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Nutritional status and hyperglycemia in the peritransplant period: a review of associations with parenteral nutrition and clinical outcomes

ABSTRACT

Hematopoietic stem cell transplantation is an established treatment option for various hematological diseases. This therapy involves complex procedures and is associated with several systemic complications. Due to the toxic effects of the conditioning regimen used in allogeneic transplantations, patients frequently suffer from severe gastrointestinal complications and are unable to feed themselves properly. This complex clinical scenario often requires specialized nutritional support, and despite the increasing number of studies available, many questions remain regarding the best way to feed these patients. Parenteral nutrition has been traditionally indicated when the effects on gastrointestinal mucosa are significant; however, the true benefits of this type of nutrition in reducing clinical complications have been questioned. Hyperglycemia is a common consequence of parenteral nutrition that seems to be correlated to poor transplantation outcomes and a higher risk of infections. Additionally, nutrition-related pre-transplantation risk factors are being studied, such as impaired nutritional status, poorly controlled diabetes mellitus and obesity. This review aims to discuss some of these recent issues. A real case of allogeneic transplant was used to illustrate the scenario and to highlight the most important topics that motivated this literature review.

Keywords:
Hematopoietic stem cell transplantation; Nutritional support; Parenteral nutrition; Hyperglycemia

Introduction

HSCT is widely used to treat hematological and non-hematological malignancies. Compared to autologous HSCT, allogeneic HSCT (allo-HSCT) causes more severe nutritional consequences and side effects due to its more intense ablative and immunosuppressive conditioning regimen. Mucositis, nausea and vomiting, diarrhea, poor oral intake, malabsorption and prolonged malnutrition are some of the complications often observed.11 Arai S, Jagasia M, Storer B, Chai X, Pidala J, Cutler C, et al. Global and organ-specific chronic graft-versus-host disease severity according to the 2005 NIH Consensus Criteria. Blood. 2011;118(15):4242-9.

2 Muscaritoli M, Grieco G, Capria S, Iori AP, Rossi Fanelli F. Nutritional and metabolic support in patients undergoing bone marrow transplantation. Am J Clin Nutr. 2002;75(2):183-90.
-33 Habschmidt MG, Bacon CA, Gregoire MB, Rasmussen HE. Medical nutrition therapy provided to adult hematopoietic stem cell transplantation patients. Nutr Clin Pract. 2012;27(5):655-60.

Therefore, adequate nutritional support is paramount during all the phases of the transplant procedure,44 So EJ, Lee JS, Kim JY. Nutritional intake and nutritional status by the type of hematopoietic stem cell transplantation. Clin Nutr Res. 2012;1(1):3-12.,55 Herrmann VM, Petruska PJ. Nutrition support in bone marrow transplant recipients. Nutr Clin Pract Off Publ Am Soc Parenter Enter Nutr. 1993;8(1):19-27. and is an important measure for better outcomes in the short and long term.66 Martin-Salces M, de Paz R, Canales MA, Mesejo A, Hernandez-Navarro F. Nutritional recommendations in hematopoietic stem cell transplantation. Nutr Burbank Los Angel Cty Calif. 2008;24(7-8):769-75. Most patients need artificial nutrition at some point and for different lengths of time. Allo-HSCT patients suffering from severe gastrointestinal symptoms usually require prolonged support, frequently via parenteral nutrition (PN) because of very poor oral intake and intolerance to enteral nutrition (EN).44 So EJ, Lee JS, Kim JY. Nutritional intake and nutritional status by the type of hematopoietic stem cell transplantation. Clin Nutr Res. 2012;1(1):3-12.

5 Herrmann VM, Petruska PJ. Nutrition support in bone marrow transplant recipients. Nutr Clin Pract Off Publ Am Soc Parenter Enter Nutr. 1993;8(1):19-27.

6 Martin-Salces M, de Paz R, Canales MA, Mesejo A, Hernandez-Navarro F. Nutritional recommendations in hematopoietic stem cell transplantation. Nutr Burbank Los Angel Cty Calif. 2008;24(7-8):769-75.
-77 Fuji S, Takano K, Mori T, Eto T, Taniguchi S, Ohashi K, et al. Impact of pretransplant body mass index on the clinical outcome after allogeneic hematopoietic SCT. Bone Marrow Transplant. 2014;49(12):1505-12. In cases of severe graft-versus-host disease (GVHD) with gastrointestinal complications, the use of PN usually becomes necessary again.88 Fuji S, Einsele H, Savani BN, Kapp M. Systematic nutritional support in allogeneic hematopoietic stem cell transplant recipients. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2015;21(10):1707-13. Nevertheless, as PN is an invasive procedure and not free of risks, its use in the quite complex scenario of allo-HSCT has been questioned.99 van der Meij BS, de Graaf P, Wierdsma NJ, Langius JAE, Janssen JJWM, van Leeuwen PAM, et al. Nutritional support in patients with GVHD of the digestive tract: state of the art. Bone Marrow Transplant. 2013;48(4):474-82.

10 Iestra JA, Fibbe WE, Zwinderman AH, Romijn JA, Kromhout D. Parenteral nutrition following intensive cytotoxic therapy: an exploratory study on the need for parenteral nutrition after various treatment approaches for haematological malignancies. Bone Marrow Transplant. 1999;23(9):933-9.
-1111 Arfons LM, Lazarus HM. Total parenteral nutrition and hematopoietic stem cell transplantation: an expensive placebo?. Bone Marrow Transplant. 2005;36(4):281-8. Recent studies demonstrate that PN can actually be harmful under some circumstances, due to higher risk of hyperglycemia and blood stream infections.1212 Szeluga DJ, Stuart RK, Brookmeyer R, Utermohlen V, Santos GW. Nutritional support of bone marrow transplant recipients: a prospective, randomized clinical trial comparing total parenteral nutrition to an enteral feeding program. Cancer Res. 1987;47(12):3309-16.

13 Fuji S, Kim S-W, Mori S, Fukuda T, Kamiya S, Yamasaki S, et al. Hyperglycemia during the neutropenic period is associated with a poor outcome in patients undergoing myeloablative allogeneic hematopoietic stem cell transplantation. Transplantation. 2007;84(7):814-20.
-1414 Sarkisian S, Fenton TR, Shaheen AA, Raman M. Parenteral nutrition-associated hyperglycemia in noncritically ill inpatients is associated with higher mortality. Can J Gastroenterol J Can Gastroenterol. 2010;24(7):453-7. In addition, despite the increasing number of studies, there is still no clear consensus regarding the benefits of EN versus PN in HSCT patients.1515 Sheean PM, Braunschweig C, Rich E. The incidence of hyperglycemia in hematopoietic stem cell transplant recipients receiving total parenteral nutrition: a pilot study. J Am Diet Assoc. 2004;104(9):1352-60.

There are several studies demonstrating the importance of a complete nutritional status assessment before the transplant.1616 Murray SM, Pindoria S. Nutrition support for bone marrow transplant patients. Cochrane Database Syst Rev. 2009;(1):CD002920.

17 Ferreira EE, Guerra DC, Baluz K, de Resende Furtado W, da Silva Bouzas LF. Nutritional status of patients submitted to transplantation of allogeneic hematopoietic stem cells: a retrospective study. Rev Bras Hematol E Hemoter. 2014;36(6):414-9.
-1818 Raynard B, Nitenberg G, Gory-Delabaere G, Bourhis JH, Bachmann P, Bensadoun RJ, et al. Summary of the Standards, Options and Recommendations for nutritional support in patients undergoing bone marrow transplantation (2002). Br J Cancer. 2003;89(Suppl. 1):S101-6. Associations between abnormal body mass index (BMI) and non-relapse mortality (NRM) have been documented.77 Fuji S, Takano K, Mori T, Eto T, Taniguchi S, Ohashi K, et al. Impact of pretransplant body mass index on the clinical outcome after allogeneic hematopoietic SCT. Bone Marrow Transplant. 2014;49(12):1505-12.,1919 Wang B, Yan X, Cai J, Wang Y, Liu P. Nutritional assessment with different tools in leukemia patients after hematopoietic stem cell transplantation. Chin J Cancer Res Chung-Kuo Yen Cheng Yen Chiu. 2013;25(6):762-9.

20 Deeg HJ, Seidel K, Bruemmer B, Pepe MS, Appelbaum FR. Impact of patient weight on non-relapse mortality after marrow transplantation. Bone Marrow Transplant. 1995;15(3):461-8.
-2121 Gleimer M, Li Y, Chang L, Paczesny S, Hanauer DA, Frame DG, et al. Baseline body mass index among children and adults undergoing allogeneic hematopoietic cell transplantation: clinical characteristics and outcomes. Bone Marrow Transplant. 2015;50(3):402-10. Correlations between pre-transplantation comorbidities and poor outcomes, especially diabetes mellitus, have also been discussed.2222 Le Blanc K, Ringdén O, Remberger M. A low body mass index is correlated with poor survival after allogeneic stem cell transplantation. Haematologica. 2003;88(9):1044-52.

The brief case scenario described below is used to illustrate some difficult situations that can be found in the context of HSCT. The importance of adequate nutritional support, the controversial findings in terms of the best approach and type of nutrition, and some of the deleterious consequences of PN in HSCT patients are emphasized here. Recent findings related to nutritional assessment, pre-transplantation diabetes mellitus and obesity are also reviewed.

Clinical vignette

WSA, a 27-year-old male with diagnosis of acute myeloid leukemia subtype M5 refractory to multiple chemotherapy regimens, was admitted to the Hospital de Clínicas de Porto Alegre for related mismatched allogeneic stem cell transplantation. He was obese (BMI: 30.5 kg/m2), an active smoker, and on anti-hypertensive treatment. His performance status was ECOG 0. He received Busulfan and Cyclophosphamide plus thymoglobulin as the conditioning regimen, as well as cyclosporine and methotrexate for GVHD prophylaxis. Engraftment occurred around the third week after transplantation; it was followed by acute gastrointestinal (grade III) and hepatic (grade II) GVHD with diagnosis based on the National Institute of Health (NIH) consensus criteria.2323 Radfar M, Faghihi T, Hadjibabaie M, Ebrahimi F, Qorbani M, Iravani M, et al. Impact of preexisting diabetes mellitus on transplantation outcomes in hematopoietic stem cell transplantation. Endocr Res. 2015;40(1):20-4. This complication was refractory to first-line corticosteroid therapy (methylprednisolone 2 mg/kg) and partially responsive to basiliximab (anti-CD25 monoclonal antibody) and infliximab (anti-TNF monoclonal antibody).

An individually compounded PN was initiated on Day 5 after transplantation due to neutropenic enterocolitis with paralytic ileus and oral mucositis grade IV. The PN was calculated based on the patient's body weight of 90 kg at that time, to provide 30-35 kcal/kg/day, at least 1.5 g of protein/kg/day and a maximum of 1.0 g of lipids/kg/day. This composition corresponded to 20-25% of total calories coming from protein (10% amino acid solution), 50-60% from dextrose (50% glucose monohydrate solution) and up to 30% of total calories from lipids (20% lipid emulsion).11 Arai S, Jagasia M, Storer B, Chai X, Pidala J, Cutler C, et al. Global and organ-specific chronic graft-versus-host disease severity according to the 2005 NIH Consensus Criteria. Blood. 2011;118(15):4242-9. This diet was maintained for approximately three weeks because of very poor oral tolerance and no safe access for tube feeding due to thrombocytopenia. However, the PN had to be discontinued for short times during this period because of severe hyperglycemia. The patient had a medium glycemic level of around 80-120 mg/dL before starting PN. This complication, related to the use of corticosteroids and immunosuppressants, became clearly worse after the introduction of PN as his serum glucose peaked at 300-400 mg/dL. Even with a reduction of the glucose infusion rate, reduction of total caloric amount of PN to 20-25 kcal/kg/day and high doses of continuous IV insulin administration, the glycemia remained poorly controlled. The PN was interrupted. The patient refused tube feeding, so oral nutrition was initiated according to his tolerance. He had several infectious complications, such as bacterial sinusitis and pneumonia, and died from gram-negative sepsis three months after hematopoietic stem cell transplantation (HSCT).

Pre-transplantation nutritional assessment

HSCT involves an increase in nutritional and metabolic demands that is partially explained by the deleterious effects of the conditioning regimen on the gastrointestinal tract.11 Arai S, Jagasia M, Storer B, Chai X, Pidala J, Cutler C, et al. Global and organ-specific chronic graft-versus-host disease severity according to the 2005 NIH Consensus Criteria. Blood. 2011;118(15):4242-9. Furthermore, the occurrence of fever, infections, and the prolonged time of immunosuppression create a hypermetabolic state that can further exacerbate nutritional deficits.55 Herrmann VM, Petruska PJ. Nutrition support in bone marrow transplant recipients. Nutr Clin Pract Off Publ Am Soc Parenter Enter Nutr. 1993;8(1):19-27.,2424 August DA, Huhmann MB. A.S.P.E.N. clinical guidelines: nutrition support therapy during adult anticancer treatment and in hematopoietic cell transplantation. JPEN J Parenter Enteral Nutr. 2009;33(5):472-500. It is known that an impaired nutritional status before transplantation can affect complications and clinical outcomes of HSCT, in particular allo-HSCT.1616 Murray SM, Pindoria S. Nutrition support for bone marrow transplant patients. Cochrane Database Syst Rev. 2009;(1):CD002920.,1919 Wang B, Yan X, Cai J, Wang Y, Liu P. Nutritional assessment with different tools in leukemia patients after hematopoietic stem cell transplantation. Chin J Cancer Res Chung-Kuo Yen Cheng Yen Chiu. 2013;25(6):762-9.,2020 Deeg HJ, Seidel K, Bruemmer B, Pepe MS, Appelbaum FR. Impact of patient weight on non-relapse mortality after marrow transplantation. Bone Marrow Transplant. 1995;15(3):461-8. In malnourished patients, there is evidence of increased mortality rates, prolonged length of hospitalization and delayed time to engraftment. Moreover, the NRM is higher for the extremely underweight, overweight and obese.2121 Gleimer M, Li Y, Chang L, Paczesny S, Hanauer DA, Frame DG, et al. Baseline body mass index among children and adults undergoing allogeneic hematopoietic cell transplantation: clinical characteristics and outcomes. Bone Marrow Transplant. 2015;50(3):402-10.,2525 Pereira AZ, Victor ES, Vidal Campregher P, Piovacari SMF, Bernardo Barban JS, Pedreira WL, et al. High body mass index among patients undergoing hematopoietic stem cell transplantation: results of a cross-sectional evaluation of nutritional status in a private hospital. Nutr Hosp. 2015;32(6):2874-9.

There are innumerous available nutritional assessment methods, although none are specific for the HSCT population. Screening questionnaires can be used when combined with a physical examination, biochemical markers, and anthropometry, i.e., the measurement of weight, height, skin folds and circumferences. Single methods have limitations and are inefficient.1818 Raynard B, Nitenberg G, Gory-Delabaere G, Bourhis JH, Bachmann P, Bensadoun RJ, et al. Summary of the Standards, Options and Recommendations for nutritional support in patients undergoing bone marrow transplantation (2002). Br J Cancer. 2003;89(Suppl. 1):S101-6. Liu et al. evaluated and compared different questionnaires in patients with leukemia, and showed a better clinical applicability of the Nutritional Risk Screening 2002 questionnaire (NRS 2002) to detect malnutrition before transplantation.2626 Liu P, Yan X, Wang B-S, Xu X-D. Three methods assess nutritional status of leukemia patients before hematopoietic stem cell transplantation. Chin Med J (Engl). 2012;125(3):440-3.,2727 Liu P, Zhang Z-F, Cai J-J, Wang B-S, Yan X. NRS2002 assesses nutritional status of leukemia patients undergoing hematopoietic stem cell transplantation. Chin J Cancer Res Chung-Kuo Yen Cheng Yen Chiu. 2012;24(4):299-303. The main components of the NRS 2002 are: (1) severity of primary disease and its impact on nutritional status, (2) recent changes of body weight, (3) changes in dietary intake and (4) body mass index. A NRS score ≥3 defines nutritional risk, information that can contribute to the planning of peritransplant nutritional support.2828 Kondrup J, Rasmussen HH, Hamberg O, Stanga Z. Nutritional risk screening (NRS 2002): a new method based on an analysis of controlled clinical trials. Clin Nutr Edinb Scotl. 2003;22(3):321-36.

In terms of body weight before the procedure, studies show a tendency of high BMI being correlated to higher risk of GVHD and NRM; similar risks are seen in patients with BMI below normal.1919 Wang B, Yan X, Cai J, Wang Y, Liu P. Nutritional assessment with different tools in leukemia patients after hematopoietic stem cell transplantation. Chin J Cancer Res Chung-Kuo Yen Cheng Yen Chiu. 2013;25(6):762-9. In addition to BMI and anthropometric measurements of body composition, Urbain et al. evaluated the benefit of using bioelectrical impedance analysis in HSCT patients.2929 Urbain P, Birlinger J, Ihorst G, Biesalski H-K, Finke J, Bertz H. Body mass index and bioelectrical impedance phase angle as potentially modifiable nutritional markers are independent risk factors for outcome in allogeneic hematopoietic cell transplantation. Ann Hematol. 2013;92(1):111-9. The phase angle, one datum obtained from this procedure, has been correlated with worse clinical prognosis in various diseases as a reduced phase angle can reflect body cell mass loss, especially muscle loss.3030 da Silva TK, Berbigier MC, Rubin Bde A, Moraes RB, Corrêa Souza G, Schweigert Perry ID. Phase angle as a prognostic marker in patients with critical illness. Nutr Clin Pract Off Publ Am SocParenter Enter Nutr. 2015;30(2):261-5. The study showed that patients with extremely low pre-transplantation phase angles had an increased risk of death in the first two years after transplantation.2929 Urbain P, Birlinger J, Ihorst G, Biesalski H-K, Finke J, Bertz H. Body mass index and bioelectrical impedance phase angle as potentially modifiable nutritional markers are independent risk factors for outcome in allogeneic hematopoietic cell transplantation. Ann Hematol. 2013;92(1):111-9.

Therefore, a complete assessment is a very important step prior to HSCT, and should combine all available tools in order to detect nutritional issues that can be improved prior to the procedure. Also, this approach allows the team to plan adequate nutritional support in advance and to take appropriate measures to maintain this support during and after the procedure.1111 Arfons LM, Lazarus HM. Total parenteral nutrition and hematopoietic stem cell transplantation: an expensive placebo?. Bone Marrow Transplant. 2005;36(4):281-8.,1616 Murray SM, Pindoria S. Nutrition support for bone marrow transplant patients. Cochrane Database Syst Rev. 2009;(1):CD002920.

Pre-transplantation comorbidities - the role of obesity and diabetes mellitus

Apart from malnutrition and low body weight, traditionally associated with poor outcomes in cancer patients, other prognostic factors associated to nutritional status have been described recently. Among these, obesity and diabetes mellitus seem to play an important role in HSCT patients.2222 Le Blanc K, Ringdén O, Remberger M. A low body mass index is correlated with poor survival after allogeneic stem cell transplantation. Haematologica. 2003;88(9):1044-52.,3131 Nakao M, Chihara D, Niimi A, Ueda R, Tanaka H, Morishima Y, et al. Impact of being overweight on outcomes of hematopoietic SCT: a meta-analysis. Bone Marrow Transplant. 2014;49(1):66-72.

32 Takano K, Fuji S, Uchida N, Ogawa H, Ohashi K, Eto T, et al. Pre-transplant diabetes mellitus is a risk factor for non-relapse mortality, especially infection-related mortality, after allogeneic hematopoietic SCT. Bone Marrow Transplant. 2015;50(4):553-8.
-3333 Fuji S, Kim S-W, Yoshimura K, Akiyama H, Okamoto S, Sao H, et al. Possible association between obesity and posttransplantation complications including infectious diseases and acute graft-versus-host disease. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2009;15(1):73-82. Sorror et al. established the hematopoietic cell transplantation-comorbidity index (HCT-CI), which is a scoring system to predict the risk of NRM after transplantation. This index, which includes dysfunction of different organs, such as pulmonary, hepatic, cardiac, and renal dysfunction, also includes diabetes and obesity as deleterious comorbidities (based on a BMI > 35 kg/m2 in adults).3434 Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106(8):2912-9. It has been validated in several countries as a predictor of HSCT complications.3535 Teixeira GM, Bittencourt H, de Macedo AV, Martinho GH, Colosimo EA, Rezende SM. Assessing the influence of different comorbidities indexes on the outcomes of allogeneic hematopoietic stem cell transplantation in a developing country. PLOS ONE. 2015;10(9):e0137390.

There is a growing number of studies, albeit retrospective studies, that show an association of high BMI before transplantation with a greater risk of GVHD and NRM.77 Fuji S, Takano K, Mori T, Eto T, Taniguchi S, Ohashi K, et al. Impact of pretransplant body mass index on the clinical outcome after allogeneic hematopoietic SCT. Bone Marrow Transplant. 2014;49(12):1505-12.,2020 Deeg HJ, Seidel K, Bruemmer B, Pepe MS, Appelbaum FR. Impact of patient weight on non-relapse mortality after marrow transplantation. Bone Marrow Transplant. 1995;15(3):461-8.,3131 Nakao M, Chihara D, Niimi A, Ueda R, Tanaka H, Morishima Y, et al. Impact of being overweight on outcomes of hematopoietic SCT: a meta-analysis. Bone Marrow Transplant. 2014;49(1):66-72.,3333 Fuji S, Kim S-W, Yoshimura K, Akiyama H, Okamoto S, Sao H, et al. Possible association between obesity and posttransplantation complications including infectious diseases and acute graft-versus-host disease. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2009;15(1):73-82. Gleimer et al. observed a significant increase in NRM among obese patients submitted to allo-HSCT.77 Fuji S, Takano K, Mori T, Eto T, Taniguchi S, Ohashi K, et al. Impact of pretransplant body mass index on the clinical outcome after allogeneic hematopoietic SCT. Bone Marrow Transplant. 2014;49(12):1505-12. To confirm these findings, Nakao et al. conducted a meta-analysis to assess whether overweight patients submitted to HSCT actually experience worse outcomes. A statistically significant association was found between excess of body weight and poor outcomes after allo-HSCT, but no significant impact was found on survival in autologous HSCT. That correlation was especially true for the occurrence of acute GVHD among overweight patients.3131 Nakao M, Chihara D, Niimi A, Ueda R, Tanaka H, Morishima Y, et al. Impact of being overweight on outcomes of hematopoietic SCT: a meta-analysis. Bone Marrow Transplant. 2014;49(1):66-72. The possible reasons involved could be inappropriate doses of conditioning regimen due to different medication pharmacokinetics in the obese, the dose of infused stem cells and of GVHD prophylaxis. In this case, the ideal body weight could be a better predictor of dose adequacy.3636 Singhal S, Gordon LI, Tallman MS, Winter JN, Evens AM, Evens AO, et al. Ideal rather than actual body weight should be used to calculate cell dose in allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2006;37(6):553-7. Other possible factors involve cytokine-related mechanisms, such as the effect of T-cell proliferation and function driven by adipocytokines.3131 Nakao M, Chihara D, Niimi A, Ueda R, Tanaka H, Morishima Y, et al. Impact of being overweight on outcomes of hematopoietic SCT: a meta-analysis. Bone Marrow Transplant. 2014;49(1):66-72.

Pre-transplantation diabetes mellitus has also been reported as an important risk factor for worse transplantation outcomes and NRM. A significantly greater number of invasive fungal diseases and impaired neutrophil function have been described in diabetic patients submitted to HSCT.2222 Le Blanc K, Ringdén O, Remberger M. A low body mass index is correlated with poor survival after allogeneic stem cell transplantation. Haematologica. 2003;88(9):1044-52.,3232 Takano K, Fuji S, Uchida N, Ogawa H, Ohashi K, Eto T, et al. Pre-transplant diabetes mellitus is a risk factor for non-relapse mortality, especially infection-related mortality, after allogeneic hematopoietic SCT. Bone Marrow Transplant. 2015;50(4):553-8. Although Takano et al. showed that pre-engraftment hyperglycemia could be a risk factor for infectious diseases, acute GVHD and NRM, hyperglycemia after the procedure can also increase the risk of subsequent NRM.1212 Szeluga DJ, Stuart RK, Brookmeyer R, Utermohlen V, Santos GW. Nutritional support of bone marrow transplant recipients: a prospective, randomized clinical trial comparing total parenteral nutrition to an enteral feeding program. Cancer Res. 1987;47(12):3309-16.,3737 Gebremedhin E, Behrendt CE, Nakamura R, Parker P, Salehian B. Severe hyperglycemia immediately after allogeneic hematopoietic stem-cell transplantation is predictive of acute graft-versus-host disease. Inflammation. 2013;36(1):177-85.,3838 Hammer MJ, Casper C, Gooley TA, O’Donnell PV, Boeckh M, Hirsch IB. The contribution of malglycemia to mortality among allogeneic hematopoietic cell transplant recipients. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2009;15(3):344-51. Fuji et al., however, stated that it is still unclear whether a better control of diabetes mellitus prior to HSCT would actually reduce these complications, and further research is still necessary.1212 Szeluga DJ, Stuart RK, Brookmeyer R, Utermohlen V, Santos GW. Nutritional support of bone marrow transplant recipients: a prospective, randomized clinical trial comparing total parenteral nutrition to an enteral feeding program. Cancer Res. 1987;47(12):3309-16.

Specialized nutritional support after HSCT - enteral versus parenteral nutrition

The prolonged gastrointestinal symptoms that occur in the first days after the transplantation give rise to the need of specialized nutritional support. The first 10-15 days are critical especially due to neutropenic mucositis, nausea and poor oral intake.44 So EJ, Lee JS, Kim JY. Nutritional intake and nutritional status by the type of hematopoietic stem cell transplantation. Clin Nutr Res. 2012;1(1):3-12.,2424 August DA, Huhmann MB. A.S.P.E.N. clinical guidelines: nutrition support therapy during adult anticancer treatment and in hematopoietic cell transplantation. JPEN J Parenter Enteral Nutr. 2009;33(5):472-500. It is suggested that maintaining the functions of the digestive tract, even with small volumes of nutrition, could bring beneficial effects in terms of maintenance of the immunological gut barrier and glucose level control.3939 Guièze R, Lemal R, Cabrespine A, Hermet E, Tournilhac O, Combal C, et al. Enteral versus parenteral nutritional support in allogeneic haematopoietic stem-cell transplantation. Clin Nutr Edinb Scotl. 2014;33(3):533-8.

40 Seguy D, Berthon C, Micol J-B, Darré S, Dalle J-H, Neuville S, et al. Enteral feeding and early outcomes of patients undergoing allogeneic stem cell transplantation following myeloablative conditioning. Transplantation. 2006;82(6):835-9.
-4141 Seguy D, Duhamel A, Rejeb MB, Gomez E, Buhl ND, Bruno B, et al. Better outcome of patients undergoing enteral tube feeding after myeloablative conditioning for allogeneic stem cell transplantation. Transplantation. 2012;94(3):287-94. However, the use of tube feeding in this population is still being studied and is not standard practice, mainly because of the challenges of establishing a safe enteral access in patients with severe mucositis, gastrointestinal tract damage and thrombocytopenia.2424 August DA, Huhmann MB. A.S.P.E.N. clinical guidelines: nutrition support therapy during adult anticancer treatment and in hematopoietic cell transplantation. JPEN J Parenter Enteral Nutr. 2009;33(5):472-500. When the caloric target is not achieved or the patient presents significant gastrointestinal intolerance, the use of PN may be justified to minimize nutrient deficiencies and maintain body weight. However, its advantages and disadvantages are still under discussion considering the potentially higher risk of bacteremia, catheter-site infections, hyperglycemia and fluid overload observed in PN recipients.1010 Iestra JA, Fibbe WE, Zwinderman AH, Romijn JA, Kromhout D. Parenteral nutrition following intensive cytotoxic therapy: an exploratory study on the need for parenteral nutrition after various treatment approaches for haematological malignancies. Bone Marrow Transplant. 1999;23(9):933-9.

The use of PN in HSCT has been described in the literature since the 1980s and these pioneering studies are still used as reference.4242 Schmidt GM, Blume KG, Bross KJ, Spruce WE, Waldron JC, Levine R. Parenteral nutrition in bone marrow transplant recipients. Exp Hematol. 1980;8(4):506-11.,4343 Weisdorf SA, Lysne J, Wind D, Haake RJ, Sharp HL, Goldman A, et al. Positive effect of prophylactic total parenteral nutrition on long-term outcome of bone marrow transplantation. Transplantation. 1987;43(6):833-8. In 1987, Weisdorf et al. compared PN versus intravenous dextrose solution to adult and pediatric patients undergoing allogeneic and autologous HSCT from seven days before cytoreductive chemotherapy until 28 days after the transplant. Patients in the allogeneic group on PN had a better 2-year overall survival, although presented a higher rate of bacteremia compared to the control group. No difference in time to engraftment, length of hospitalization and incidence of GVHD were observed.4343 Weisdorf SA, Lysne J, Wind D, Haake RJ, Sharp HL, Goldman A, et al. Positive effect of prophylactic total parenteral nutrition on long-term outcome of bone marrow transplantation. Transplantation. 1987;43(6):833-8. Over the last decades, similar studies have been published.99 van der Meij BS, de Graaf P, Wierdsma NJ, Langius JAE, Janssen JJWM, van Leeuwen PAM, et al. Nutritional support in patients with GVHD of the digestive tract: state of the art. Bone Marrow Transplant. 2013;48(4):474-82.,3939 Guièze R, Lemal R, Cabrespine A, Hermet E, Tournilhac O, Combal C, et al. Enteral versus parenteral nutritional support in allogeneic haematopoietic stem-cell transplantation. Clin Nutr Edinb Scotl. 2014;33(3):533-8.,4444 Cetin T, Arpaci F, Dere Y, Turan M, Oztürk B, Kömürcü S, et al. Total parenteral nutrition delays platelet engraftment in patients who undergo autologous hematopoietic stem cell transplantation. Nutr Burbank Los Angel Cty Calif. 2002;18(7-8):599-603.

45 Lough M, Watkins R, Campbell M, Carr K, Burnett A, Shenkin A. Parenteral nutrition in bone marrow transplantation. Clin Nutr Edinb Scotl. 1990;9(2):97-101.
-4646 Muscaritoli M, Conversano L, Torelli GF, Arcese W, Capria S, Cangiano C, et al. Clinical and metabolic effects of different parenteral nutrition regimens in patients undergoing allogeneic bone marrow transplantation. Transplantation. 1998;66(5):610-6. Nevertheless, most of them had heterogeneous populations of children and adults undergoing autologous and allogeneic HSCT, making an analysis of the results a difficult task. Lough et al. for example, compared total PN (TPN) and intravenous 5% dextrose solution in adults submitted to both types of HSCT; there was a trend towards more fluid overload, longer time of fever and a higher number of positive blood cultures in the TPN arm.4545 Lough M, Watkins R, Campbell M, Carr K, Burnett A, Shenkin A. Parenteral nutrition in bone marrow transplantation. Clin Nutr Edinb Scotl. 1990;9(2):97-101. Muscaritoli et al., in 1998, compared glucose-based and lipid-based PN in both types of transplant, demonstrating a trend towards more acute GVHD and hyperglycemia in the glucose group.4646 Muscaritoli M, Conversano L, Torelli GF, Arcese W, Capria S, Cangiano C, et al. Clinical and metabolic effects of different parenteral nutrition regimens in patients undergoing allogeneic bone marrow transplantation. Transplantation. 1998;66(5):610-6. More recently, Cetin et al. evaluated the effects of TPN versus partial PN in autologous patients; the TPN group had higher rates of hyperglycemia, more infections and delayed platelet engraftment.4444 Cetin T, Arpaci F, Dere Y, Turan M, Oztürk B, Kömürcü S, et al. Total parenteral nutrition delays platelet engraftment in patients who undergo autologous hematopoietic stem cell transplantation. Nutr Burbank Los Angel Cty Calif. 2002;18(7-8):599-603. Therefore, as Arfons et al. demonstrated, to construct clear recommendations about the use of PN in this scenario is still challenging considering the heterogeneity of the available studies.1010 Iestra JA, Fibbe WE, Zwinderman AH, Romijn JA, Kromhout D. Parenteral nutrition following intensive cytotoxic therapy: an exploratory study on the need for parenteral nutrition after various treatment approaches for haematological malignancies. Bone Marrow Transplant. 1999;23(9):933-9.

In terms of timing to initiate PN in HSCT patients, there are two described approaches in recent literature: soon after the transplantation (Day 0 or 1) independently of oral tolerance, or according to the nutritional needs of the patient. The former approach is less used, although some centers still prefer this form of nutritional intervention: starting on the first day after allo-HSCT and continuing for 15-21 days.11 Arai S, Jagasia M, Storer B, Chai X, Pidala J, Cutler C, et al. Global and organ-specific chronic graft-versus-host disease severity according to the 2005 NIH Consensus Criteria. Blood. 2011;118(15):4242-9. Therefore, when to start PN is another matter of controversy. The European Society for Clinical Nutrition and Metabolism (ESPEN) proposes to initiate PN once oral feeding falls below 60-70% of requirements for three consecutive days,4747 Bozzetti F, Arends J, Lundholm K, Micklewright A, Zurcher G, Muscaritoli M, et al. ESPEN guidelines on parenteral nutrition: non-surgical oncology. Clin Nutr. 2009;28(4):445-54. and this recommendation is followed by the Sociedade Brasileira de Nutrição Parenteral e Enteral (SBNPE).4848 Terapia Nutricional no Transplante de Célula Hematopoiética. Sociedade Brasileira de Nutrição Parenteral e Enteral (SBNPE) e Associação Brasileira de Nutrologia (ABRAN). 2011. The American Society for Parenteral and Enteral Nutrition considers 7-14 days an appropriate definition of “prolonged period of time” of unsatisfactory oral/enteral nutrition before establishing PN.2424 August DA, Huhmann MB. A.S.P.E.N. clinical guidelines: nutrition support therapy during adult anticancer treatment and in hematopoietic cell transplantation. JPEN J Parenter Enteral Nutr. 2009;33(5):472-500. Table 1 shows the current recommendations of nutritional support and use of PN in HSCT from different societies and study groups.

Table 1
Nutritional support recommendations and use of PN in HSCT by different societies and study groups.

When PN is compared to EN, most studies showed several benefits of maintaining the use of the digestive tract during the transplant phases.3939 Guièze R, Lemal R, Cabrespine A, Hermet E, Tournilhac O, Combal C, et al. Enteral versus parenteral nutritional support in allogeneic haematopoietic stem-cell transplantation. Clin Nutr Edinb Scotl. 2014;33(3):533-8.

40 Seguy D, Berthon C, Micol J-B, Darré S, Dalle J-H, Neuville S, et al. Enteral feeding and early outcomes of patients undergoing allogeneic stem cell transplantation following myeloablative conditioning. Transplantation. 2006;82(6):835-9.
-4141 Seguy D, Duhamel A, Rejeb MB, Gomez E, Buhl ND, Bruno B, et al. Better outcome of patients undergoing enteral tube feeding after myeloablative conditioning for allogeneic stem cell transplantation. Transplantation. 2012;94(3):287-94. In the same year as Weisdorf et al. published their study on PN, Szeluga et al. conducted a study to compare EN and PN in pediatric and adult HSCT patients. There were no differences between groups in terms of survival, immunological recovery, length of hospitalization, and GVHD; however, a non-statistically significant difference was observed in the incidence of bacteremia, catheter-site infections, hyperglycemia and fluid overload in the PN patients.1111 Arfons LM, Lazarus HM. Total parenteral nutrition and hematopoietic stem cell transplantation: an expensive placebo?. Bone Marrow Transplant. 2005;36(4):281-8. Since then, a growing number of trials have been conducted to demonstrate the safety and feasibility of EN in this context, but up-to-date guidelines with clear recommendations are still lacking. According to Guiese et al., there are few studies comparing EN to PN among allo-HSCT patients, although the available evidence shows a clear trend of reduction in the incidence of acute GVHD and low infection-related mortality within the first 100 days after transplant in patients receiving EN.3939 Guièze R, Lemal R, Cabrespine A, Hermet E, Tournilhac O, Combal C, et al. Enteral versus parenteral nutritional support in allogeneic haematopoietic stem-cell transplantation. Clin Nutr Edinb Scotl. 2014;33(3):533-8.,4040 Seguy D, Berthon C, Micol J-B, Darré S, Dalle J-H, Neuville S, et al. Enteral feeding and early outcomes of patients undergoing allogeneic stem cell transplantation following myeloablative conditioning. Transplantation. 2006;82(6):835-9. The only meta-analysis available until today, published in 2008, concluded that there is still insufficient data to determine clear benefits of EN versus PN in patients undergoing allo-HSCT.1515 Sheean PM, Braunschweig C, Rich E. The incidence of hyperglycemia in hematopoietic stem cell transplant recipients receiving total parenteral nutrition: a pilot study. J Am Diet Assoc. 2004;104(9):1352-60. Even with these limitations, the authors propose that EN should be adopted as the first choice for nutritional support while the gut remains functional, with supplementary PN being added only when energy requirements are not achieved or there is a clear intolerance to tube feeding.1515 Sheean PM, Braunschweig C, Rich E. The incidence of hyperglycemia in hematopoietic stem cell transplant recipients receiving total parenteral nutrition: a pilot study. J Am Diet Assoc. 2004;104(9):1352-60. The ESPEN also shares these recommendations: PN should be reserved for use in patients with severe mucositis (grade 3-4), prolonged ileus, and intractable vomiting.4747 Bozzetti F, Arends J, Lundholm K, Micklewright A, Zurcher G, Muscaritoli M, et al. ESPEN guidelines on parenteral nutrition: non-surgical oncology. Clin Nutr. 2009;28(4):445-54. A prospective randomized controlled trial comparing PN and EN after myeloablative HSCT is ongoing in France (NEPHA study), and hopefully will elucidate this important issue in the near future.4949 Lemal R, Cabrespine A, Pereira B, Combal C, Ravinet A, Hermet E, et al. Could enteral nutrition improve the outcome of patients with haematological malignancies undergoing allogeneic haematopoietic stem cell transplantation? A study protocol for a randomized controlled trial (the NEPHA study). Trials. 2015;16:136.

Post-transplantation hyperglycemia: the role of parenteral nutrition

Hyperglycemia frequently occurs after HSCT, mainly because of the effects of glucocorticosteroids, immunosuppressive drugs and the use of PN.1212 Szeluga DJ, Stuart RK, Brookmeyer R, Utermohlen V, Santos GW. Nutritional support of bone marrow transplant recipients: a prospective, randomized clinical trial comparing total parenteral nutrition to an enteral feeding program. Cancer Res. 1987;47(12):3309-16.,3737 Gebremedhin E, Behrendt CE, Nakamura R, Parker P, Salehian B. Severe hyperglycemia immediately after allogeneic hematopoietic stem-cell transplantation is predictive of acute graft-versus-host disease. Inflammation. 2013;36(1):177-85.,3838 Hammer MJ, Casper C, Gooley TA, O’Donnell PV, Boeckh M, Hirsch IB. The contribution of malglycemia to mortality among allogeneic hematopoietic cell transplant recipients. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2009;15(3):344-51. The hyperglycemic environment may cause a delay in neutrophil recovery, impair neutrophil function, promote greater risk of infections and prolong engraftment times.5050 Sheean PM, Freels SA, Helton WS, Braunschweig CA. Adverse clinical consequences of hyperglycemia from total parenteral nutrition exposure during hematopoietic stem cell transplantation. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2006;12(6):656-64. Additionally, the metabolic alterations that occur in the early phase after transplantation result in more endogenous glucose production, increased insulin resistance and an impaired capacity to oxidize plasma glucose.5151 Braunschweig CL, Levy P, Sheean PM, Wang X. Enteral compared with parenteral nutrition: a meta-analysis. Am J Clin Nutr. 2001;74(4):534-42. Factors that were independently associated with hyperglycemia during the first ten days after allo-HSCT were greater BMI and insulin resistance, use of tacrolimus and glucocorticoids, myeloablative conditioning with total body irradiation and the use of total PN.3737 Gebremedhin E, Behrendt CE, Nakamura R, Parker P, Salehian B. Severe hyperglycemia immediately after allogeneic hematopoietic stem-cell transplantation is predictive of acute graft-versus-host disease. Inflammation. 2013;36(1):177-85. It has been demonstrated that the odds of developing hyperglycemia after PN is nearly four-fold (odds ratio: 3.9; 95% confidence interval: 2.7-5.5) that of patients not submitted to PN after controlling for donor type, race, age, and conditioning chemotherapy.5050 Sheean PM, Freels SA, Helton WS, Braunschweig CA. Adverse clinical consequences of hyperglycemia from total parenteral nutrition exposure during hematopoietic stem cell transplantation. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2006;12(6):656-64.

It has been hypothesized that the negative consequences of impaired glucose control in the inflammatory cascade can also increase the risk of acute GVHD, which itself raises hyperglycemia even further, creating a vicious cycle.5252 Olveira G, Tapia MJ, Ocón J, Cabrejas-Gómez C, Ballesteros-Pomar MD, Vidal-Casariego A, et al. Parenteral nutrition-associated hyperglycemia in non-critically ill inpatients increases the risk of in-hospital mortality (multicenter study). Diabetes Care. 2013;36(5):1061-6.,5353 Turina M, Fry DE, Polk HC. Acute hyperglycemia and the innate immune system: clinical, cellular, and molecular aspects. Crit Care Med. 2005;33(7):1624-33. Gebremedhin et al. showed a higher incidence of acute GVHD after allo-HSCT when severe hyperglycemia was present. However, this association varied by category of BMI: among normal-to-overweight subjects, severe hyperglycemia was markedly associated with acute GVHD, and lean BMI seemed to be a protective factor against this complication.3737 Gebremedhin E, Behrendt CE, Nakamura R, Parker P, Salehian B. Severe hyperglycemia immediately after allogeneic hematopoietic stem-cell transplantation is predictive of acute graft-versus-host disease. Inflammation. 2013;36(1):177-85. Fuji et al. also demonstrated a greater cumulative incidence of grade II-IV GVHD in patients presenting hyperglycemia (glucose levels > 150 mg/dL) during the neutropenic phase after transplant. According to these authors, it is reasonable to speculate that the increased production of inflammatory cytokines by hyperglycemia can act as a risk factor in the pathogenesis of acute GVHD and organ dysfunction.1212 Szeluga DJ, Stuart RK, Brookmeyer R, Utermohlen V, Santos GW. Nutritional support of bone marrow transplant recipients: a prospective, randomized clinical trial comparing total parenteral nutrition to an enteral feeding program. Cancer Res. 1987;47(12):3309-16. According to Sheean et al., PN has inherently greater risks of infections when compared with EN or standard oral diets, and because of its adverse consequences, several authors have challenged the intuitive conclusion that PN is beneficial and necessary during HSCT.1414 Sarkisian S, Fenton TR, Shaheen AA, Raman M. Parenteral nutrition-associated hyperglycemia in noncritically ill inpatients is associated with higher mortality. Can J Gastroenterol J Can Gastroenterol. 2010;24(7):453-7. A higher risk of catheter-related bloodstream infections in PN recipients is well described in the literature5454 Beghetto MG, Victorino J, Teixeira L, de Azevedo MJ. Parenteral nutrition as a risk factor for central venous catheter-related infection. JPEN J Parenter Enteral Nutr. 2005;29(5):367-73. as the micro- and macronutrient composition of PN can facilitate the growth of microorganisms.5555 Machado JD, Suen VM, Figueiredo JF, Marchini JS. Biofilms, infection, and parenteral nutrition therapy. JPEN J Parenter Enteral Nutr. 2009;33(4):397-403. Furthermore, it has been suggested that these infectious complications could also be related to bacterial translocation due to atrophy of the gut mucosa and gut-associated lymphoid tissue, as a consequence of PN or absence of EN.5656 Anastasilakis CD, Ioannidis O, Gkiomisi AI, Botsios D. Artificial nutrition and intestinal mucosal barrier functionality. Digestion. 2013;88(3):193-208. However, according to Jeejeebhoy et al., human studies did not demonstrate intestinal atrophy related to PN and there is little evidence that EN can prevent bacterial translocation.5757 Jeejeebhoy KN. Total parenteral nutrition: potion or poison?. Am J Clin Nutr. 2001;74(2):160-3.

A multicenter study conducted with non-critically ill inpatients that received PN demonstrated increased in-hospital mortality, mainly because of hyperglycemia and infections.5252 Olveira G, Tapia MJ, Ocón J, Cabrejas-Gómez C, Ballesteros-Pomar MD, Vidal-Casariego A, et al. Parenteral nutrition-associated hyperglycemia in non-critically ill inpatients increases the risk of in-hospital mortality (multicenter study). Diabetes Care. 2013;36(5):1061-6. The goal of glycemic control in non-critically ill patients that receive PN should be up to 180 mg/dL according to the authors.5252 Olveira G, Tapia MJ, Ocón J, Cabrejas-Gómez C, Ballesteros-Pomar MD, Vidal-Casariego A, et al. Parenteral nutrition-associated hyperglycemia in non-critically ill inpatients increases the risk of in-hospital mortality (multicenter study). Diabetes Care. 2013;36(5):1061-6. Contrarily, Sheean et al. proposes that until more experimental evidence is available, blood glucose levels during TPN administration should not exceed 150 mg/dL.5858 Sheean P, Braunschweig C. The incidence and impact of dextrose dose on hyperglycemia from parenteral nutrition (PN) exposure in hematopoietic stem cell transplant (HSCT) recipients. JPEN J Parenter Enteral Nutr. 2006;30(4):345-50. In the critically-ill, Van den Berghe et al. showed that rigid control of hyperglycemia with intensive insulin therapy (blood glucose level from 80 to 110 mg/dL) reduced morbidity and mortality.5959 van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345(19):1359-67. Nonetheless, the NICE SUGAR study demonstrated worse clinical outcomes with such tight glucose control in the intensive care unit.6060 Finfer S, Liu B, Chittock DR, Norton R, Myburgh JA, et al. Hypoglycemia and risk of death in critically ill patients. N Engl J Med. 2012;367(12):1108-18. Currently, glucose levels between 140-180 mg/dL in critically ill patients are acceptable, and recent data suggest that the glycemic goal in non-critically ill patients receiving TPN should be at a mean level of 180 mg/dL.5252 Olveira G, Tapia MJ, Ocón J, Cabrejas-Gómez C, Ballesteros-Pomar MD, Vidal-Casariego A, et al. Parenteral nutrition-associated hyperglycemia in non-critically ill inpatients increases the risk of in-hospital mortality (multicenter study). Diabetes Care. 2013;36(5):1061-6.

Conclusions

This review aimed to discuss some relevant topics related to nutritional status of patients submitted to HSCT and complications caused by PN in this population, in particular hyperglycemia and its adverse effects. The amount of scientific evidence regarding the best nutritional approach for HSCT patients is still insufficient and inconclusive, as there is no consensus or clear recommendations regarding the timing and criteria to initiate EN and PN. A complete nutritional assessment prior to HSCT is recommended by all societies, as it gives information essential to build a nutritional support plan for the peritransplant period.

Despite the inherent risks of PN, and the insufficient amount of studies demonstrating clear benefits of this type of nutrition in the HSCT population, it continues to be recommended as part of transplant care. Therefore, assessment of risk factors for hyperglycemia prior to HSCT, a careful choice of the conditioning regimen and all efforts to avoid prolonged PN in patients at higher risk for this complication contribute to successful post-transplant recovery.

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Publication Dates

  • Publication in this collection
    Apr-Jun 2017

History

  • Received
    26 July 2016
  • Accepted
    9 Sept 2016
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