrol 2006; 1(suppl 1):S4–S8.
- Cavill I. Intravenous iron as adjuvant therapy: a two-edged sword? Nephrol Dial Transplant 2003; 18(suppl 8):viii24–viii28.
- Pieracci FM, Barie PS. Diagnosis and management of iron-related anemias in critical illness. Crit Care Med 2006; 34:1898–1905.
- Wish JB. Assessing iron status: beyond serum ferritin and transferrin saturation. Clin J Am Soc Nephrol 2006; 1(suppl 1):S4–S8.
Is iron therapy for anemia harmful in the setting of infection?
The harmful effects of iron therapy in the setting of infection are more theoretical than observed, with no irrefutable data to support them. On the other hand, there are also no convincing data to support the benefit of this therapy. If iron is to be used, frequent monitoring of serum iron markers is prudent to avoid iron overload during treatment.
ANEMIA OF INFLAMMATION IS COMPLEX
Anemia that develops in the hospital, especially in the setting of infection or inflammation, is similar hematologically to anemia of chronic disease, except for its acute onset.1
The pathogenesis of anemia in such settings is complex, but the most important causes of this common syndrome include shortening of red cell survival, impaired erythropoietin production, blunted responsiveness of the bone marrow to endogenous erythropoietin, and impaired iron metabolism mediated through the action of inflammatory cytokines.2,3 Other important causes include nutritional deficiencies (iron, vitamin B12, and folic acid)4 and blood loss.5,6
Moreover, anemia of inflammation may be difficult to differentiate from iron-deficiency anemia because the serum iron markers are unreliable in inflammation.1
The reported prevalence of anemia during hospitalization has ranged from 55% on hospital wards7 to 95% in intensive care units.8
Transfusion of packed red blood cells is the fastest treatment for anemia in hospitalized patients and it is the one traditionally used, but many concerns have been raised about its efficacy and adverse effects.9 Erythropoietin, with or without iron therapy, has emerged as an alternative in treating anemia of inflammation.10,11
IRON THERAPY
Iron is widely used to treat anemia, especially in hospitalized patients and those with chronic kidney disease.2 The intravenous route is more commonly used than the oral route, since it has faster action, is better tolerated, and has better bioavailability.1,2
Controversy over benefit
Whether iron supplementation increases the red blood cell mass and reduces the need for blood transfusion is controversial.10,12 Pieracci et al13 documented these benefits in critically ill surgical patients, whereas van Iperen et al11 did not find such benefits in critically ill patients receiving intravenous iron and erythropoietin.
Harmful effects
Some authors1,14 object to giving iron to hospitalized patients (especially critically ill patients) who have infections on the grounds that it is risky, although definitive evidence is lacking.15
Most of the harmful effects of iron have been linked to elevated serum ferritin levels and to non–transferrin-bound iron, more than to iron per se.16 Ferritin is an acute-phase reactant; thus, ferritin levels may be elevated in inflammation and infection regardless of the body iron status.1
Anaphylactic reaction. This rare complication of iron dextran therapy is not much of a concern at present with the newer formulations of iron such as iron gluconate and iron sucrose.16
Oxidative stress. Iron-derived free radicals can cause a rise in inflammatory cytokine levels, especially if the ferritin level is elevated (> 500 μg/L). This cytokine rise is worrisome, as it may have acute detrimental effects on cellular homeostasis, leading to tissue injury,15 while chronically it might be related to enhanced atherosclerosis and cardiac disease.16
Iron overload. In vitro and animal studies have documented an association between elevated ferritin levels (500–650 μg/L) and decreases in T-cell function, polymorphonuclear neutrophil migration, phagocytosis, and bacterial eradication.15 Studies in hemodialysis patients have identified iron overload as an independent risk factor for bacterial infection, but the confounding role of the dialysis process cannot be disregarded.17,18
Bacterial growth. Many bacteria depend on iron for their growth; examples are Escherichia coli; Klebsiella, Pseudomonas, Salmonella, Yersinia, Listeria, and Staphylococcus species; and Haemophilus influenzae. In vitro studies have linked increased bacterial growth with increased transferrin saturation in plasma.15,19
Iron therapy and infection risk
The theory linking iron with risk of infection arose from the observation that patients with hemochromatosis are more susceptible to certain bacterial infections, especially Vibrio vulnificus.20 A few human studies, most of them in chronic hemodialysis patients, have examined the relation between iron therapy and infection risk, with conflicting results.21–26 Multiple studies13,19,21,22,25–27 found no relation between iron therapy and risk of infection or death.
Canziani et al23 found that the risk of infection was higher with higher intravenous doses of iron than with lower doses.
Collins et al24 found a higher risk of sepsis and hospitalization in patients who received iron for a prolonged duration (5–6 months) than in those who did not.
Feldman et al,27 in their report of a study of iron therapy in hemodialysis patients, suggested that previously observed associations between iron administration and higher death rates may have been confounded by other factors.
Iron therapy in concurrent infection
There are no data in humans on the effects of iron therapy on outcomes during concurrent infection or sepsis.15,28 However, mice with sepsis had worse outcomes when treated with intravenous iron.28
A CONUNDRUM IN CLINICAL PRACTICE
After reviewing the available literature, we concur with most of the authors1,15,16,18,19,29 that despite the worrisome theoretical adverse effects of iron therapy in patients with infections, there are no convincing data to support those fears. On the other hand, there are also no convincing data to favor its benefit.
More definitive studies are needed to answer this question, which has been a conundrum in clinical practice. Patients who might benefit from iron therapy should not be deprived of it on the basis of the available data. Frequent monitoring of serum iron markers during therapy to avoid iron overload seems prudent.
- Pieracci FM, Barie PS. Diagnosis and management of iron-related anemias in critical illness. Crit Care Med 2006; 34:1898–1905.
- Krantz SB. Pathogenesis and treatment of the anemia of chronic disease. Am J Med Sci 1994; 307:353–359.
- Price EA, Schrier SL. Unexplained aspects of anemia of inflammation. Review article. Adv Hematol 2010; 2010:508739.
- Rodriguez RM, Corwin HL, Gettinger A, Corwin MJ, Gubler D, Pearl RG. Nutritional deficiencies and blunted erythropoietin response as causes of the anemia of critical illness. J Crit Care 2001; 16:36–41.
- Wong P, Intragumtornchai T. Hospital-acquired anemia. J Med Assoc Thai 2006; 89:63–67.
- Thavendiranathan P, Bagai A, Ebidia A, Detsky AS, Choudhry NK. Do blood tests cause anemia in hospitalized patients? The effect of diagnostic phlebotomy on hemoglobin and hematocrit levels. J Gen Intern Med 2005; 20:520–524.
- Reade MC, Weissfeld L, Angus DC, Kellum JA, Milbrandt EB. The prevalence of anemia and its association with 90-day mortality in hospitalized community-acquired pneumonia. BMC Pulm Med 2010; 10:15.
- Debellis RJ. Anemia in critical care patients: incidence, etiology, impact, management, and use of treatment guidelines and protocols. Am J Health Syst Pharm 2007; 64:S14–S21.
- Marik PE. The hazards of blood transfusion. Br J Hosp Med (Lond) 2009; 70:12–15.
- Corwin HL, Gettinger A, Fabian TC, et al. Efficacy and safety of epoetin alfa in critically ill patients. N Engl J Med 2007; 357:965–976.
- van Iperen CE, Gaillard CA, Kraaijenhagen RJ, Braam BG, Marx JJ, van de Wiel A. Response of erythropoiesis and iron metabolism to recombinant human erythropoietin in intensive care unit patients. Crit Care Med 2000; 28:2773–2778.
- Muñoz M, Breymann C, García-Erce JA, Gómez-Ramirez S, Comin J, Bisbe E. Efficacy and safety of intravenous iron therapy as an alternative/adjunct to allogeneic blood transfusion. Vox Sang 2008; 94:172–183.
- Pieracci FM, Henderson P, Rodney JR, et al. Randomized, double-blind, placebo-controlled trial of effects of enteral iron supplementation on anemia and risk of infection during surgical critical illness. Surg Infect 2009; 10:9–19.
- Pieracci FM, Barie PS. Iron and the risk of infection. Surg Infect 2005; 6(suppl 1):S41–S46.
- Maynor L, Brophy DF. Risk of infections with intravenous iron therapy. Ann Pharmacother 2007; 41:1476–1480.
- Cavill I. Intravenous iron as adjuvant therapy: a two-edged sword? Nephrol Dial Transplant 2003; 18(suppl 8):viii24–viii28.
- Kessler M, Hoen B, Mayeux D, Hestin D, Fontenaille C. Bacteremia in patients on chronic hemodialysis. A multicenter prospective survey. Nephron 1993; 64:95–100.
- Hoen B, Kessler M, Hestin D, Mayeux D. Risk factors for bacterial infections in chronic haemodialysis adult patients: a multicentre prospective survey. Nephrol Dial Transplant 1995; 10:377–381.
- Cieri E. Does iron cause bacterial infections in patients with end stage renal disease? ANNA J 1999; 26:591–596.
- Jurado RL. Iron, infections, and anemia of inflammation. Clin Infect Dis 1997; 25:888–895.
- Brewster UC, Coca SG, Reilly RF, Perazella MA. Effect of intravenous iron on hemodialysis catheter microbial colonization and blood-borne infection. Nephrology 2005; 10:124–128.
- Aronoff GR, Bennett WM, Blumenthal S, et al; United States Iron Sucrose (Venofer) Clinical Trials Group. Iron sucrose in hemodialysis patients: safety of replacement and maintenance regimens. Kidney Int 2004; 66:1193–1198.
- Canziani ME, Yumiya ST, Rangel EB, Manfredi SR, Neto MC, Draibe SA. Risk of bacterial infection in patients under intravenous iron therapy: dose versus length of treatment. Artif Organs 2001; 25:866–869.
- Collins A, Ma J, Xia H, et al. I.V. iron dosing patterns and hospitalization. J Am Soc Nephrol 1998; 9:204A.
- Burns DL, Mascioli EA, Bistrian BR. Effect of iron-supplemented total parenteral nutrition in patients with iron deficiency anemia. Nutrition 1996; 12:411–415.
- Olijhoek G, Megens JG, Musto P, et al. Role of oral versus IV iron supplementation in the erythropoietic response to rHuEPO: a randomized, placebo-controlled trial. Transfusion 2001; 41:957–963.
- Feldman HI, Joffe M, Robinson B, et al. Administration of parenteral iron and mortality among hemodialysis patients. J Am Soc Nephrol 2004; 15:1623–1632.
- Javadi P, Buchman TG, Stromberg PE, et al. High-dose exogenous iron following cecal ligation and puncture increases mortality rate in mice and is associated with an increase in gut epithelial and splenic apoptosis. Crit Care Med 2004; 32:1178–1185.
- Lapointe M. Iron supplementation in the intensive care unit: when, how much, and by what route? Crit Care 2004; 8(suppl 2):S37–S41.
The harmful effects of iron therapy in the setting of infection are more theoretical than observed, with no irrefutable data to support them. On the other hand, there are also no convincing data to support the benefit of this therapy. If iron is to be used, frequent monitoring of serum iron markers is prudent to avoid iron overload during treatment.
ANEMIA OF INFLAMMATION IS COMPLEX
Anemia that develops in the hospital, especially in the setting of infection or inflammation, is similar hematologically to anemia of chronic disease, except for its acute onset.1
The pathogenesis of anemia in such settings is complex, but the most important causes of this common syndrome include shortening of red cell survival, impaired erythropoietin production, blunted responsiveness of the bone marrow to endogenous erythropoietin, and impaired iron metabolism mediated through the action of inflammatory cytokines.2,3 Other important causes include nutritional deficiencies (iron, vitamin B12, and folic acid)4 and blood loss.5,6
Moreover, anemia of inflammation may be difficult to differentiate from iron-deficiency anemia because the serum iron markers are unreliable in inflammation.1
The reported prevalence of anemia during hospitalization has ranged from 55% on hospital wards7 to 95% in intensive care units.8
Transfusion of packed red blood cells is the fastest treatment for anemia in hospitalized patients and it is the one traditionally used, but many concerns have been raised about its efficacy and adverse effects.9 Erythropoietin, with or without iron therapy, has emerged as an alternative in treating anemia of inflammation.10,11
IRON THERAPY
Iron is widely used to treat anemia, especially in hospitalized patients and those with chronic kidney disease.2 The intravenous route is more commonly used than the oral route, since it has faster action, is better tolerated, and has better bioavailability.1,2
Controversy over benefit
Whether iron supplementation increases the red blood cell mass and reduces the need for blood transfusion is controversial.10,12 Pieracci et al13 documented these benefits in critically ill surgical patients, whereas van Iperen et al11 did not find such benefits in critically ill patients receiving intravenous iron and erythropoietin.
Harmful effects
Some authors1,14 object to giving iron to hospitalized patients (especially critically ill patients) who have infections on the grounds that it is risky, although definitive evidence is lacking.15
Most of the harmful effects of iron have been linked to elevated serum ferritin levels and to non–transferrin-bound iron, more than to iron per se.16 Ferritin is an acute-phase reactant; thus, ferritin levels may be elevated in inflammation and infection regardless of the body iron status.1
Anaphylactic reaction. This rare complication of iron dextran therapy is not much of a concern at present with the newer formulations of iron such as iron gluconate and iron sucrose.16
Oxidative stress. Iron-derived free radicals can cause a rise in inflammatory cytokine levels, especially if the ferritin level is elevated (> 500 μg/L). This cytokine rise is worrisome, as it may have acute detrimental effects on cellular homeostasis, leading to tissue injury,15 while chronically it might be related to enhanced atherosclerosis and cardiac disease.16
Iron overload. In vitro and animal studies have documented an association between elevated ferritin levels (500–650 μg/L) and decreases in T-cell function, polymorphonuclear neutrophil migration, phagocytosis, and bacterial eradication.15 Studies in hemodialysis patients have identified iron overload as an independent risk factor for bacterial infection, but the confounding role of the dialysis process cannot be disregarded.17,18
Bacterial growth. Many bacteria depend on iron for their growth; examples are Escherichia coli; Klebsiella, Pseudomonas, Salmonella, Yersinia, Listeria, and Staphylococcus species; and Haemophilus influenzae. In vitro studies have linked increased bacterial growth with increased transferrin saturation in plasma.15,19
Iron therapy and infection risk
The theory linking iron with risk of infection arose from the observation that patients with hemochromatosis are more susceptible to certain bacterial infections, especially Vibrio vulnificus.20 A few human studies, most of them in chronic hemodialysis patients, have examined the relation between iron therapy and infection risk, with conflicting results.21–26 Multiple studies13,19,21,22,25–27 found no relation between iron therapy and risk of infection or death.
Canziani et al23 found that the risk of infection was higher with higher intravenous doses of iron than with lower doses.
Collins et al24 found a higher risk of sepsis and hospitalization in patients who received iron for a prolonged duration (5–6 months) than in those who did not.
Feldman et al,27 in their report of a study of iron therapy in hemodialysis patients, suggested that previously observed associations between iron administration and higher death rates may have been confounded by other factors.
Iron therapy in concurrent infection
There are no data in humans on the effects of iron therapy on outcomes during concurrent infection or sepsis.15,28 However, mice with sepsis had worse outcomes when treated with intravenous iron.28
A CONUNDRUM IN CLINICAL PRACTICE
After reviewing the available literature, we concur with most of the authors1,15,16,18,19,29 that despite the worrisome theoretical adverse effects of iron therapy in patients with infections, there are no convincing data to support those fears. On the other hand, there are also no convincing data to favor its benefit.
More definitive studies are needed to answer this question, which has been a conundrum in clinical practice. Patients who might benefit from iron therapy should not be deprived of it on the basis of the available data. Frequent monitoring of serum iron markers during therapy to avoid iron overload seems prudent.
The harmful effects of iron therapy in the setting of infection are more theoretical than observed, with no irrefutable data to support them. On the other hand, there are also no convincing data to support the benefit of this therapy. If iron is to be used, frequent monitoring of serum iron markers is prudent to avoid iron overload during treatment.
ANEMIA OF INFLAMMATION IS COMPLEX
Anemia that develops in the hospital, especially in the setting of infection or inflammation, is similar hematologically to anemia of chronic disease, except for its acute onset.1
The pathogenesis of anemia in such settings is complex, but the most important causes of this common syndrome include shortening of red cell survival, impaired erythropoietin production, blunted responsiveness of the bone marrow to endogenous erythropoietin, and impaired iron metabolism mediated through the action of inflammatory cytokines.2,3 Other important causes include nutritional deficiencies (iron, vitamin B12, and folic acid)4 and blood loss.5,6
Moreover, anemia of inflammation may be difficult to differentiate from iron-deficiency anemia because the serum iron markers are unreliable in inflammation.1
The reported prevalence of anemia during hospitalization has ranged from 55% on hospital wards7 to 95% in intensive care units.8
Transfusion of packed red blood cells is the fastest treatment for anemia in hospitalized patients and it is the one traditionally used, but many concerns have been raised about its efficacy and adverse effects.9 Erythropoietin, with or without iron therapy, has emerged as an alternative in treating anemia of inflammation.10,11
IRON THERAPY
Iron is widely used to treat anemia, especially in hospitalized patients and those with chronic kidney disease.2 The intravenous route is more commonly used than the oral route, since it has faster action, is better tolerated, and has better bioavailability.1,2
Controversy over benefit
Whether iron supplementation increases the red blood cell mass and reduces the need for blood transfusion is controversial.10,12 Pieracci et al13 documented these benefits in critically ill surgical patients, whereas van Iperen et al11 did not find such benefits in critically ill patients receiving intravenous iron and erythropoietin.
Harmful effects
Some authors1,14 object to giving iron to hospitalized patients (especially critically ill patients) who have infections on the grounds that it is risky, although definitive evidence is lacking.15
Most of the harmful effects of iron have been linked to elevated serum ferritin levels and to non–transferrin-bound iron, more than to iron per se.16 Ferritin is an acute-phase reactant; thus, ferritin levels may be elevated in inflammation and infection regardless of the body iron status.1
Anaphylactic reaction. This rare complication of iron dextran therapy is not much of a concern at present with the newer formulations of iron such as iron gluconate and iron sucrose.16
Oxidative stress. Iron-derived free radicals can cause a rise in inflammatory cytokine levels, especially if the ferritin level is elevated (> 500 μg/L). This cytokine rise is worrisome, as it may have acute detrimental effects on cellular homeostasis, leading to tissue injury,15 while chronically it might be related to enhanced atherosclerosis and cardiac disease.16
Iron overload. In vitro and animal studies have documented an association between elevated ferritin levels (500–650 μg/L) and decreases in T-cell function, polymorphonuclear neutrophil migration, phagocytosis, and bacterial eradication.15 Studies in hemodialysis patients have identified iron overload as an independent risk factor for bacterial infection, but the confounding role of the dialysis process cannot be disregarded.17,18
Bacterial growth. Many bacteria depend on iron for their growth; examples are Escherichia coli; Klebsiella, Pseudomonas, Salmonella, Yersinia, Listeria, and Staphylococcus species; and Haemophilus influenzae. In vitro studies have linked increased bacterial growth with increased transferrin saturation in plasma.15,19
Iron therapy and infection risk
The theory linking iron with risk of infection arose from the observation that patients with hemochromatosis are more susceptible to certain bacterial infections, especially Vibrio vulnificus.20 A few human studies, most of them in chronic hemodialysis patients, have examined the relation between iron therapy and infection risk, with conflicting results.21–26 Multiple studies13,19,21,22,25–27 found no relation between iron therapy and risk of infection or death.
Canziani et al23 found that the risk of infection was higher with higher intravenous doses of iron than with lower doses.
Collins et al24 found a higher risk of sepsis and hospitalization in patients who received iron for a prolonged duration (5–6 months) than in those who did not.
Feldman et al,27 in their report of a study of iron therapy in hemodialysis patients, suggested that previously observed associations between iron administration and higher death rates may have been confounded by other factors.
Iron therapy in concurrent infection
There are no data in humans on the effects of iron therapy on outcomes during concurrent infection or sepsis.15,28 However, mice with sepsis had worse outcomes when treated with intravenous iron.28
A CONUNDRUM IN CLINICAL PRACTICE
After reviewing the available literature, we concur with most of the authors1,15,16,18,19,29 that despite the worrisome theoretical adverse effects of iron therapy in patients with infections, there are no convincing data to support those fears. On the other hand, there are also no convincing data to favor its benefit.
More definitive studies are needed to answer this question, which has been a conundrum in clinical practice. Patients who might benefit from iron therapy should not be deprived of it on the basis of the available data. Frequent monitoring of serum iron markers during therapy to avoid iron overload seems prudent.
- Pieracci FM, Barie PS. Diagnosis and management of iron-related anemias in critical illness. Crit Care Med 2006; 34:1898–1905.
- Krantz SB. Pathogenesis and treatment of the anemia of chronic disease. Am J Med Sci 1994; 307:353–359.
- Price EA, Schrier SL. Unexplained aspects of anemia of inflammation. Review article. Adv Hematol 2010; 2010:508739.
- Rodriguez RM, Corwin HL, Gettinger A, Corwin MJ, Gubler D, Pearl RG. Nutritional deficiencies and blunted erythropoietin response as causes of the anemia of critical illness. J Crit Care 2001; 16:36–41.
- Wong P, Intragumtornchai T. Hospital-acquired anemia. J Med Assoc Thai 2006; 89:63–67.
- Thavendiranathan P, Bagai A, Ebidia A, Detsky AS, Choudhry NK. Do blood tests cause anemia in hospitalized patients? The effect of diagnostic phlebotomy on hemoglobin and hematocrit levels. J Gen Intern Med 2005; 20:520–524.
- Reade MC, Weissfeld L, Angus DC, Kellum JA, Milbrandt EB. The prevalence of anemia and its association with 90-day mortality in hospitalized community-acquired pneumonia. BMC Pulm Med 2010; 10:15.
- Debellis RJ. Anemia in critical care patients: incidence, etiology, impact, management, and use of treatment guidelines and protocols. Am J Health Syst Pharm 2007; 64:S14–S21.
- Marik PE. The hazards of blood transfusion. Br J Hosp Med (Lond) 2009; 70:12–15.
- Corwin HL, Gettinger A, Fabian TC, et al. Efficacy and safety of epoetin alfa in critically ill patients. N Engl J Med 2007; 357:965–976.
- van Iperen CE, Gaillard CA, Kraaijenhagen RJ, Braam BG, Marx JJ, van de Wiel A. Response of erythropoiesis and iron metabolism to recombinant human erythropoietin in intensive care unit patients. Crit Care Med 2000; 28:2773–2778.
- Muñoz M, Breymann C, García-Erce JA, Gómez-Ramirez S, Comin J, Bisbe E. Efficacy and safety of intravenous iron therapy as an alternative/adjunct to allogeneic blood transfusion. Vox Sang 2008; 94:172–183.
- Pieracci FM, Henderson P, Rodney JR, et al. Randomized, double-blind, placebo-controlled trial of effects of enteral iron supplementation on anemia and risk of infection during surgical critical illness. Surg Infect 2009; 10:9–19.
- Pieracci FM, Barie PS. Iron and the risk of infection. Surg Infect 2005; 6(suppl 1):S41–S46.
- Maynor L, Brophy DF. Risk of infections with intravenous iron therapy. Ann Pharmacother 2007; 41:1476–1480.
- Cavill I. Intravenous iron as adjuvant therapy: a two-edged sword? Nephrol Dial Transplant 2003; 18(suppl 8):viii24–viii28.
- Kessler M, Hoen B, Mayeux D, Hestin D, Fontenaille C. Bacteremia in patients on chronic hemodialysis. A multicenter prospective survey. Nephron 1993; 64:95–100.
- Hoen B, Kessler M, Hestin D, Mayeux D. Risk factors for bacterial infections in chronic haemodialysis adult patients: a multicentre prospective survey. Nephrol Dial Transplant 1995; 10:377–381.
- Cieri E. Does iron cause bacterial infections in patients with end stage renal disease? ANNA J 1999; 26:591–596.
- Jurado RL. Iron, infections, and anemia of inflammation. Clin Infect Dis 1997; 25:888–895.
- Brewster UC, Coca SG, Reilly RF, Perazella MA. Effect of intravenous iron on hemodialysis catheter microbial colonization and blood-borne infection. Nephrology 2005; 10:124–128.
- Aronoff GR, Bennett WM, Blumenthal S, et al; United States Iron Sucrose (Venofer) Clinical Trials Group. Iron sucrose in hemodialysis patients: safety of replacement and maintenance regimens. Kidney Int 2004; 66:1193–1198.
- Canziani ME, Yumiya ST, Rangel EB, Manfredi SR, Neto MC, Draibe SA. Risk of bacterial infection in patients under intravenous iron therapy: dose versus length of treatment. Artif Organs 2001; 25:866–869.
- Collins A, Ma J, Xia H, et al. I.V. iron dosing patterns and hospitalization. J Am Soc Nephrol 1998; 9:204A.
- Burns DL, Mascioli EA, Bistrian BR. Effect of iron-supplemented total parenteral nutrition in patients with iron deficiency anemia. Nutrition 1996; 12:411–415.
- Olijhoek G, Megens JG, Musto P, et al. Role of oral versus IV iron supplementation in the erythropoietic response to rHuEPO: a randomized, placebo-controlled trial. Transfusion 2001; 41:957–963.
- Feldman HI, Joffe M, Robinson B, et al. Administration of parenteral iron and mortality among hemodialysis patients. J Am Soc Nephrol 2004; 15:1623–1632.
- Javadi P, Buchman TG, Stromberg PE, et al. High-dose exogenous iron following cecal ligation and puncture increases mortality rate in mice and is associated with an increase in gut epithelial and splenic apoptosis. Crit Care Med 2004; 32:1178–1185.
- Lapointe M. Iron supplementation in the intensive care unit: when, how much, and by what route? Crit Care 2004; 8(suppl 2):S37–S41.
- Pieracci FM, Barie PS. Diagnosis and management of iron-related anemias in critical illness. Crit Care Med 2006; 34:1898–1905.
- Krantz SB. Pathogenesis and treatment of the anemia of chronic disease. Am J Med Sci 1994; 307:353–359.
- Price EA, Schrier SL. Unexplained aspects of anemia of inflammation. Review article. Adv Hematol 2010; 2010:508739.
- Rodriguez RM, Corwin HL, Gettinger A, Corwin MJ, Gubler D, Pearl RG. Nutritional deficiencies and blunted erythropoietin response as causes of the anemia of critical illness. J Crit Care 2001; 16:36–41.
- Wong P, Intragumtornchai T. Hospital-acquired anemia. J Med Assoc Thai 2006; 89:63–67.
- Thavendiranathan P, Bagai A, Ebidia A, Detsky AS, Choudhry NK. Do blood tests cause anemia in hospitalized patients? The effect of diagnostic phlebotomy on hemoglobin and hematocrit levels. J Gen Intern Med 2005; 20:520–524.
- Reade MC, Weissfeld L, Angus DC, Kellum JA, Milbrandt EB. The prevalence of anemia and its association with 90-day mortality in hospitalized community-acquired pneumonia. BMC Pulm Med 2010; 10:15.
- Debellis RJ. Anemia in critical care patients: incidence, etiology, impact, management, and use of treatment guidelines and protocols. Am J Health Syst Pharm 2007; 64:S14–S21.
- Marik PE. The hazards of blood transfusion. Br J Hosp Med (Lond) 2009; 70:12–15.
- Corwin HL, Gettinger A, Fabian TC, et al. Efficacy and safety of epoetin alfa in critically ill patients. N Engl J Med 2007; 357:965–976.
- van Iperen CE, Gaillard CA, Kraaijenhagen RJ, Braam BG, Marx JJ, van de Wiel A. Response of erythropoiesis and iron metabolism to recombinant human erythropoietin in intensive care unit patients. Crit Care Med 2000; 28:2773–2778.
- Muñoz M, Breymann C, García-Erce JA, Gómez-Ramirez S, Comin J, Bisbe E. Efficacy and safety of intravenous iron therapy as an alternative/adjunct to allogeneic blood transfusion. Vox Sang 2008; 94:172–183.
- Pieracci FM, Henderson P, Rodney JR, et al. Randomized, double-blind, placebo-controlled trial of effects of enteral iron supplementation on anemia and risk of infection during surgical critical illness. Surg Infect 2009; 10:9–19.
- Pieracci FM, Barie PS. Iron and the risk of infection. Surg Infect 2005; 6(suppl 1):S41–S46.
- Maynor L, Brophy DF. Risk of infections with intravenous iron therapy. Ann Pharmacother 2007; 41:1476–1480.
- Cavill I. Intravenous iron as adjuvant therapy: a two-edged sword? Nephrol Dial Transplant 2003; 18(suppl 8):viii24–viii28.
- Kessler M, Hoen B, Mayeux D, Hestin D, Fontenaille C. Bacteremia in patients on chronic hemodialysis. A multicenter prospective survey. Nephron 1993; 64:95–100.
- Hoen B, Kessler M, Hestin D, Mayeux D. Risk factors for bacterial infections in chronic haemodialysis adult patients: a multicentre prospective survey. Nephrol Dial Transplant 1995; 10:377–381.
- Cieri E. Does iron cause bacterial infections in patients with end stage renal disease? ANNA J 1999; 26:591–596.
- Jurado RL. Iron, infections, and anemia of inflammation. Clin Infect Dis 1997; 25:888–895.
- Brewster UC, Coca SG, Reilly RF, Perazella MA. Effect of intravenous iron on hemodialysis catheter microbial colonization and blood-borne infection. Nephrology 2005; 10:124–128.
- Aronoff GR, Bennett WM, Blumenthal S, et al; United States Iron Sucrose (Venofer) Clinical Trials Group. Iron sucrose in hemodialysis patients: safety of replacement and maintenance regimens. Kidney Int 2004; 66:1193–1198.
- Canziani ME, Yumiya ST, Rangel EB, Manfredi SR, Neto MC, Draibe SA. Risk of bacterial infection in patients under intravenous iron therapy: dose versus length of treatment. Artif Organs 2001; 25:866–869.
- Collins A, Ma J, Xia H, et al. I.V. iron dosing patterns and hospitalization. J Am Soc Nephrol 1998; 9:204A.
- Burns DL, Mascioli EA, Bistrian BR. Effect of iron-supplemented total parenteral nutrition in patients with iron deficiency anemia. Nutrition 1996; 12:411–415.
- Olijhoek G, Megens JG, Musto P, et al. Role of oral versus IV iron supplementation in the erythropoietic response to rHuEPO: a randomized, placebo-controlled trial. Transfusion 2001; 41:957–963.
- Feldman HI, Joffe M, Robinson B, et al. Administration of parenteral iron and mortality among hemodialysis patients. J Am Soc Nephrol 2004; 15:1623–1632.
- Javadi P, Buchman TG, Stromberg PE, et al. High-dose exogenous iron following cecal ligation and puncture increases mortality rate in mice and is associated with an increase in gut epithelial and splenic apoptosis. Crit Care Med 2004; 32:1178–1185.
- Lapointe M. Iron supplementation in the intensive care unit: when, how much, and by what route? Crit Care 2004; 8(suppl 2):S37–S41.
Are antibiotics indicated for the treatment of aspiration pneumonia?
Antibiotics are indicated for primary bacterial aspiration pneumonia and secondary bacterial infection of aspiration (chemical) pneumonitis, but not for uncomplicated chemical pneumonitis.
THREE TYPES OF ‘ASPIRATION PNEUMONIA’
Aspiration pneumonia is a broad and vague term mainly used to refer to the pulmonary consequences of abnormal entry of exogenous or endogenous substances into the lower airways. It can be classified as:
- Aspiration (chemical) pneumonitis
- Primary bacterial aspiration pneumonia
- Secondary bacterial infection of chemical pneumonitis.
These three are sometimes difficult to differentiate, as their signs and symptoms can overlap.
CHEMICAL PNEUMONITIS
Aspiration of stomach contents is relatively common, even in healthy people, and usually has no clinical consequences.1 However, it has also been closely related to community-acquired and nosocomial pneumonia in some studies.2,3
Chemical pneumonitis is usually a consequence of the aspiration of a large volume (≥ 4 mL/kg) of sterile acidic (pH < 2.5) gastric contents into the lower airways (Mendelson syndrome).4,5 The clinical picture varies from asymptomatic to signs of severe dyspnea, hypoxia, cough, and low-grade fever; these signs and symptoms may develop rapidly, within minutes to hours after a witnessed or suspected episode of aspiration.2,6,7 However, they represent an inflammatory reaction to the gastric acid rather than a reaction to bacterial infection.8–10
Chemical pneumonitis affects the most dependent regions of the lungs
Chest radiography shows infiltrates in the most dependent regions of the lung. If aspiration occurs while the patient is supine, the posterior segments of the upper lobes and the apical segments of the lower lobes are most affected. The basal segments of the lower lobes are usually affected if aspiration occurs while the patient is standing or upright.1,2,11,12
Clinical course varies
The clinical course varies. In almost 60% of cases, the patient’s condition improves and the lung infiltrates resolve rapidly, within 2 to 4 days. On the other hand, in about 15% of cases, the patient’s condition deteriorates quickly, within 24 to 36 hours, and progresses to hypoxic respiratory failure and acute respiratory distress syndrome.
In the other 25% of cases, the patient’s condition may improve initially but then worsen as a secondary bacterial infection sets in. The death rate in these patients is almost three times higher than the rate in patients with uncomplicated chemical pneumonitis.11,13
Treatment of uncomplicated cases is mainly supportive
The treatment of uncomplicated chemical pneumonitis involves supportive measures such as airway clearance, oxygen supplementation, and positive pressure ventilation if needed. An obstructing foreign body may need to be removed.12,14 Corticosteroids have been tried, without success.11–13,15
Empiric antibiotic treatment is controversial
Chemical pneumonitis can be difficult to differentiate from bacterial aspiration pneumonia, and whether to give antibiotics is controversial. 16 A survey of current practices among intensivists showed that antimicrobial therapy was often given empirically for noninfectious chemical pneumonitis.17 This practice raises concerns of higher treatment costs and antibiotic resistance.16,18,19 Additionally, antibiotics do not seem to alter the clinical outcome, including radiographic resolution, duration of hospitalization, or death rate, nor do they influence the subsequent development of infection.1,11,13,20
In cases of witnessed or strongly suspected aspiration of gastric contents, antibiotics are not warranted since bacterial infection is not likely to be the cause of any signs or symptoms. 2,7,16 However, to detect secondary infection early, the patient’s respiratory status should be monitored carefully and chest radiography should be repeated.
In less clear-cut cases, ie, if it is not clear whether the patient actually has chemical pneumonitis or primary bacterial aspiration pneumonia, it is prudent to start antibiotics empirically after obtaining lower-respiratory-tract secretions for stains and cultures, and then to reassess within 48 to 72 hours. The antibiotics can be discontinued if the patient has rapid clinical and radiographic improvement and negative cultures. Those whose condition does not improve or who have positive cultures should receive a full course of antibiotics.21,22
PRIMARY BACTERIAL ASPIRATION PNEUMONIA
Primary bacterial aspiration pneumonia—ie, caused by bacteria residing in the upper airways and stomach gaining access to lower airways through aspiration in small or large amounts—is the most common form of aspiration pneumonia, although the actual episode of aspiration is seldom observed.
Signs of bacterial pneumonia
Primary bacterial aspiration pneumonia bears the hallmarks of bacterial pneumonia.12 The clinical picture is more indolent than chemical pneumonitis and includes cough, fever, and putrid sputum, mainly in patients who have clinical conditions predisposing to aspiration (eg, coma, stroke, alcoholism, poor dentition, tube feedings).1,12,20
The characteristic signs on chest radiography are infiltrates involving mainly the lung bases (the right more then the left). If untreated or inadequately treated, complications such as lung abscess, empyema, bronchiectasis, and broncopleural fistula are common.23
Are aerobic organisms replacing anaerobic ones in the community?
The causative organisms in community-acquired aspiration pneumonia are still debated despite abundant research. Older studies1,24,25 found mostly anaerobic organisms (pepto-streptococci, peptococci, Fusobacterium, Prevotela, Bacteroides) as the underlying pathogens, whereas more recent studies16,26,27 found mostly aerobic organisms (Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Enterobacteriaceae) and failed to recover anaerobic organisms. These discrepancies may be the result of different techniques used to isolate organisms: older studies used transtracheal sampling, and transtracheal aspirates may be easily contaminated or colonized by oropharyngeal flora; more recent studies used protected specimen brushes to collect lower-airway specimens.2
In addition, the pathogenic organisms that predominate in community-acquired aspiration pneumonia, as listed above, are different from those most often found in nosocomial cases; gram-negative bacilli (Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli) are most often isolated in patients with aspiration pneumonia acquired in hospitals and nursing homes.16,27,28S aureus also is an important causative organism in nosocomial cases.16,28
Knowing the causative organisms in bacterial aspiration pneumonia is important for guiding antimicrobial therapy.
Antibiotics are required for bacterial aspiration pneumonia
A course of antibiotics is required for bacterial aspiration pneumonia. While there are no definitive recommendations for the duration of treatment, 7 to 8 days is probably appropriate in uncomplicated cases (ie, no lung abscess, empyema, bronchopleural fistula).22,29 Patients who have complications may need drainage of abscesses or empyema along with a longer duration of antibiotic therapy until clinical and radiographic signs improve.
For community-acquired cases of aspiration pneumonia, a number of antibiotics have proven effective:
- Clindamycin (Cleocin) is still the agent most commonly used, although it lacks gram-negative bacterial coverage.
- Beta-lactam penicillins and newer quinolones have been used successfully.2,29–31 In addition to covering the previously mentioned bacteria, these antibiotics have the added benefit of covering anaerobic bacteria.
- Metronidazole (Flagyl) should not be used alone because it has a higher clinical failure rate.32,33
For nosocomial aspiration pneumonia, giving a broad-spectrum antibiotic empirically is warranted. Beta-lactam penicillins with extended gram-negative coverage, carbapenems, or monobactams in combination with an anti-staphylococcal drug have been advocated for nosocomial aspiration.2,22 A strategy of broad-spectrum coverage followed by narrowing or de-escalating coverage according to lower respiratory tract cultures is encouraged.21,22,34
SECONDARY BACTERIAL INFECTION OF CHEMICAL PNEUMONITIS
Nearly 25% of patients with chemical pneumonitis improve initially, then show clinical deterioration secondary to superimposed bacterial infection.13 Chest radiographs show worsening of initial infiltrates or the development of new ones. The causative organisms and treatment depend on whether the superimposed infection is community-acquired or nosocomial, as is the case in primary bacterial aspiration pneumonia.
PREVENTING ASPIRATION
Measures should be taken to prevent aspiration pneumonia and chemical pneumonitis, especially in institutionalized patients at high risk.12
Elevation of the head of the bed while feeding, dental prophylaxis, and good oral hygiene are known to reduce the incidence of these problems.35–37
A swallowing evaluation for patients with dysphagia can identify those at higher risk of aspiration. These patients may be candidates for postural adjustments, diet modification, strengthening, and other measures offered by the speech and language pathology teams to improve swallowing physiology, biomechanics, safety, and endurance.2,35
Although percutaneous endoscopic gastrostomy tubes are often placed in patients who have aspirated or who are at high risk of aspiration, they do not protect against aspiration, nor do orogastric or nasogastric tubes.38
To date, we have no evidence that prophylactic antibiotic therapy prevents bacterial aspiration pneumonia. In addition, this practice encourages the development of resistant organisms.19,39,40
- Bartlett JG, Gorbach SL. The triple threat of aspiration pneumonia. Chest 1975; 68:560–566.
- Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Engl J Med 2001; 344:665–671.
- Kikuchi R, Watabe N, Konno T, Mishina N, Sekizawa K, Sasaki H. High incidence of silent aspiration in elderly patients with community-acquired pneumonia. Am J Respir Crit Care Med 1994; 150:251–253.
- Mendelson CL. The aspiration of stomach contents into lungs during obstetric anesthesia. Am J Obstet Gynecol 1946; 52:191–205.
- Cameron JL, Caldini P, Toung JK, Zuidema GD. Aspiration pneumonia: physiologic data following experimental aspiration. Surgery 1972; 72:238–245.
- Warner MA, Warner ME, Weber JG. Clinical significance of pulmonary aspiration during the perioperative period. Anesthesiology 1993; 78:56–62.
- DePaso WJ. Aspiration pneumonia. Clin Chest Med 1991; 12:269–284.
- Folkesson HG, Matthay MA, Hébert CA, Broaddus VC. Acid aspiration-induced lung injury in rabbits is mediated by interleukin-8-dependent mechanisms. J Clin Invest 1995; 96:107–116.
- Goldman G, Welbourn R, Kobzik L, Valeri CR, Shepro D, Hechtman HB. Tumor necrosis factor-alpha mediates acid aspiration-induced systemic organ injury. Ann Surg 1990; 212:513–519.
- LeFrock JL, Clark TS, Davies B, Klainer AS. Aspiration pneumonia: a ten-year review. Am Surg 1979; 45:305–313.
- Cameron JL, Mitchell WH, Zuidema GD. Aspiration pneumonia. Clinical outcome following documented aspiration. Arch Surg 1973; 106:49–52.
- Arms RA, Dines DE, Tinstman TC. Aspiration pneumonia. Chest 1974; 65:136–139.
- Bynum LJ, Pierce AK. Pulmonary aspiration of gastric contents. Am Rev Respir Dis 1976; 114:1129–1136.
- Merchant SN, Kirtane MV, Shah KL, Karnik PP. Foreign bodies in the bronchi (a 10 year review of 132 cases). J Postgrad Med 1984; 30:219–223.
- Wolfe JE, Bone RC, Ruth WE. Effects of corticosteroids in the treatment of patients with gastric aspiration. Am J Med 1977; 63:719–722.
- Kane-Gill SL, Olsen KM, Rebuck JA, et al; Aspiration Evaluation Group of the Clinical Pharmacy and Pharmacology Section. Multicenter treatment and outcome evaluation of aspiration syndromes in critically ill patients. Ann Pharmacother 2007; 41:549–555.
- Rebuck JA, Rasmussen JR, Olsen KM. Clinical aspiration-related practice patterns in the intensive care unit: a physician survey. Crit Care Med 2001; 29:2239–2244.
- Singh N, Rogers P, Atwood CW, Wagener MM, Yu VL. Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. A proposed solution for indiscriminate antibiotic prescription. Am J Respir Crit Care Med 2000; 162:505–511.
- Kollef MH, Fraser VJ. Antibiotic resistance in the intensive care unit. Ann Intern Med 2001; 134:298–314.
- Lewis RT, Burgess JH, Hampson LG. Cardiorespiratory studies in critical illness. Changes in aspiration pneumonitis. Arch Surg 1971; 103:335–340.
- Rello J. Importance of appropriate initial antibiotic therapy and de-escalation in the treatment of nosocomial pneumonia. Eur Respir Rev 2007; 16:33–39.
- American Thoracic Society. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005; 171:388–416.
- Bartlett JG. Anaerobic bacterial infections of the lung and pleural space. Clin Infect Dis 1993; 16(suppl 4):S248–S255.
- Lorber B, Swenson RM. Bacteriology of aspiration pneumonia. A prospective study of community- and hospital-acquired cases. Ann Intern Med 1974; 81:329–331.
- Bartlett JG, Gorbach SL, Finegold SM. The bacteriology of aspiration pneumonia. Am J Med 1974; 56:202–207.
- Mier L, Dreyfuss D, Darchy B, et al. Is penicillin G an adequate initial treatment for aspiration pneumonia? A prospective evaluation using a protected specimen brush and quantitative cultures. Intensive Care Med 1993; 19:279–284.
- Marik PE, Careau P. The role of anaerobes in patients with ventilator-associated pneumonia and aspiration pneumonia: a prospective study. Chest 1999; 115:178–183.
- El-Solh AA, Pietrantoni C, Bhat A, et al. Microbiology of severe aspiration pneumonia in institutionalized elderly. Am J Respir Crit Care Med 2003; 167:1650–1654.
- Mandell LA, Wunderink RG, Anzueto A, et al; Infectious Diseases Society of America. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44(suppl 2):S27–S72.
- Kadowaki M, Demura Y, Mizuno S, et al. Reappraisal of clindamycin IV monotherapy for treatment of mild-to-moderate aspiration pneumonia in elderly patients. Chest 2005; 127:1276–1282.
- Ott SR, Allewelt M, Lorenz J, Reimnitz P, Lode H; German Lung Abscess Study Group. Moxifloxacin vs ampicillin/sulbactam in aspiration pneumonia and primary lung abscess. Infection 2008; 36:23–30.
- Perlino CA. Metronidazole vs clindamycin treatment of anerobic pulmonary infection. Failure of metronidazole therapy. Arch Intern Med 1981; 141:1424–1427.
- Sanders CV, Hanna BJ, Lewis AC. Metronidazole in the treatment of anaerobic infections. Am Rev Respir Dis 1979; 120:337–343.
- Alvarez-Lerma F, Alvarez B, Luque P, et al; ADANN Study Group. Empiric broad-spectrum antibiotic therapy of nosocomial pneumonia in the intensive care unit: a prospective observational study. Crit Care 2006; 10:R78.
- Johnson JL, Hirsch CS. Aspiration pneumonia. Recognizing and managing a potentially growing disorder. Postgrad Med 2003; 113:99–112.
- Scolapio JS. Methods for decreasing risk of aspiration pneumonia in critically ill patients. JPEN J Parenter Enteral Nutr 2002; 26(suppl 6):S58–S61.
- Orozco-Levi M, Torres A, Ferrer M, et al. Semirecumbent position protects from pulmonary aspiration but not completely from gastroesophageal reflux in mechanically ventilated patients. Am J Respir Crit Care Med 1995; 152:1387–1390.
- Park RH, Allison MC, Lang J, et al. Randomised comparison of percutaneous endoscopic gastrostomy and nasogastric tube feeding in patients with persisting neurological dysphagia. BMJ 1992; 304( 6839):1406–1409.
- Donskey CJ, Chowdhry TK, Hecker MT, et al. Effect of antibiotic therapy on the density of vancomycin-resistant enterococci in the stool of colonized patients. N Engl J Med 2000; 343:1925–1932.
- Mouw DR, Langlois JP, Turner LF, Neher JO. Clinical inquiries. Are antibiotics effective in preventing pneumonia for nursing home patients? J Fam Pract 2004; 53:994–996.
Antibiotics are indicated for primary bacterial aspiration pneumonia and secondary bacterial infection of aspiration (chemical) pneumonitis, but not for uncomplicated chemical pneumonitis.
THREE TYPES OF ‘ASPIRATION PNEUMONIA’
Aspiration pneumonia is a broad and vague term mainly used to refer to the pulmonary consequences of abnormal entry of exogenous or endogenous substances into the lower airways. It can be classified as:
- Aspiration (chemical) pneumonitis
- Primary bacterial aspiration pneumonia
- Secondary bacterial infection of chemical pneumonitis.
These three are sometimes difficult to differentiate, as their signs and symptoms can overlap.
CHEMICAL PNEUMONITIS
Aspiration of stomach contents is relatively common, even in healthy people, and usually has no clinical consequences.1 However, it has also been closely related to community-acquired and nosocomial pneumonia in some studies.2,3
Chemical pneumonitis is usually a consequence of the aspiration of a large volume (≥ 4 mL/kg) of sterile acidic (pH < 2.5) gastric contents into the lower airways (Mendelson syndrome).4,5 The clinical picture varies from asymptomatic to signs of severe dyspnea, hypoxia, cough, and low-grade fever; these signs and symptoms may develop rapidly, within minutes to hours after a witnessed or suspected episode of aspiration.2,6,7 However, they represent an inflammatory reaction to the gastric acid rather than a reaction to bacterial infection.8–10
Chemical pneumonitis affects the most dependent regions of the lungs
Chest radiography shows infiltrates in the most dependent regions of the lung. If aspiration occurs while the patient is supine, the posterior segments of the upper lobes and the apical segments of the lower lobes are most affected. The basal segments of the lower lobes are usually affected if aspiration occurs while the patient is standing or upright.1,2,11,12
Clinical course varies
The clinical course varies. In almost 60% of cases, the patient’s condition improves and the lung infiltrates resolve rapidly, within 2 to 4 days. On the other hand, in about 15% of cases, the patient’s condition deteriorates quickly, within 24 to 36 hours, and progresses to hypoxic respiratory failure and acute respiratory distress syndrome.
In the other 25% of cases, the patient’s condition may improve initially but then worsen as a secondary bacterial infection sets in. The death rate in these patients is almost three times higher than the rate in patients with uncomplicated chemical pneumonitis.11,13
Treatment of uncomplicated cases is mainly supportive
The treatment of uncomplicated chemical pneumonitis involves supportive measures such as airway clearance, oxygen supplementation, and positive pressure ventilation if needed. An obstructing foreign body may need to be removed.12,14 Corticosteroids have been tried, without success.11–13,15
Empiric antibiotic treatment is controversial
Chemical pneumonitis can be difficult to differentiate from bacterial aspiration pneumonia, and whether to give antibiotics is controversial. 16 A survey of current practices among intensivists showed that antimicrobial therapy was often given empirically for noninfectious chemical pneumonitis.17 This practice raises concerns of higher treatment costs and antibiotic resistance.16,18,19 Additionally, antibiotics do not seem to alter the clinical outcome, including radiographic resolution, duration of hospitalization, or death rate, nor do they influence the subsequent development of infection.1,11,13,20
In cases of witnessed or strongly suspected aspiration of gastric contents, antibiotics are not warranted since bacterial infection is not likely to be the cause of any signs or symptoms. 2,7,16 However, to detect secondary infection early, the patient’s respiratory status should be monitored carefully and chest radiography should be repeated.
In less clear-cut cases, ie, if it is not clear whether the patient actually has chemical pneumonitis or primary bacterial aspiration pneumonia, it is prudent to start antibiotics empirically after obtaining lower-respiratory-tract secretions for stains and cultures, and then to reassess within 48 to 72 hours. The antibiotics can be discontinued if the patient has rapid clinical and radiographic improvement and negative cultures. Those whose condition does not improve or who have positive cultures should receive a full course of antibiotics.21,22
PRIMARY BACTERIAL ASPIRATION PNEUMONIA
Primary bacterial aspiration pneumonia—ie, caused by bacteria residing in the upper airways and stomach gaining access to lower airways through aspiration in small or large amounts—is the most common form of aspiration pneumonia, although the actual episode of aspiration is seldom observed.
Signs of bacterial pneumonia
Primary bacterial aspiration pneumonia bears the hallmarks of bacterial pneumonia.12 The clinical picture is more indolent than chemical pneumonitis and includes cough, fever, and putrid sputum, mainly in patients who have clinical conditions predisposing to aspiration (eg, coma, stroke, alcoholism, poor dentition, tube feedings).1,12,20
The characteristic signs on chest radiography are infiltrates involving mainly the lung bases (the right more then the left). If untreated or inadequately treated, complications such as lung abscess, empyema, bronchiectasis, and broncopleural fistula are common.23
Are aerobic organisms replacing anaerobic ones in the community?
The causative organisms in community-acquired aspiration pneumonia are still debated despite abundant research. Older studies1,24,25 found mostly anaerobic organisms (pepto-streptococci, peptococci, Fusobacterium, Prevotela, Bacteroides) as the underlying pathogens, whereas more recent studies16,26,27 found mostly aerobic organisms (Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Enterobacteriaceae) and failed to recover anaerobic organisms. These discrepancies may be the result of different techniques used to isolate organisms: older studies used transtracheal sampling, and transtracheal aspirates may be easily contaminated or colonized by oropharyngeal flora; more recent studies used protected specimen brushes to collect lower-airway specimens.2
In addition, the pathogenic organisms that predominate in community-acquired aspiration pneumonia, as listed above, are different from those most often found in nosocomial cases; gram-negative bacilli (Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli) are most often isolated in patients with aspiration pneumonia acquired in hospitals and nursing homes.16,27,28S aureus also is an important causative organism in nosocomial cases.16,28
Knowing the causative organisms in bacterial aspiration pneumonia is important for guiding antimicrobial therapy.
Antibiotics are required for bacterial aspiration pneumonia
A course of antibiotics is required for bacterial aspiration pneumonia. While there are no definitive recommendations for the duration of treatment, 7 to 8 days is probably appropriate in uncomplicated cases (ie, no lung abscess, empyema, bronchopleural fistula).22,29 Patients who have complications may need drainage of abscesses or empyema along with a longer duration of antibiotic therapy until clinical and radiographic signs improve.
For community-acquired cases of aspiration pneumonia, a number of antibiotics have proven effective:
- Clindamycin (Cleocin) is still the agent most commonly used, although it lacks gram-negative bacterial coverage.
- Beta-lactam penicillins and newer quinolones have been used successfully.2,29–31 In addition to covering the previously mentioned bacteria, these antibiotics have the added benefit of covering anaerobic bacteria.
- Metronidazole (Flagyl) should not be used alone because it has a higher clinical failure rate.32,33
For nosocomial aspiration pneumonia, giving a broad-spectrum antibiotic empirically is warranted. Beta-lactam penicillins with extended gram-negative coverage, carbapenems, or monobactams in combination with an anti-staphylococcal drug have been advocated for nosocomial aspiration.2,22 A strategy of broad-spectrum coverage followed by narrowing or de-escalating coverage according to lower respiratory tract cultures is encouraged.21,22,34
SECONDARY BACTERIAL INFECTION OF CHEMICAL PNEUMONITIS
Nearly 25% of patients with chemical pneumonitis improve initially, then show clinical deterioration secondary to superimposed bacterial infection.13 Chest radiographs show worsening of initial infiltrates or the development of new ones. The causative organisms and treatment depend on whether the superimposed infection is community-acquired or nosocomial, as is the case in primary bacterial aspiration pneumonia.
PREVENTING ASPIRATION
Measures should be taken to prevent aspiration pneumonia and chemical pneumonitis, especially in institutionalized patients at high risk.12
Elevation of the head of the bed while feeding, dental prophylaxis, and good oral hygiene are known to reduce the incidence of these problems.35–37
A swallowing evaluation for patients with dysphagia can identify those at higher risk of aspiration. These patients may be candidates for postural adjustments, diet modification, strengthening, and other measures offered by the speech and language pathology teams to improve swallowing physiology, biomechanics, safety, and endurance.2,35
Although percutaneous endoscopic gastrostomy tubes are often placed in patients who have aspirated or who are at high risk of aspiration, they do not protect against aspiration, nor do orogastric or nasogastric tubes.38
To date, we have no evidence that prophylactic antibiotic therapy prevents bacterial aspiration pneumonia. In addition, this practice encourages the development of resistant organisms.19,39,40
Antibiotics are indicated for primary bacterial aspiration pneumonia and secondary bacterial infection of aspiration (chemical) pneumonitis, but not for uncomplicated chemical pneumonitis.
THREE TYPES OF ‘ASPIRATION PNEUMONIA’
Aspiration pneumonia is a broad and vague term mainly used to refer to the pulmonary consequences of abnormal entry of exogenous or endogenous substances into the lower airways. It can be classified as:
- Aspiration (chemical) pneumonitis
- Primary bacterial aspiration pneumonia
- Secondary bacterial infection of chemical pneumonitis.
These three are sometimes difficult to differentiate, as their signs and symptoms can overlap.
CHEMICAL PNEUMONITIS
Aspiration of stomach contents is relatively common, even in healthy people, and usually has no clinical consequences.1 However, it has also been closely related to community-acquired and nosocomial pneumonia in some studies.2,3
Chemical pneumonitis is usually a consequence of the aspiration of a large volume (≥ 4 mL/kg) of sterile acidic (pH < 2.5) gastric contents into the lower airways (Mendelson syndrome).4,5 The clinical picture varies from asymptomatic to signs of severe dyspnea, hypoxia, cough, and low-grade fever; these signs and symptoms may develop rapidly, within minutes to hours after a witnessed or suspected episode of aspiration.2,6,7 However, they represent an inflammatory reaction to the gastric acid rather than a reaction to bacterial infection.8–10
Chemical pneumonitis affects the most dependent regions of the lungs
Chest radiography shows infiltrates in the most dependent regions of the lung. If aspiration occurs while the patient is supine, the posterior segments of the upper lobes and the apical segments of the lower lobes are most affected. The basal segments of the lower lobes are usually affected if aspiration occurs while the patient is standing or upright.1,2,11,12
Clinical course varies
The clinical course varies. In almost 60% of cases, the patient’s condition improves and the lung infiltrates resolve rapidly, within 2 to 4 days. On the other hand, in about 15% of cases, the patient’s condition deteriorates quickly, within 24 to 36 hours, and progresses to hypoxic respiratory failure and acute respiratory distress syndrome.
In the other 25% of cases, the patient’s condition may improve initially but then worsen as a secondary bacterial infection sets in. The death rate in these patients is almost three times higher than the rate in patients with uncomplicated chemical pneumonitis.11,13
Treatment of uncomplicated cases is mainly supportive
The treatment of uncomplicated chemical pneumonitis involves supportive measures such as airway clearance, oxygen supplementation, and positive pressure ventilation if needed. An obstructing foreign body may need to be removed.12,14 Corticosteroids have been tried, without success.11–13,15
Empiric antibiotic treatment is controversial
Chemical pneumonitis can be difficult to differentiate from bacterial aspiration pneumonia, and whether to give antibiotics is controversial. 16 A survey of current practices among intensivists showed that antimicrobial therapy was often given empirically for noninfectious chemical pneumonitis.17 This practice raises concerns of higher treatment costs and antibiotic resistance.16,18,19 Additionally, antibiotics do not seem to alter the clinical outcome, including radiographic resolution, duration of hospitalization, or death rate, nor do they influence the subsequent development of infection.1,11,13,20
In cases of witnessed or strongly suspected aspiration of gastric contents, antibiotics are not warranted since bacterial infection is not likely to be the cause of any signs or symptoms. 2,7,16 However, to detect secondary infection early, the patient’s respiratory status should be monitored carefully and chest radiography should be repeated.
In less clear-cut cases, ie, if it is not clear whether the patient actually has chemical pneumonitis or primary bacterial aspiration pneumonia, it is prudent to start antibiotics empirically after obtaining lower-respiratory-tract secretions for stains and cultures, and then to reassess within 48 to 72 hours. The antibiotics can be discontinued if the patient has rapid clinical and radiographic improvement and negative cultures. Those whose condition does not improve or who have positive cultures should receive a full course of antibiotics.21,22
PRIMARY BACTERIAL ASPIRATION PNEUMONIA
Primary bacterial aspiration pneumonia—ie, caused by bacteria residing in the upper airways and stomach gaining access to lower airways through aspiration in small or large amounts—is the most common form of aspiration pneumonia, although the actual episode of aspiration is seldom observed.
Signs of bacterial pneumonia
Primary bacterial aspiration pneumonia bears the hallmarks of bacterial pneumonia.12 The clinical picture is more indolent than chemical pneumonitis and includes cough, fever, and putrid sputum, mainly in patients who have clinical conditions predisposing to aspiration (eg, coma, stroke, alcoholism, poor dentition, tube feedings).1,12,20
The characteristic signs on chest radiography are infiltrates involving mainly the lung bases (the right more then the left). If untreated or inadequately treated, complications such as lung abscess, empyema, bronchiectasis, and broncopleural fistula are common.23
Are aerobic organisms replacing anaerobic ones in the community?
The causative organisms in community-acquired aspiration pneumonia are still debated despite abundant research. Older studies1,24,25 found mostly anaerobic organisms (pepto-streptococci, peptococci, Fusobacterium, Prevotela, Bacteroides) as the underlying pathogens, whereas more recent studies16,26,27 found mostly aerobic organisms (Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Enterobacteriaceae) and failed to recover anaerobic organisms. These discrepancies may be the result of different techniques used to isolate organisms: older studies used transtracheal sampling, and transtracheal aspirates may be easily contaminated or colonized by oropharyngeal flora; more recent studies used protected specimen brushes to collect lower-airway specimens.2
In addition, the pathogenic organisms that predominate in community-acquired aspiration pneumonia, as listed above, are different from those most often found in nosocomial cases; gram-negative bacilli (Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli) are most often isolated in patients with aspiration pneumonia acquired in hospitals and nursing homes.16,27,28S aureus also is an important causative organism in nosocomial cases.16,28
Knowing the causative organisms in bacterial aspiration pneumonia is important for guiding antimicrobial therapy.
Antibiotics are required for bacterial aspiration pneumonia
A course of antibiotics is required for bacterial aspiration pneumonia. While there are no definitive recommendations for the duration of treatment, 7 to 8 days is probably appropriate in uncomplicated cases (ie, no lung abscess, empyema, bronchopleural fistula).22,29 Patients who have complications may need drainage of abscesses or empyema along with a longer duration of antibiotic therapy until clinical and radiographic signs improve.
For community-acquired cases of aspiration pneumonia, a number of antibiotics have proven effective:
- Clindamycin (Cleocin) is still the agent most commonly used, although it lacks gram-negative bacterial coverage.
- Beta-lactam penicillins and newer quinolones have been used successfully.2,29–31 In addition to covering the previously mentioned bacteria, these antibiotics have the added benefit of covering anaerobic bacteria.
- Metronidazole (Flagyl) should not be used alone because it has a higher clinical failure rate.32,33
For nosocomial aspiration pneumonia, giving a broad-spectrum antibiotic empirically is warranted. Beta-lactam penicillins with extended gram-negative coverage, carbapenems, or monobactams in combination with an anti-staphylococcal drug have been advocated for nosocomial aspiration.2,22 A strategy of broad-spectrum coverage followed by narrowing or de-escalating coverage according to lower respiratory tract cultures is encouraged.21,22,34
SECONDARY BACTERIAL INFECTION OF CHEMICAL PNEUMONITIS
Nearly 25% of patients with chemical pneumonitis improve initially, then show clinical deterioration secondary to superimposed bacterial infection.13 Chest radiographs show worsening of initial infiltrates or the development of new ones. The causative organisms and treatment depend on whether the superimposed infection is community-acquired or nosocomial, as is the case in primary bacterial aspiration pneumonia.
PREVENTING ASPIRATION
Measures should be taken to prevent aspiration pneumonia and chemical pneumonitis, especially in institutionalized patients at high risk.12
Elevation of the head of the bed while feeding, dental prophylaxis, and good oral hygiene are known to reduce the incidence of these problems.35–37
A swallowing evaluation for patients with dysphagia can identify those at higher risk of aspiration. These patients may be candidates for postural adjustments, diet modification, strengthening, and other measures offered by the speech and language pathology teams to improve swallowing physiology, biomechanics, safety, and endurance.2,35
Although percutaneous endoscopic gastrostomy tubes are often placed in patients who have aspirated or who are at high risk of aspiration, they do not protect against aspiration, nor do orogastric or nasogastric tubes.38
To date, we have no evidence that prophylactic antibiotic therapy prevents bacterial aspiration pneumonia. In addition, this practice encourages the development of resistant organisms.19,39,40
- Bartlett JG, Gorbach SL. The triple threat of aspiration pneumonia. Chest 1975; 68:560–566.
- Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Engl J Med 2001; 344:665–671.
- Kikuchi R, Watabe N, Konno T, Mishina N, Sekizawa K, Sasaki H. High incidence of silent aspiration in elderly patients with community-acquired pneumonia. Am J Respir Crit Care Med 1994; 150:251–253.
- Mendelson CL. The aspiration of stomach contents into lungs during obstetric anesthesia. Am J Obstet Gynecol 1946; 52:191–205.
- Cameron JL, Caldini P, Toung JK, Zuidema GD. Aspiration pneumonia: physiologic data following experimental aspiration. Surgery 1972; 72:238–245.
- Warner MA, Warner ME, Weber JG. Clinical significance of pulmonary aspiration during the perioperative period. Anesthesiology 1993; 78:56–62.
- DePaso WJ. Aspiration pneumonia. Clin Chest Med 1991; 12:269–284.
- Folkesson HG, Matthay MA, Hébert CA, Broaddus VC. Acid aspiration-induced lung injury in rabbits is mediated by interleukin-8-dependent mechanisms. J Clin Invest 1995; 96:107–116.
- Goldman G, Welbourn R, Kobzik L, Valeri CR, Shepro D, Hechtman HB. Tumor necrosis factor-alpha mediates acid aspiration-induced systemic organ injury. Ann Surg 1990; 212:513–519.
- LeFrock JL, Clark TS, Davies B, Klainer AS. Aspiration pneumonia: a ten-year review. Am Surg 1979; 45:305–313.
- Cameron JL, Mitchell WH, Zuidema GD. Aspiration pneumonia. Clinical outcome following documented aspiration. Arch Surg 1973; 106:49–52.
- Arms RA, Dines DE, Tinstman TC. Aspiration pneumonia. Chest 1974; 65:136–139.
- Bynum LJ, Pierce AK. Pulmonary aspiration of gastric contents. Am Rev Respir Dis 1976; 114:1129–1136.
- Merchant SN, Kirtane MV, Shah KL, Karnik PP. Foreign bodies in the bronchi (a 10 year review of 132 cases). J Postgrad Med 1984; 30:219–223.
- Wolfe JE, Bone RC, Ruth WE. Effects of corticosteroids in the treatment of patients with gastric aspiration. Am J Med 1977; 63:719–722.
- Kane-Gill SL, Olsen KM, Rebuck JA, et al; Aspiration Evaluation Group of the Clinical Pharmacy and Pharmacology Section. Multicenter treatment and outcome evaluation of aspiration syndromes in critically ill patients. Ann Pharmacother 2007; 41:549–555.
- Rebuck JA, Rasmussen JR, Olsen KM. Clinical aspiration-related practice patterns in the intensive care unit: a physician survey. Crit Care Med 2001; 29:2239–2244.
- Singh N, Rogers P, Atwood CW, Wagener MM, Yu VL. Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. A proposed solution for indiscriminate antibiotic prescription. Am J Respir Crit Care Med 2000; 162:505–511.
- Kollef MH, Fraser VJ. Antibiotic resistance in the intensive care unit. Ann Intern Med 2001; 134:298–314.
- Lewis RT, Burgess JH, Hampson LG. Cardiorespiratory studies in critical illness. Changes in aspiration pneumonitis. Arch Surg 1971; 103:335–340.
- Rello J. Importance of appropriate initial antibiotic therapy and de-escalation in the treatment of nosocomial pneumonia. Eur Respir Rev 2007; 16:33–39.
- American Thoracic Society. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005; 171:388–416.
- Bartlett JG. Anaerobic bacterial infections of the lung and pleural space. Clin Infect Dis 1993; 16(suppl 4):S248–S255.
- Lorber B, Swenson RM. Bacteriology of aspiration pneumonia. A prospective study of community- and hospital-acquired cases. Ann Intern Med 1974; 81:329–331.
- Bartlett JG, Gorbach SL, Finegold SM. The bacteriology of aspiration pneumonia. Am J Med 1974; 56:202–207.
- Mier L, Dreyfuss D, Darchy B, et al. Is penicillin G an adequate initial treatment for aspiration pneumonia? A prospective evaluation using a protected specimen brush and quantitative cultures. Intensive Care Med 1993; 19:279–284.
- Marik PE, Careau P. The role of anaerobes in patients with ventilator-associated pneumonia and aspiration pneumonia: a prospective study. Chest 1999; 115:178–183.
- El-Solh AA, Pietrantoni C, Bhat A, et al. Microbiology of severe aspiration pneumonia in institutionalized elderly. Am J Respir Crit Care Med 2003; 167:1650–1654.
- Mandell LA, Wunderink RG, Anzueto A, et al; Infectious Diseases Society of America. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44(suppl 2):S27–S72.
- Kadowaki M, Demura Y, Mizuno S, et al. Reappraisal of clindamycin IV monotherapy for treatment of mild-to-moderate aspiration pneumonia in elderly patients. Chest 2005; 127:1276–1282.
- Ott SR, Allewelt M, Lorenz J, Reimnitz P, Lode H; German Lung Abscess Study Group. Moxifloxacin vs ampicillin/sulbactam in aspiration pneumonia and primary lung abscess. Infection 2008; 36:23–30.
- Perlino CA. Metronidazole vs clindamycin treatment of anerobic pulmonary infection. Failure of metronidazole therapy. Arch Intern Med 1981; 141:1424–1427.
- Sanders CV, Hanna BJ, Lewis AC. Metronidazole in the treatment of anaerobic infections. Am Rev Respir Dis 1979; 120:337–343.
- Alvarez-Lerma F, Alvarez B, Luque P, et al; ADANN Study Group. Empiric broad-spectrum antibiotic therapy of nosocomial pneumonia in the intensive care unit: a prospective observational study. Crit Care 2006; 10:R78.
- Johnson JL, Hirsch CS. Aspiration pneumonia. Recognizing and managing a potentially growing disorder. Postgrad Med 2003; 113:99–112.
- Scolapio JS. Methods for decreasing risk of aspiration pneumonia in critically ill patients. JPEN J Parenter Enteral Nutr 2002; 26(suppl 6):S58–S61.
- Orozco-Levi M, Torres A, Ferrer M, et al. Semirecumbent position protects from pulmonary aspiration but not completely from gastroesophageal reflux in mechanically ventilated patients. Am J Respir Crit Care Med 1995; 152:1387–1390.
- Park RH, Allison MC, Lang J, et al. Randomised comparison of percutaneous endoscopic gastrostomy and nasogastric tube feeding in patients with persisting neurological dysphagia. BMJ 1992; 304( 6839):1406–1409.
- Donskey CJ, Chowdhry TK, Hecker MT, et al. Effect of antibiotic therapy on the density of vancomycin-resistant enterococci in the stool of colonized patients. N Engl J Med 2000; 343:1925–1932.
- Mouw DR, Langlois JP, Turner LF, Neher JO. Clinical inquiries. Are antibiotics effective in preventing pneumonia for nursing home patients? J Fam Pract 2004; 53:994–996.
- Bartlett JG, Gorbach SL. The triple threat of aspiration pneumonia. Chest 1975; 68:560–566.
- Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Engl J Med 2001; 344:665–671.
- Kikuchi R, Watabe N, Konno T, Mishina N, Sekizawa K, Sasaki H. High incidence of silent aspiration in elderly patients with community-acquired pneumonia. Am J Respir Crit Care Med 1994; 150:251–253.
- Mendelson CL. The aspiration of stomach contents into lungs during obstetric anesthesia. Am J Obstet Gynecol 1946; 52:191–205.
- Cameron JL, Caldini P, Toung JK, Zuidema GD. Aspiration pneumonia: physiologic data following experimental aspiration. Surgery 1972; 72:238–245.
- Warner MA, Warner ME, Weber JG. Clinical significance of pulmonary aspiration during the perioperative period. Anesthesiology 1993; 78:56–62.
- DePaso WJ. Aspiration pneumonia. Clin Chest Med 1991; 12:269–284.
- Folkesson HG, Matthay MA, Hébert CA, Broaddus VC. Acid aspiration-induced lung injury in rabbits is mediated by interleukin-8-dependent mechanisms. J Clin Invest 1995; 96:107–116.
- Goldman G, Welbourn R, Kobzik L, Valeri CR, Shepro D, Hechtman HB. Tumor necrosis factor-alpha mediates acid aspiration-induced systemic organ injury. Ann Surg 1990; 212:513–519.
- LeFrock JL, Clark TS, Davies B, Klainer AS. Aspiration pneumonia: a ten-year review. Am Surg 1979; 45:305–313.
- Cameron JL, Mitchell WH, Zuidema GD. Aspiration pneumonia. Clinical outcome following documented aspiration. Arch Surg 1973; 106:49–52.
- Arms RA, Dines DE, Tinstman TC. Aspiration pneumonia. Chest 1974; 65:136–139.
- Bynum LJ, Pierce AK. Pulmonary aspiration of gastric contents. Am Rev Respir Dis 1976; 114:1129–1136.
- Merchant SN, Kirtane MV, Shah KL, Karnik PP. Foreign bodies in the bronchi (a 10 year review of 132 cases). J Postgrad Med 1984; 30:219–223.
- Wolfe JE, Bone RC, Ruth WE. Effects of corticosteroids in the treatment of patients with gastric aspiration. Am J Med 1977; 63:719–722.
- Kane-Gill SL, Olsen KM, Rebuck JA, et al; Aspiration Evaluation Group of the Clinical Pharmacy and Pharmacology Section. Multicenter treatment and outcome evaluation of aspiration syndromes in critically ill patients. Ann Pharmacother 2007; 41:549–555.
- Rebuck JA, Rasmussen JR, Olsen KM. Clinical aspiration-related practice patterns in the intensive care unit: a physician survey. Crit Care Med 2001; 29:2239–2244.
- Singh N, Rogers P, Atwood CW, Wagener MM, Yu VL. Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. A proposed solution for indiscriminate antibiotic prescription. Am J Respir Crit Care Med 2000; 162:505–511.
- Kollef MH, Fraser VJ. Antibiotic resistance in the intensive care unit. Ann Intern Med 2001; 134:298–314.
- Lewis RT, Burgess JH, Hampson LG. Cardiorespiratory studies in critical illness. Changes in aspiration pneumonitis. Arch Surg 1971; 103:335–340.
- Rello J. Importance of appropriate initial antibiotic therapy and de-escalation in the treatment of nosocomial pneumonia. Eur Respir Rev 2007; 16:33–39.
- American Thoracic Society. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005; 171:388–416.
- Bartlett JG. Anaerobic bacterial infections of the lung and pleural space. Clin Infect Dis 1993; 16(suppl 4):S248–S255.
- Lorber B, Swenson RM. Bacteriology of aspiration pneumonia. A prospective study of community- and hospital-acquired cases. Ann Intern Med 1974; 81:329–331.
- Bartlett JG, Gorbach SL, Finegold SM. The bacteriology of aspiration pneumonia. Am J Med 1974; 56:202–207.
- Mier L, Dreyfuss D, Darchy B, et al. Is penicillin G an adequate initial treatment for aspiration pneumonia? A prospective evaluation using a protected specimen brush and quantitative cultures. Intensive Care Med 1993; 19:279–284.
- Marik PE, Careau P. The role of anaerobes in patients with ventilator-associated pneumonia and aspiration pneumonia: a prospective study. Chest 1999; 115:178–183.
- El-Solh AA, Pietrantoni C, Bhat A, et al. Microbiology of severe aspiration pneumonia in institutionalized elderly. Am J Respir Crit Care Med 2003; 167:1650–1654.
- Mandell LA, Wunderink RG, Anzueto A, et al; Infectious Diseases Society of America. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44(suppl 2):S27–S72.
- Kadowaki M, Demura Y, Mizuno S, et al. Reappraisal of clindamycin IV monotherapy for treatment of mild-to-moderate aspiration pneumonia in elderly patients. Chest 2005; 127:1276–1282.
- Ott SR, Allewelt M, Lorenz J, Reimnitz P, Lode H; German Lung Abscess Study Group. Moxifloxacin vs ampicillin/sulbactam in aspiration pneumonia and primary lung abscess. Infection 2008; 36:23–30.
- Perlino CA. Metronidazole vs clindamycin treatment of anerobic pulmonary infection. Failure of metronidazole therapy. Arch Intern Med 1981; 141:1424–1427.
- Sanders CV, Hanna BJ, Lewis AC. Metronidazole in the treatment of anaerobic infections. Am Rev Respir Dis 1979; 120:337–343.
- Alvarez-Lerma F, Alvarez B, Luque P, et al; ADANN Study Group. Empiric broad-spectrum antibiotic therapy of nosocomial pneumonia in the intensive care unit: a prospective observational study. Crit Care 2006; 10:R78.
- Johnson JL, Hirsch CS. Aspiration pneumonia. Recognizing and managing a potentially growing disorder. Postgrad Med 2003; 113:99–112.
- Scolapio JS. Methods for decreasing risk of aspiration pneumonia in critically ill patients. JPEN J Parenter Enteral Nutr 2002; 26(suppl 6):S58–S61.
- Orozco-Levi M, Torres A, Ferrer M, et al. Semirecumbent position protects from pulmonary aspiration but not completely from gastroesophageal reflux in mechanically ventilated patients. Am J Respir Crit Care Med 1995; 152:1387–1390.
- Park RH, Allison MC, Lang J, et al. Randomised comparison of percutaneous endoscopic gastrostomy and nasogastric tube feeding in patients with persisting neurological dysphagia. BMJ 1992; 304( 6839):1406–1409.
- Donskey CJ, Chowdhry TK, Hecker MT, et al. Effect of antibiotic therapy on the density of vancomycin-resistant enterococci in the stool of colonized patients. N Engl J Med 2000; 343:1925–1932.
- Mouw DR, Langlois JP, Turner LF, Neher JO. Clinical inquiries. Are antibiotics effective in preventing pneumonia for nursing home patients? J Fam Pract 2004; 53:994–996.