Relationship of Hormonal Resuscitation Therapy and Central Venous Pressure on Increasing Organs for Transplant

ORGAN PRESERVATION Relationship of Hormonal Resuscitation Therapy and Central Venous Pressure on Increasing Organs for Transplant Tina Abdelnour, RN, BSN, and Steve Rieke, RN, BSN Background: Methods: Results: Conclusions: Hormonal resuscitation therapy (HRT) has been shown to increase the number of organs available for transplant. Likewise, optimal fluid balance, as measured by central venous pressure (CVP), impacts the function of donor lungs. The purpose of this study is to examine the interplay of these two variables in donor management and the impact they have on organs transplanted, with particular emphasis on hearts and lungs. Management of brain-dead potential organ donors was standardized in the regional OPO, including utilization of HRT in combination with a goal CVP of 4 to 8 mm Hg. Outcomes of organs transplanted per donor (OTPD) were compared between donors receiving 15 hours and 15 hours of L-thyroxine (T4); between donors with a final CVP 1 mm Hg vs 1 mm Hg; between donors in whom T4 was applied for 15 hours, and a final CVP 1 mm Hg was achieved; and those in whom one or both variables were not achieved. Seventy-nine percent more hearts were transplanted from donors in whom HRT was initiated and maintained for 15 hours. When a final CVP 1 mm Hg was achieved, 44% more hearts, 95% more lungs and 13% more kidneys were able to be transplanted. When both variables were met, 64% more hearts, 13% more lungs, 6% more kidneys and 44% more pancreata were available for transplantation, without compromise of liver or intestinal outcomes. Standardization of HRT, in combination with a CVP 1 mm Hg, significantly increases the utilization of hearts and lungs for transplantation, without negatively impacting other organ systems. J Heart Lung Transplant 29;28:48 5. Copyright 29 by the International Society for Heart and Lung Transplantation. Maximizing the number of transplantable organs from every donor remains a priority for both the transplant and procurement community. Efforts such as the Organ Donation and Transplantation Breakthrough Collaborative have heightened awareness of the need to identify and share best practices nationally. Although recommendations exist for certain donor management interventions and parameters, data to substantiate the impact of these interventions on recipient outcomes are limited. As methods for donor management and organ yield vary considerably across organ procurement organizations (OPOs), the need to study outcomes and standardize successful practices is crucial. From the Department of Procurement, LifeSource Upper Midwest Organ Procurement Organization, St. Paul, Minnesota. Submitted July 11, 28; revised November 11, 28; accepted January 14, 29. Reprint requests: Tina Abdelnour, RN, Department of Procurement, LifeSource Upper Midwest Organ Procurement Organization, 255 University Avenue West, Suite 315 South, St. Paul, MN 55114. Telephone: 651-815-5175. Fax: 651-63-783. E-mail: tabdelnour@lifesource.org Copyright 29 by the International Society for Heart and Lung Transplantation. 153-2498/9/$ see front matter. doi:1.116/ j.healun.29.1.18 The physiologic effects of brain death on the cardiovascular, pulmonary and endocrine/metabolic systems have been well documented and explain the need for a systematic approach to the management of the braindead organ donor. 1,2 Strategies to restore hemodynamic stability and preserve viability of all organ systems are crucial. Among these, several studies have suggested that the use of hormonal resuscitation therapy (HRT) as an adjunct to donor management may serve a role in helping to maintain metabolic stability and prevent loss of donors to hemodynamic collapse. 2 8 Fluid management of the organ donor has also been a focus, particularly in regard to preservation of cardiac and pulmonary function. 2,6,7,9,1,11,12 Although the use of pulmonary artery catheters can provide valuable data to guide donor management, most OPOs rely heavily on the measurement of central venous pressure (CVP) as an indirect indicator of fluid status. This may be necessary due to issues with accessibility, cost and associated risk factors of line placement, but there is some question as to whether this is an adequate method of assessment. 13,14 The objective of this study was a systematic evaluation of the impact of standardization of HRT and optimal fluid balance, as indicated by CVP, on increasing organs recovered for transplant. 48

The Journal of Heart and Lung Transplantation Abdelnour and Rieke 481 Volume 28, Number 5 Table 1. Levothyroxine (T4) Protocol a 1. Pre-medicate in rapid succession as follows: 1 amp 5% Dextrose in water 2 g solumedrol IV 2 U regular insulin IV 2 g levothyroxine IV 2. Levothyroxine 4 g/5 ml NS Start infusion at 1 g/h, goal 5 g/h Titrate to effect to wean vasopressors off a Weight 35 kg. METHODS From November 1, 25 to November 3, 27, the LifeSource Upper Midwest Organ Procurement Organization facilitated the evaluation and management of 343 productive organ donors, 38 of whom were brain dead. Donors from this group were included in our study if they were: brain dead; standard criteria donors, as per the United Network for Organ Sharing (UNOS) definition; and between 1 and 6 years of age (N 219). Donor Management All donors were managed according to standardized organizational guidelines that included: the use of intravenous fluids and inotropic agents (preferably dopamine or phenylephrine) to maintain a systolic blood pressure (SBP) 9 mm Hg, CVP 4 to 8 mm Hg and urine output 1 to 2 ml/kg/h; transfusion to maintain hemoglobin 8. g/dl; electrolyte replacement; highdose methylprednisolone (2 g, followed by 1 g every 12 hours, or 3 mg/kg, followed by 15 mg/kg every 12 hours in donors 7 kg); vasopressin drip for diabetes insipidus; and ventilator management to achieve partial pressure of oxygen (PaO 2 ) 9 mm Hg; and ph 7.35 to 7.45. Lung management included: target tidal volume of 1 ml/kg ideal body weight; inspiratory:expiratory (I:E) ratios of 1:1 to 1:2; early bronchoscopy to clear secretions; routine chest physiotherapy and pulmonary toilet; prophylactic broad-spectrum antibiotic therapy; and manual recruitment maneuvers when indicated. From November 1, 25 to October 31, 26, HRT was initiated in donors who required multiple inotropes, were hemodynamically unstable, or had an initial ejection fraction by transthoracic echo of 5%. After October 31, 26, our practice was changed to initiate HRT on every brain-dead donor at the start of donor management. The protocol includes intravenous L-thyroxine (T4), methylprednisolone, dextrose 5% and regular insulin (Table 1). Donor Evaluation and Data Collection Demographic and clinical data were collected retrospectively by review of the OPO donor management records. These included: age; cause of death; minutes of cardiac down time; initial and final vasopressor requirements; hours of HRT; hours of vasopressin; initial and final CVP; smoking history 2 years; history of hypertension and diabetes mellitus; history of previous chest surgery; positive serologies; and classification of highrisk donor status, as per UNOS guidelines. Recipient Data Collection Early graft outcomes for heart and lung recipients of this data set were collected from UNOS data available to the local OPO. Statistical Analysis Statistical analysis was performed to evaluate the effect of the HRT and CVP measurements on overall organs and individual organs transplanted per donor (OTPD). Analysis of scatterplots to examine the relationship between the two variables suggested that more organs transplanted corresponded with longer time on HRT and with lower CVP (Figure 1). The two variables also correlated inversely with one another; the longer the time on HRT, the lower the CVP. Using Student s t-test, we tested three hypotheses: (1) the mean OTPD would be higher in the group receiving 15 hours of HRT than in the group receiving 15 hours or no HRT; (2) there would be an increase in the mean OTPD in the group with a CVP measurement of 1 mm Hg, when OTPD OTPD 7 6 5 4 3 2 1 7 6 5 4 3 2 1 1 5 Fi tte d L i n e Pl o t O T P D = 3. 2 1 9 +. 5 2 4 1 H o ur s o f T 4 2 3 H o u r s of T 4 1 15 Final CVP 4 2 5 Fitted Line Plot OTPD = 5.62 -.159 Final CVP 6 25 S 1.57582 R-Sq 9.% R-Sq(adj) 7.4% S 1.56559 R-Sq 13.1% R-Sq(adj) 11.5% Figure 1. Relationship between hours of T4 and CVP on OPTD.

482 Abdelnour and Rieke The Journal of Heart and Lung Transplantation May 29 compared with the group with a CVP 1 mm Hg; and (3) donors with a combination of HRT 15 hours and a CVP 1 mm Hg would have a higher mean OTPD. We then compared the same groups based on individual organs transplanted, including heart, lung, liver, kidney and pancreas. Proportional t-tests were performed to identify demographic differences between the groups, and multivariate regression analysis was then performed to determine whether age or trauma death was an independent predictor of OTPD. An.5 was accepted as the boundary for rejection of the null hypotheses. Statistical analyses were performed using MINITAB v14.. RESULTS Donor Characteristics Data were collected on 38 brain-dead organ donors from October 25 through November 27; 219 were included in the study. Exclusion criteria included: donor age 6 years, due to age-related decline in organ function; and age 1 years, due to size limitations that impact organ allocation. Donors classified as extended criteria donors, as per UNOS guidelines, were also excluded, due to co-morbid factors that negatively impact organ function. The median age of the study group was 35 years (range 12 to 59 years) and 63% were male. The cohort was analyzed to determine whether donor age, gender, trauma death, prior chest surgery, history of hypertension, history of smoking 2 years, a positive serology, or classification as high risk per guidelines of the Centers for Disease Control (CDC) were different in the populations receiving 15 hours vs 15 hours of HRT and those with CVP 1 mm Hg vs 1 mm Hg. Significant differences between the HRT groups were found for age and percent trauma death. History of hypertension was significantly different between the CVP groups (Tables 2 and 3). However, multivariate analysis did not reveal these factors to be independent predictors of outcomes. Effect of HRT on Organs Transplanted To evaluate the impact of time of T4 administration on OTPD, data were analyzed with regard to time-frames of Table 2. Demographic Characteristics of the HRT Groups HRT 15 h HRT 15 h p-value Age (years) 33.6 38.2.26 Male gender 66% 59% Death by trauma 49% 31.5%.12 Prior chest surgery 4% High risk (CDC) 3% 7% Positive serology 5% 7% Smoking 2 pack-years 25% 34% History of hypertension 19% 22% HRT, hormonal resuscitation therapy; CDC, Centers for Disease Control. Table 3. Demographic Characteristics of the CVP Groups CVP 1 mm Hg CVP 1 mm Hg p-value Age (years) 34.2 36.9 Male gender 64% 62% Death by trauma 42% 45% Prior chest surgery 1% 3% High risk (CDC) 4% 4% Positive serology 5% 8% Smoking 2 packyears 27% 3% History of hypertension 24% 12%.31 CVP, central venous pressure; CDC, Centers for Disease Control. 1, 15 and 2 hours. The largest difference in outcomes was observed between those donors with HRT 15 hours and those with 15 hours or no T4 received. Fifteen hours or more of HRT trended toward significantly higher OTPD (4.31 vs 3.86, p.8). When looking at individual organ outcomes, number of hearts recovered per donor was higher in the 15-hour group than the 15-hour group (.59 vs.33, p.1) (Table 4). Effect of CVP on Organs Transplanted Our initial analysis indicated that more organs were transplanted from donors with a lower final CVP reading. When the cohort was dichotomized into those donors with a final CVP of 1 mm Hg and those with a final CVP 1 mm Hg, CVP 1 mm Hg correlated significantly with a higher overall OTPD (4.54 in the 1 group vs 3.38 in the 1 group, p.1). A CVP 1 mm Hg also correlated significantly with a higher rate of hearts, lungs and kidneys transplanted (p.19, p.1 and p.1, respectively) (Table 5). Effect of HRT >15 Hours and Final CVP <1 mm Hg on Organs Transplanted Outcomes were evaluated in donors who had HRT administered for at least 15 hours in combination with achieving a final CVP of 1 mm Hg (N 98, 45%), and then compared with donors in whom either one or both variables were not met. Again, overall OTPD was significantly higher in the group with HRT 15 hours and a CVP 1 mm Hg (4.67 vs 3.74, p.1). This Table 4. Effect of HRT on Organs Transplanted per Donor (OPTD) T4 15 h (N 73) T4 15 h (N 146) p-value OTPD 3.86 4.31.8 Heart/donor.33.59.1 Lungs/donor.48.61 Liver/donor.96.86 Kidneys/donor 1.78 1.85 Pancreas/donor.29.39

The Journal of Heart and Lung Transplantation Abdelnour and Rieke 483 Volume 28, Number 5 Table 5. Effect of CVP on Organs Transplanted per Donor (OPTD) Final CVP 1 (N 73) Final CVP 1 (N 146) p-value OTPD 3.38 4.54.1 Heart/donor.39.56.19 Lungs/donor.19.75.1 Liver/donor.83.93 Kidneys/donor 1.68 1.9.1 Pancreas/donor.29.39 CVP, central venous pressure. group also yielded more hearts, lungs and pancreata per donor (p.1, p.1 and p.23, respectively) (Table 6). Early Heart and Lung Graft Outcomes Of the 219 donors included in this study, 129 hearts, one heart lung block, 43 en bloc lungs and 49 singlelung transplants were performed. Of the 129 hearts transplanted, 6 graft failures were reported, including 4 within the first week post-transplant and 2 others at 132 and 542 days post-transplant. Of the 92 lung transplants performed, 2 double- and 4 single-lung graft failures were reported, all within 3 months post-transplant. The 1 heart lung block also failed. Of the first 87 heart transplants for which 1-year patient survival data were available, patient survival was 93%. Of the first 68 lung transplants for which 1-year patient survival data were available, patient survival was 85%. The donors of the failed grafts had a mean time on T4 of 25 hours (range to 52 hours). Only 1 donor did not receive T4. The mean final CVP in the group was 7 mm Hg. All donors were multiple-organ donors, with an average OTPD of 5.9, as compared with 4.8 in the non-failure cohort. DISCUSSION The use of HRT is one practice that, despite documented outcomes, continues to be utilized inconsistently. In 23, Rosendale et al 3 showed, through a retrospective review of the UNOS database, that more organs were recovered in donors who had received HRT. However, the investigators were not able to specify how donors were selected to receive the therapy, what specific protocols were utilized, at what point in donor management the therapy was initiated, or how practices differed among OPOs. As long ago as 1988 and as recently as 25, studies indicated that triiodothyronine (T3) can positively impact the metabolic processes after brain death, and that HRT in donors is warranted to help restore hemodynamic stability after brain death by promoting a return to aerobic metabolism. 2,4 Its effectiveness in helping to decrease donors lost to hemodynamic instability prior to brain-death declaration and procurement has been documented, 5 and benefit has been shown in both the function of donor hearts and in recipient graft function after transplant. 6 9 Despite these findings, many OPOs still institute HRT only in the presence of high-dose vasopressor requirements and/or hemodynamic instability. Recommendations regarding optimal donor fluid balance are fairly consistent in recommending a CVP of 1 mm Hg. Although largely focusing on heart and lung outcomes, the benefit to other organs is implied. 14 For example, the report from the Crystal City meeting in 22 stated that, standardization and simplification of donor management and procurement protocols would benefit all transplant organs and all transplant patients, as the better the cardiopulmonary function, the better the organ function after transplantation. 1 A CVP of 6 to 1 mm Hg is the recommended range, which aligns with standard critical care medical practice. Animal models suggest that a CVP 1 mm Hg has a detrimental effect on heart function. 11 Fluid loading in potential lung donors has also been shown to have adverse effects on lung function 12,14 and on the incidence of lungs recovered for transplant. 13 Kutsogiannis et al 7 recommended a CVP 8 mm Hg, and have linked both of these practices to better outcomes in transplant recipients: Aggressive hemodynamic and respiratory management of... donors, coupled with the use of hormonal therapy, improves the rate of conversion and graft survival in solid organ recipients. Of the many factors that impact how many organs are transplanted from each donor, many of these variables are intrinsic and cannot be manipulated. Our study has demonstrated how controlling two extrinsic variables can have a significant impact on the number of viable organs available for transplant. Fully 79% more hearts were transplanted from donors in whom HRT was initiated and maintained for at least 15 hours. In donors with a final CVP 1 mm Hg, increased availability of hearts, lungs and kidneys was realized. When both Table 6. Effect of HRT and CVP on Organs Transplanted per Donor (OPTD) T4 15 h and/or final CVP 1 (N 121) T4 15 h and final CVP 1 (N 98) p-value OTPD 3.74 4.67.1 Heart/donor.39.64.1 Lungs/donor.39.79.1 Liver/donor.89.9 Kidneys/donor 1.78 1.89 Pancreas/donor.3.44.23 HRT, hormonal resuscitation therapy; CVP, central venous pressure.

484 Abdelnour and Rieke The Journal of Heart and Lung Transplantation May 29 variables were met, the gains were even more dramatic. Although discussion has arisen over apparently competing fluid requirements in multiple-organ donors, 14,15 it has been purported in the transplant community that what s good for the heart and lungs is good for all organs, and the present study supports this concept. Although the goal of OPOs is to increase the number of viable organs available for transplantation, the goal of the accepting transplant physicians is to transplant organs that will function well in the recipients and afford them every opportunity for long-term survival. Therefore, early outcomes in recipients should be considered in any donor management practice. In this study, early outcomes for both heart and lung recipients are comparable, if not superior to, national outcomes. Levothyroxine, in conjunction with high-dose methylprednisolone, can be utilized to support hemodynamic stability in donors and allow for recovery of heart function after brain death. Likewise, optimal fluid balance supports adequate perfusion to vital organ systems, without compromising heart and lung function due to volume overload, or leading to edematous organs at procurement. Standardized institutional protocols have been shown to increase the number of organs for transplant, 16 and standardizing these practices across OPOs can contribute to increasing the donor pool of hearts, lungs, kidneys and pancreata for transplant across the nation. Likewise, educating intensive care physicians on the devastating effects of profound hypervolemia prior to and during brain-death declaration can help to decrease the number of organs lost due to declining function. Limitations The use of CVP as a single indicator of fluid status can be misleading. There are many factors that can influence CVP, such as underlying heart failure, expansion of the right atrium in response to increased volume in healthy hearts, and intracellular and extracellular fluid shifts that occur with traumatic injury and illness, and resuscitative efforts prior to brain death. Therefore, reliance on CVP must be coupled with an extensive understanding of overall fluid balance and hemodynamic status of the donor. When profound instability is present, other measures, such as those obtained by use of pulmonary artery catheters, can be beneficial. Perhaps other methods of measuring fluids status, such as pulse-pressure variation, should be explored. Dosing guidelines for HRT protocols have not been studied. One protocol was standardized in this single OPO study, but other dosing strategies or drug combinations could have similar or improved outcomes. Many factors can impact the length of time that a donor is managed prior to organ procurement. These can include donor issues, such as hemodynamic stability and organ function at the beginning of donor management, or recipient issues, such as time for preliminary cross-matching, travel time to recipient centers, and time needed for pre-transplant work-up at transplant centers. Allocation efforts can impact the timing of donor management, as can many logistical factors, such as availability of local operating suites, travel time of transplant teams to donor hospital, and delays in serology or histocompatibility results. In this study, efforts were made to control for differences in donor age and preexisting morbidities and conditions through exclusion criteria. The cohorts had similar ages and incidence of underlying pathologies and complicating factors (Table 2), but the potential impact of other unmeasured factors on time of HRT cannot be excluded. The benefit of HRT on recipient heart grafts has been explored, and data from critical care medicine support optimal functioning of hearts and lungs when fluid balance it ideal. However, no studies have supported the use of HRT or specific fluid status indicators as they impact other recipient grafts, such as kidney, pancreas and liver. This would be a logical next step in support of other organ recipients also benefiting from these practices. As with any study exploring specific treatment options, a large prospective trial would be ideal. However, it is our opinion that the impact of HRT in certain donor situations has been adequately documented, and the influence of fluid status on donor organs well supported. Therefore, withholding either of these modalities from any donor subset in order to study outcomes was not an ethically acceptable option, given the limited resource pool that exists. In conclusion, the scarce supply of donor organs available for transplant recipients demands that every effort be made to maximize the outcome from every organ donor. Practices that increase the number of organs transplanted and that improve recipient graft outcomes must be standardized across OPOs. The use of hormonal resuscitation therapy and management of fluid status are two practices that should be a focus of any donor management protocol. REFERENCES 1. Salim A, Martin M, Brown C, et al. Complications of brain death: frequency and impact on organ retrieval. Am Surgeon 26;72:377 81. 2. Arbour R, March K. Clinical management of the organ donor. AACN Clin Issues 25;16:551 8. 3. Rosendale J, Kauffman H, McBride M, et al. Aggressive pharmacologic donor management results in more transplanted organs. Transplantation 23;75:482 7. 4. Novitzky T, Cooper D, Morrell D, et al. Change from aerobic to anaerobic metabolism after brain death, and reversal following triiodothyronine therapy. Transplantation 1988;45:32 6. 5. Salim A, Velmahos G, Brown C, et al. Aggressive organ donor management significantly increases the number of organs available for transplantation. J Trauma Injury Infect Crit Care 25; 58:991 4.

The Journal of Heart and Lung Transplantation Abdelnour and Rieke 485 Volume 28, Number 5 6. Powner D. Treatment goals during care of adult donors that can influence outcomes of heart transplantation. Progr Transplant 25;15:226 31. 7. Kutsogiannis D, Pagliarello G, Doig C, et al. Medical management to optimize donor organ potential: review of the literature. Can J Anaesth 26;53:82 3. 8. Rosendale J, Kauffman H, McBride M, et al. Hormonal resuscitation yields more transplanted hearts, with improved early function. Transplantation 23;75:1336 41. 9. Novitsky D, Cooper D, Chaffin J, et al. Improved cardiac allograft function following triiodothyronine therapy to both donor and recipient. Transplantation 199;49:311 6. 1. Rosengard B, Feng S, Alfrey E, et al. Report of the Crystal City meeting to maximize the use of organs recovered from the cadaver donor. Am J Transplant 22;2:71 11. 11. de Perrot M, Weder W, Patterson GA, et al. Strategies to increase limited donor resources. Eur Respir J 24;23:477 82. 12. Pennefather S, Bullock R, Dark J. The effect of fluid therapy on alveolar arterial oxygen gradient in brain-dead organ donors. Transplantation 1993;56:1418 22. 13. Reilly P, Morgan L, Grossman M, et al. Lung procurement from solid organ donors: role of fluid resuscitation in procurement failures. Int J Emerg Intens Care Med 1999;3:2. 14. Wood K. Lung transplant donor: selection and management. Chest 1996;11(suppl):222S. 15. O Conner K, Wood K, Lord K. Intensive management of organ donors to maximize transplantation. Crit Care Nurse 26;26:94 1. 16. Rosendale J, Chabalewski F, McBride M, et al. Increased transplanted organs from the use of a standardized donor management protocol. Am J Transplant 22;2:761 8.