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a Department of Cardiothoracic Surgery Heart and Lung Transplantation Unit, University Hospital Birmingham NHS Foundation Trust, Birmingham, United Kingdom
b Department of Medicine, University Hospital Birmingham NHS Foundation Trust, Birmingham, United Kingdom
c Department of Physiology, University of Birmingham, Birmingham, United Kingdom
Accepted for publication July 31, 2007.
* Address correspondence to Prof Bonser, Department of Cardiothoracic Surgery, University Hospital Birmingham NHS Foundation Trust, Edgbaston, Birmingham, B15 2TH, United Kingdom (Email: robert.bonser{at}uhb.nhs.uk).
Presented at the Forty-third Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 29–31, 2007.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsCommentDiscussionReferences |
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Methods: We studied 182 potential lung donors (arterial oxygen tension [PaO
2]/fractional inspired oxygen [FIO
2] ratio 
230). From this group, 60 patients (120 lungs) were allocated, within a randomized trial, to receive methylprednisolone (1 g), triiodothyronine (0.8 µg/kg bolus and 0.113 µg/kg/h infusion), both methylprednisolone and triiodothyronine, or placebo as soon as feasible after consent and initial assessment. Trial donors underwent protocol-guided optimization of ventilation and hemodynamics, lung water assessment, and bronchoscopy. Function was assessed by PaO
2/FIO
2 ratio, extravascular lung water index (EVLWI), and pulmonary vascular resistance (PVR). A nontrial group of 122 donors (244 lungs) received similar management without bronchoscopy, pulmonary artery flotation catheter monitoring, or lung water assessment.
Results: Within the trial, management commenced within a median of 2 hours (interquartile range, 0.5 to 3.5 hours) of consent and continued for an average of 6.9 ± 1.2 hours. The PaO 2/FIO 2 ratio deteriorated (p = 0.028) from 397 ± 78 (95% CL, 376 to 417) to 359 ± 126 (95% CL, 328 to 390) and EVLWI from 9.7 ± 4.5 mL/kg (95% CL, 8.6 to 10.9 mL/kg) to 10.8 ± 5.2 mL/kg (95% CL, 9.4 to 12.2 mL/kg; p = 0.009). PVR remained unchanged (p = 0.28). At end management, 48 of 120 trial lungs (40%) were transplanted versus 66 of 244 nontrial lungs (27%; p = 0.016). Neither methylprednisolone and triiodothyronine nor T3 increased lung yield or affected PaO 2/FIO 2 or EVLWI; however, methylprednisolone attenuated the increase in EVLWI (p = 0.009).
Conclusions: Early active management of lung donors increases yield. Steroid administration reduces progressive lung water accumulation.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
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Steroids may stabilize cellular membranes, reduce upregulation of human leukocyte antibody antigens [7], inhibit or prevent alterations in cytokines [8], and upregulate alveolar fluid clearance [9, 10]. A retrospective study reported increased yield and improved donor lung function after early methylprednisolone (MP) administration [11]. Triiodothyronine (T3) is commonly used to putatively improve donor heart function. Improved cardiac function, with reduced hydrostatic pressures, might limit lung water accumulation, and in addition, T3 increases alveolar fluid clearance [9]. We therefore conducted a randomized trial to investigate the effects of MP and T3 administered early after consent for organ donation on heart and lung function in potential heart and lung donors.
Within this trial, in addition to receiving hormone therapy, potential donors were actively managed to try to maintain organ function. Because combination, MP, T3, and vasopressin therapy has been associated with higher organ retrieval rates [12] and active management of marginal lung donors is reported to increase retrieval rate [13–16], we also compared lung yield between the trial donors and a contemporary cohort of donors who were not part of the trial. Both heart and lung donor outcomes were studied. This article details the lung outcomes; cardiac outcomes will be reported separately.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
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Within this cohort, provided donation was in an intensive care unit (ICU) within 2 hours’ road distance of our recipient center, we approached the next of kin for consent to enter into a prospective, double-blind, placebo-controlled, randomized trial. The research was supported by 33 accessible ICUs and approved by a multicenter research ethics committee, all UK cardiothoracic transplant centers, and all zonal liver and kidney retrieval teams. Consent was obtained from the next of kin for all participating donors according to the multicenter research ethics committee approval. The trial was conducted independent of whether donor lungs were provisionally accepted for lung transplantation. Lungs previously declined were not reoffered after management.
Assessment and Management of Nontrial Donors
Nontrial donors were managed using a standard protocol by donor procurement coordinators in collaboration with local ICU staff with the aims of maintaining hemodynamic stability, limiting fluid overload, and substituting norepinephrine with vasopressors in donors provisionally accepted for cardiac transplantation. In nontrial donors, pulmonary artery flotation catheter (PAFC) insertion, bronchoscopy, and hormone replacement therapy with MP and T3 only occurs in accepted heart or lung donors after transfer to the operating room (OR) for the retrieval procedure several hours after initial assessment. EVLWI measurement would not be routinely undertaken in this cohort.
Assessment and Management of Trial Donors
Trial donors were attended in the ICU by a donor research fellow as soon as feasible after consent was given for donation and study participation. At the initial assessment they underwent ABG (mm Hg) measurement (FIO
2 1.0; positive end-expiratory pressure [PEEP], 5 cm H2O). This was followed by insertion of a PAFC (Baxter Healthcare USA, Deerfield, IL) and femoral arterial thermodilution catheter (PiCCO, Pulsion Medical UK Ltd, Middlesex, UK) for measurement of central venous (CVP), mean arterial (MAP) and pulmonary capillary wedge pressures (PCWP), cardiac output, extravascular lung water index (EVLWI; normal range, 6 to 10 mL/kg), pulmonary vascular permeability index (PVPI), and pulmonary vascular resistance (PVR). The underlying principles and analysis of lung water assessment have been previously reported [17]. The PVPI is the EVLW/pulmonary blood volume ratio. Elevated EVLW with low PVPI implies hydrostatic edema, whereas a high EVLW and PVPI imply permeability edema.
After the initial assessment, bronchoscopy was performed to assess anatomy and endotracheal tube placement, to aspirate secretions, to detect evidence of active bronchitis or aspiration and to obtain a bronchoalveolar lavage (BAL) specimen for culture. Thereafter, ventilation was adjusted to maintain a tidal volume oft 10 mL/kg with PEEP of 5 cm H2O reducing inspired FIO 2 to maintain a PaO 2 of 80 mm Hg or higher and adjusting minute volume to maintain PaCO 2 at 35 to 55 mm Hg. Frequent endotracheal tube suctioning and volume recruitment by turning every 2 hours was also initiated.
Trial medication was then administered: T3 (0.8 µg/kg intravenous [IV] bolus, followed by 0.113 µg/kg/hr IV infusion), MP (1000 mg IV) as a single dose, both drugs, or placebo (dextrose 5%), and the T3/placebo infusion continued until retrieval. The MP dose was an empirical immunosuppressive dose, approximating 15 mg/kg for a 70-kg donor. The T3 dose was based on reports of positive hemodynamic effect after cardiac operations [18, 19]. The drugs and infusions were pre-prepared in identical volumes in code-labelled syringes by uninvolved recipient center staff according to a weight-based nomogram. Randomization was 1:1:1:1 and generated by a computer model with permuted blocks of four and a sealed envelope system. All medical, nursing, and technical staff involved in the research or donor care remained blinded to treatment allocation until study completion.
Active hemodynamic management was simultaneously commenced according to specific algorithms to achieve a cardiac index exceeding 2.5 L/min/m2, with CVP and PCWP at 12 mm Hg or less, and MAP at 65 to 85 mm Hg [20]. Fluid administration was restricted to small amounts of blood (to achieve a hemoglobin level 10 g/dL), gelatin colloid, or both, to maintain CVP/PCWP. Systemic vascular resistance was maintained in the range 800 to 1200 dynes/cm/sec5 by actively substituting vasopressin for norepinephrine. Blood glucose level was maintained between 80 and 120 mg/dL by using IV insulin, and hypothermia was prevented by standard measures. Crystalloid infusions were not used to replace urine output except in 3 donors who were hypernatremic.
Management continued in the ICU and OR until retrieval. Changes in lung function and bronchoscopy findings were conveyed to the recipient centers that had provisionally accepted lungs for transplantation. The duration of treatment and time of coning (detection of fixed dilated pupils and BP surge) were noted.
Hemodynamic studies, PaO 2/FIO 2 ratio at FIO 2 1.0, EVLWI, PVPI, and PVR were performed at baseline and repeated after initial bronchoscopic examination, 1 hour thereafter, and immediately before retrieval. Pre-retrieval ABG measurements were performed after direct inspection and manual inflation to recruit atelectatic lung segments, where possible. After each measurement, FIO 2 was reduced, as after initial assessment.
End Points and Statistics
The preplanned primary trial end point was a difference in PaO
2/FIO
2 of one standard deviation (SD) between groups at the end of management. The trial had 80% power (
= 0.05) to detect this with recruitment of four groups of 24 allowing for multiple comparisons. Actual recruitment did not reach this target, but the study remained powered to allow satisfactory comparison of this end point in donors receiving MP or no MP, or T3 or no T3. The trial was also initially powered to detect a 20% absolute increase in the number of lungs transplanted versus a historical or nontrial cohort.
Secondary trial end points included other functional data, the effect of norepinephrine administration in donors, and the transplant suitability at the end of management. Suitability was defined as a PaO 2/FIO 2 of 300 or more, without identifying lung trauma, aspiration, infection, or nonrecruitable atelectasis during assessment and at direct inspection.
Data were analyzed using SPSS 12.0 software (SPSS Inc, Chicago, IL). Continuous data were assessed for normality and are presented as mean ± SD with 95% confidence limits (CL) or median with interquartile range (IQR). Normally distributed variables were tested using independent or paired sample t tests. Skewed data were tested using nonparametric Mann-Whitney and Kruskal-Wallis tests. Categoric data were analyzed using 
2 and Fisher exact tests. Serial measurements were compared using repeated measures analysis of variance. Statistical significance was assigned at p 
0.05. Univariate and multivariate analysis (stepwise logistic regression) was used to identify factors that predicted suitability for transplant at the end assessment.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
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Bronchoscopy revealed abnormalities in 20 donors, including endotracheal tube malposition in 7, evidence consistent with aspiration in 4, edema in 2, and excessive purulent secretions in 7. Malposition was corrected and secretions were cleared. Bronchoalveolar lavage yielded positive cultures in 31 donors (5 of 7 with excessive secretions). Organisms cultured included Staphylococcus aureus in 10, Streptococcus pneumoniae in 6, Gram-positive anaerobes in 1, Serratia spp in 3, Escherichia coli in 3, Pseudomonas spp in 2, Klebsiella pneumoniae in 4, and Candida albicans in 2.
Donor Lung Function Within the Treatment Groups
Demographic details, suitability, and donor lung function for the four treatment groups are summarized in Table 2. Baseline lung function did not differ, and the administration of MP and T3, alone or in combination, did not affect the PaO
2/FIO
2 ratio (Fig 2) or any other variable compared with placebo.
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Suitability of Lungs for Transplantation and Transplant Outcomes
More trial donors yielded lungs for transplantation (26 of 60 versus 35 of 122; p = 0.054). Fifty-two trial donor lungs (26 pairs) were accepted and retrieved as suitable for transplantation, but single-lung transplantation was performed in four instances. Sixty-six nontrial lungs were transplanted (4 single lungs and 31 lung pairs). In the trial cohort, 43% (48 of 120) of the lungs were transplanted, which was significantly higher (p = 0.016 Fisher exact test) than the 27% (66 of 244) rate in the nontrial cohort (Fig 1). Although 48 of 120 trial donor lungs were transplanted, 12 lungs (4 from retrieved lung pairs and 8 not provisionally accepted for transplantation) were suitable for transplantation at end management on the aforementioned criteria.
Sixty trial lungs were deemed unsuitable due to deteriorating PaO 2/FIO 2 or hemodynamic instability in 30, abnormality on inspection in 16 (bullous disease, adhesions, intractable atelectasis), marginal PaO 2/FIO 2 ratio ± excessive secretions in conjunction with adverse donor history in 10 (age >60 years, mild asthma and smoking), and hepatitis C positivity in 4. In 15 marginal trial donors, PaO 2/FIO 2 increased slightly from 292 ± 34 (95% CL, 273 to 311) to 331 ± 152 (95% CL, 247 to 416), although this change was not significant (p = 0.34). Administration of MP in these marginal lung donors did not influence the change in EVLWI (p = 0.15) during management. Four of 30 marginal lungs were transplanted and 8 of 30 lungs met suitability criteria.
On univariate analysis, lower baseline EVLWI, particularly EVLWI of less than 10 mL/kg and shorter time from coning, predicted suitability for transplant at end management (Table 5).
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-EVLWI (OR, 1.66; 95% CL, 1.13 to 2.5; p = 0.01) independently predicted suitability. These data were not available in nontrial donors, preventing further analysis. The 30-day and 1-year survivals for trial and nontrial lung transplant recipients were 96.3% versus 92.1% (p = 0.636) and 77.8% versus 76.3% respectively (p = 0.99).
Effect of Trial Management on Other Solid Organ Retrieval
Within the trial, 26 hearts, 57 livers, and 118 kidneys were transplanted. Nonuse of these organs was because of intrinsic abnormality or failure to identify suitable recipients. In 4 donors, the study assessment identified poor heart function and hemodynamic decline despite maintained MAP. In these, cardiothoracic organ offering was abandoned, allowing rapid procurement of liver and kidneys.
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Comment |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
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A third of donors with normal chest roentgenogram have bronchoscopic abnormalities that may be correctable [21]. Bronchoscopy, by clearance of secretions and blood clots and correction of endotracheal tube malposition, may improve lung function. It may also identify factors precluding lung donation and may thereby avoid a delay in the retrieval of other organs. Limited crystalloid administration also appears important and may maintain better gas exchange [22].
We postulated that MP ± T3 might improve donor lung function by their effects on the heart, endothelium, and lung epithelium. T3 had no effect, but MP attenuated the accumulation of EVLWI, supporting its use in lung donors. Despite such active management, PaO 2/FIO 2 deteriorated with rising EVLWI and PVPI, suggesting increasing permeability. The deterioration of PaO 2/FIO 2 ratio was not affected by MP or T3. Early MP (15 mg/kg) administration has been associated with improved lung yield in a retrospective report but in this report, MP-treated donors were actively managed for a longer period, which may have contributed to the observed changes. Our study may have been underpowered to corroborate these findings but our results suggest that MP use in isolation is not a substitute for active management. Neither T3 nor MP administration was associated with worsening lung function, and a beneficial posttransplantation effect cannot be excluded. Moreover, MP administration took place 12.5 hours after coning was recognized, and earlier administration may be necessary to realize any beneficial effect.
Vasoparetic hypotension post-BSD is commonly treated by norepinephrine, a potent but cardiotoxic -adrenergic agonist [23]. In the trial, PaO
2/FIO
2 ratio and EVLWI deteriorated in donors receiving norepinephrine, and this was not prevented by norepinephrine withdrawal. The reason for the association between norepinephrine and lung dysfunction is unclear. Norepinephrine requirement may reflect greater cardiac dysfunction, a greater proinflammatory response, or a deleterious effect on pulmonary endothelium. Donor pressor support with norepinephrine has been associated with worse prognosis in heart and lung transplantation [24] and inferior posttransplant gas exchange [25]. Although norepinephrine usage did not affect yield in this study, its use in potential lung or heart donors may be inadvisable.
EVLWI is a validated index of pulmonary edema and may be elevated before changes in gas exchange, clinical status, or chest roentgenogram [26, 27]. On univariate analysis, a normal EVLWI (<10 mL/kg), and on multivariate analysis, a lower -EVLWI and higher baseline PaO
2/FIO
2, predicted the eventual suitability of lungs for transplantation. Alveolar fluid clearance, the capacity to remove alveolar water by active ion transport, remains normal in most donor lungs, even those rejected for transplantation [28, 29], and normal alveolar fluid clearance hastens resolution of posttransplantation edema [30]. Because increased alveolar fluid clearance, in response to steroids and β-adrenergic stimulation has been documented in experimental neurogenic pulmonary edema and human acute lung injury, this may be the mechanism for the reduced -EVLWI observed with MP. Thus, measurement and manipulation of lung water may become important in the assessment and management of potential lung donors [31, 32].
On univariate analysis, a shorter time from coning predicted transplant suitability. This may reflect less time for secondary lung injury to occur due to fluid overload, aspiration, ventilatory barotrauma, and nosocomial colonization, as well as a shorter duration of lung exposure to a hostile hemodynamic and proinflammatory environment. Earlier truncation of this exposure may retain better lung function.
Although this trial was prospective, randomized, blinded, and controlled, it remains numerically small, and it is underpowered to detect differences between individual therapy groups because recruitment did not reach the intended sample size. However, because both donor cohorts had similar ages, initial PaO 2/FIO 2 ratios, proportions with marginal PaO 2/FIO 2 ratios, and provisional acceptance rates, the study demonstrates the importance of donor management in increasing yield, especially because trial lungs were not reoffered after initial rejection.
Although nontrial donor care was based on a similar management protocol, albeit without bronchoscopy or invasive monitoring, management was overseen by donor procurement coordinators, who are simultaneously engaged in a logistic process that includes acquisition of consent, donor family support, offering of organs to recipient centers, arranging the multiorgan retrieval procedure, and transportation of organs and tissue. In contrast, the donor research fellow was wholly dedicated to donor management, and we would suggest that this dedicated donor management role is fundamental to maximize yield. This yield could be further increased if marginal lungs, that were rejected for transplantation on initial data but improve after management, were reoffered. Lung transplant availability can be increased by better management of lung donors. Early steroid administration is a component part of this management but is not a substitute for intensive donor care.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
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DR VENKATESWARAN: Prior to starting the study, we had prepared an envelope system for random allocation of donors into one of the four treatment arms using a computer-generated model. The organ procurement coordinator informed me about the availability of a study donor, after obtaining informed consent from the donor’s next of kin for organ donation and the study. I was also given the donor’s body weight at the same time over the phone. The nurse who was in charge of the cardiothoracic intensive care unit that night picked up the first numbered envelope in the box, and prepared the drugs according to the weight-based nomogram, and the envelope was sealed back. All investigators involved in the donor pathway—including myself, the nursing team, and the OR team—were completely blinded to the treatment until the analysis at end of the study.
DR PATTERSON: But did you say that you personally traveled to the donor hospitals?
DR VENKATESWARAN: Yes, I traveled to all the donor hospitals with the drugs, which were labeled as drugs A and B. Because the envelopes were picked up by the nurse who prepared the drugs according to the donor weight and handed them to me in syringes labeled as drug A and B, I was blind to the treatment allocation. I didn’t have any access to any of the randomization until the end of the study.
DR PATTERSON: So you traveled to the donor hospital in every single case ...
DR VENKATESWARAN: That’s correct.
DR PATTERSON: ... but you only gave drugs.
DR VENKATESWARAN: No, I was there, as I said in my presentation, within 2 hours of consent. I traveled with the drugs and with all my equipment, and inserted the pulmonary artery catheter and femoral arterial line. Bronchoscopy was performed. Using strict guidelines managed the donor, as I had described, and the donors were managed for a mean period of 7 hours. I continued the management in the operating theatre until organ retrieval.
DR MICHAEL S. MULLIGAN (Seattle, WA): He didn’t know whether drug A, B, or C was the placebo or drug.
DR VENKATESWARAN: I didn’t know. That’s correct.
DR DIRK VAN RAEMDONCK (Leuven, Belgium): I understand your study protocol started only after certification of brain death. My question is, what happened to the donors prior to brain death? Because a significant percentage of the donors may already have received steroids for treatment of craniocerebral injury prior to randomization.
DR VENKATESWARAN: I attended the donors only after confirmation of brain death and the consent for the study. We had multicenter research ethics committee approval to undertake the study. As far as your question regarding the steroid use, there is no evidence to prove that steroid use is beneficial in head injury. It is not a practice in the United Kingdom to give steroids to the donors with a head injury. If patients had brain tumors with intracranial hypertension, they would receive steroids. But just for head trauma, none of the neurosurgical units give steroids. I had gone through the case notes and treatment charts to make sure that the donors in the placebo group did not receive steroids at any point during their treatment.
DR MULLIGAN: That adds to what we have learned from the folks at Royal Perth in Australia, and what many of us have suspected, it would have been nice to have some even longer donor resuscitation ties as currently being advocated around the US, and to find out what happens with those folks that start out that are even more hypoxemic than a P/F ratio of 230. But you’re to be commended for your willingness to drive to so many donor hospitals and do that critical care work. Very nice paper. Thank you for a tremendous effort.
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References |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
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