Objectives: Our aim was to investigate the negative effects of transferring brain-dead donors to the intensive care unit on the ratio of PaO2 to inspired oxygen fraction and the benefits of recruitment maneuvers on its reversal.

Materials and Methods: In this randomized trial, we assigned 30 brain-dead donors to an intervention group and a control group. After transfer to the intensive care unit, donors in the intervention group received a lung recruitment maneuver according to protocol for 1 hour, whereas the control group did not receive this intervention. Arterial blood gas was drawn before transfer, immediately after transfer, and 3 hours after transfer.

Results: Before transfer to immediately after transfer, the PaO₂-to-inspired oxygen fraction ratio decreased from 281.30 ± 100.33 to 225.03 ± 95.72 mm Hg (P < .01). At 3 hours after transfer, the PaO₂-to-inspired oxygen fraction ratio in the intervention and control groups was 280.4 ± 120.4 and 213.4 ± 75.5 mm Hg (P = .017), respectively. The absolute difference in PaO₂-to-inspired oxygen fraction ratio from before to 3 hours after transfer was -16.9 ± 44.1 and 51.8 ± 61.4 mm Hg (P < .001), in the intervention and control groups, respectively. Increasing central venous pressure and/or transfer time further potentiated the decrease of the PaO₂-to-inspired oxygen fraction ratio.

Conclusions: The PaO₂-to-inspired oxygen fraction ratio decreased after transfer of brain-dead donors to the intensive care unit. This was partially reversible by standardized recruitment maneuvers.

Key words : Brain-dead donors, Central venous pressure, Intensive care unit, Lung transplant

Introduction

Brain death refers to complete and irreversible loss of all brain functions. In most cases, this is the result of devastating head trauma, cerebrovascular accident, poisoning, or cerebral hypoxia after cardiac arrest.^1-3 The diagnosis of brain death is important for 2 reasons: First, brain death is death according to medical science.⁴ Second, organs of deceased individuals can be recovered for organ transplant after proper authorization.⁵ Recovery of organs can occur in donors after brain death (DBD)⁴ in accordance to the pathway of the Madrid Resolution.

Based on national data, the number of possible organ donors in Iran is 2500 to 4000; however, there are more than 25 000 people needing an organ transplant where the number of donors was only 808.⁶

Among donor organs, the lung is less likely to be used compared with other organs.³ In DBD, the lung is exposed to multiple harming events, such as contact with the external environment and the resulting increased risks of infections, existing pathophysiology during the process from devastating cerebral injury to establishment of brain death, and the consequent interventions during neuro-based critical care.^4,5 Having proper pulmonary function in DBD is an overall issue for organ recovery, as inappropriate oxygenation may harm the heart, lung, kidney, liver, pancreas, and intestine due to secondary com­plications. Therefore, it is important to manage DBDs without unnecessary interventions to avoid complications that could compromise pulmonary function.

Paries and associates indicated that airway disconnection during apnea test, as a mandatory component to confirm brain death, caused regional atelectasis and consequently reduced the PaO2 to inspired oxygen fraction (PaO₂/FiO₂) ratio, which was reversible after proper recruitment maneuvers.⁷ de Perrot and associates concluded that oxygenation could be improved by a recruitment maneuver after any event of temporary airway disconnection.⁸ In another study that included critically ill ventilated patients, Parmentier-Decrucq and colleagues demonstrated that serious adverse events related to ventilation occurred during intrahospital transport.⁹ Approximately 45% of such patients encountered cardiorespiratory, metabolic, hypo-hyperemia or circulatory problems in organs, which consequently complicated the transfer process and critical care. Metabolic-respiratory complications can include increased arterial blood acidity, atrial fibrillation, desaturation, and cardiorespiratory arrest.^9,10

In this study, we aimed to investigate whether donor transfer from one intensive care unit (ICU) to the ICU of the organ procurement unit (OPU) affected pulmonary function. We used the PaO₂/FiO₂ ratio as an endpoint surrogate. We also investigated PCO₂ and the number of suitable lungs for donation as outcome variables.

Materials and Methods

This study was conducted in the ICU of hospitals affiliated with the OPU of Shahid Beheshti University of Medical Sciences and involved DBDs from the Masih Daneshvari Hospital ICU. After impaired pulmonary function was identified in eligible DBDs4 transferred from the ICU to the OPU (as a result of unchangeable local infrastructural and health care system issues), our center developed a pretransfer recruitment maneuver protocol (see below) to be applied to all DBDs when a transfer was mandatory. Our randomized study (Figure 1) was set up to confirm the therapeutic effectiveness of this intervention.

Between May 2015 and December 2015, all consecutive DBDs meeting study inclusion and requiring transfer were enrolled in our study (after formal consent from DBD’s next of kin). Of 85 eligible donors, 25 were excluded from the study due to existing acute respiratory distress syndrome or hemodynamic instability. In total, we randomly assigned 30 DBDs to the intervention group (received recruitment maneuver, performed according to protocol, before transfer). The remaining 30 DBDs were assigned to the control group (did not receive the intervention). The study was approved by the Ethical Committee of the National Research Institute of Tuberculosis and Lung Disease (ethical code IR.SBMU.NRITLD.REC.1396.28).

Although the PaO₂/FiO₂ ratio can be calculated from the PaO₂ obtained with arterial blood gas (ABG) analysis divided by FiO₂, all ABG measurements for this study were taken after ventilation for 15 minutes at FiO₂ = 1.0 (100%).

Study procedures
After brain death was confirmed and formal consent was obtained, including consent for DBD transfer to the OPU for organ retrieval, the coordinator performed a final assessment of the donor and organ suitability for transplant. If at least 1 organ was deemed to be suitable for transplant, the attending ICU physician confirmed hemodynamic stability and agreed to transfer the DBD to the OPU. At this stage, the initial positive end-expiratory pressure (PEEP) for all DBDs was 5 cm H₂O.

The first ABG sample (T1) was taken immediately before the DBD was disconnected from the fixed ventilator at the first ICU and connected to the portable ventilator for transfer.

After transfer, immediately at arrival to the OPU, the DBD was reconnected to the fixed ventilator at OPU, and the second ABG sample (T2) was taken. A chest radiography was then conducted to identify pulmonary edema, infiltration, atelectasis, pneumo­thorax, or pleural effusions. Hemodynamic stability was assessed, including hemoglobin oxygen saturation percentage. The DBDs in the intervention group received a recruitment maneuver, whereas those in the control group only received standard care. A third ABG sample (T3) was taken in both groups 3 hours after transfer.

Recruitment maneuver protocol
The recruitment maneuver was performed by making changes to ventilator settings for 1 hour as follows: mode set to pressure-controlled ventilation, tidal volume set to 4 to 8 cm3/kg body weight, PEEP maintained at 15 mm Hg, and respiratory rate maintained as indicated by the anesthesiologist and based on the DBD tests.

The overall 1-hour duration of the maneuver was subsequently subdivided into 10-minute intervals. Every 10 minutes, PEEP was increased by 2 to 3 cm H₂O to reach a final goal of 15 cm H₂O. Because this maneuver results in alveolar expansion but avoids high PEEP levels, it is normally used in patients with acute respiratory distress syndrome. Two hours after completion of the maneuver, the last blood sample was taken at FiO₂ = 1.0 (100%).

Other study parameters
In addition to examination of PaO₂/FiO₂ ratio, we also examined duration of the transfer process, DBD age, type and quantity of fluids infused, use of vasopressors, findings of endotracheal tube suction during transfer, ventilator settings (at T1, T2, T3), and chest radiography results. Chest radiography was examined by a transplant pulmonologist blinded to all other donor data.

Statistical analyses
Significant difference in measurements was assumed at P < .05 (two-sided). We used SPSS software version 21 (SPSS, Chicago, IL, USA) for statistical analyses. All numerical data are shown as means and standard deviations, and all categorical data are shown as absolute numbers and percentages. Comparisons of groups were performed by the chi-square test, repeated-measures analysis of variance, and t test according to the result of a 1-sample Kolmogorov-Smirnov test.

Results

Donor demographics
Age of DBDs in both groups ranged from 7 to 67 years old (38.1 ± 15.9 y). In the intervention group (n = 30), donor age ranged from 15 to 66 years old (37.1 ± 14.29 y); in the control group (n = 30), donor age ranged from 7 to 67 years old (38.4 ± 17.0 y), with no significant difference between groups. Of 60 DBDs, 30 (50%) died after head trauma. Table 1 summarizes all further donor data.

Transfer data
Transfer time was significantly longer in the intervention group than in the control group (Table 1; P = .03). Adverse events during transfer, including cardiac arrhythmias, were equal between groups, with adverse events shown in 4 DBDs in the intervention group (13%) and in 4 DBDs in the control group (13%). Two DBDs (1 from each group; 3%) required cardiopulmonary resuscitation in the ambulance.

Effects of recruitment maneuvers and transfer on PaO2-to-inspired oxygen fraction ratio
At T1 (Figure 2A), PaO₂/FiO₂ ratio was 297.30 ± 118.99 versus 265.30 ± 76.11 mm Hg (P = .220) in the intervention versus control group, respectively. At T2, the results were 239.79 ± 109.21 versus 216.27 ± 80 mm Hg (P = .345). At T3, the intervention group showed increased PaO₂/FiO₂ ratio to 280.4 ± 120.4 mm Hg; however, the control group showed decreased PaO₂/FiO₂ ratio to 213.4 ± 75.5 mm Hg (P = .017). The absolute difference in PaO₂/FiO₂ ratio between T1 and T3 in the intervention and control group was -16.9 ± 44.1 mm Hg and -51.8 ± 61.4 mmHg, respectively (P < .001). When we applied a PaO₂/FiO₂ ratio of > 300 mm Hg as the cutoff for considering the lung to be suitable for transplant, the percentage of donors achieving this threshold value from T1 to T3 changed in the intervention group from 50.0% to 46.7% and in the control group from 33.3% to 13.3% (Figure 2B).

Effects of recruitment maneuvers and transfer on other parameters
The PaCO₂ value was affected by the transfer process and recruitment maneuver. At T1, PaCO₂ was lower in the intervention group than in the control group (36 ± 9.7 vs 42.7 ± 12.1 mm Hg; P = .021). At T2, these values changed to 39.6 ± 10.8 and 34.3 ± 10.9 mm Hg, respectively. At T3, the PaCO₂ remained lower in the control group than in the intervention group (Figure 3; P = .04).

Figure 4 illustrates the relationship between central venous pressure and deterioration of PaO₂/FiO₂ ratio. An adverse correlation existed between higher central venous pressure values and reduced PaO₂/FiO₂ ratio at T2 for the whole population (P < .001; Pearson correlation coefficient: 0.567).

Lung transplant data
After the subsequent clinical and radiologic assessments, 11 DBDs in the intervention group (36.7%) and 6 DBDs in the control group (20.0%) underwent bronchoscopy for final evaluation as lung donors. In total, 4 DBDs in the intervention group (13.3%) and 1 DBD in the control group (3.3%) were considered suitable for lung donation; however, these results may be biased due to lack of donor-recipient matching and other considerations by the surgeon.

Discussion

Supply and demand have remained problematic for lung transplant worldwide. A 42% increase in the number of wait list candidates versus only 22% of lungs from donors being utilized have led to increased mortality for critically ill patients waiting for lung transplant.^11,12 The selection criteria defined 3 decades ago are still being used today to define the “ideal” lung donor criteria (donor age < 55 years, clear chest radiography, PaO₂/FiO₂ ratio ≥ 300 mm Hg, history of smoking < 20 pack-years, no chest injury, no aspiration, no sepsis, no putrid secretions at bronchoscopy, and short duration of mechanical ventilation).^13,14 Most donors do not meet these criteria, which may contribute to lung transplant rates from DBDs of less than 15% to 25%.¹⁵

The PaO₂/FiO₂ ratio is an important decision criterion when determining when to use or not to use a lung graft. It should be noted that, in our study population, only 36% of the DBDs had a PaO₂/FiO₂ ratio exceeding 300 mm Hg. In a study from Mascia and associates¹⁶ that analyzed interventions to improve lung donation rates, 54% of the DBDs had a PaO₂/FiO₂ ratio of ≥ 300 mm Hg and a mean value of 396 mm Hg after proper lung donor management. These results are in line with the key result of our study investigating whether pulmonary function is affected during transfer of a DBD from one ICU to the next ICU. Once compromised pulmonary function occurs during transfer, the only option to revise this harm is appropriate donor management after transport, including lung recruitment maneuvers as shown in our study (Figure 2). Prolonged transfer times are associated with increased harm to lungs, as shown by reduced PaO₂/FiO₂ ratio despite intervention (data not shown). Of note, Figure 3 indicates a difference in PaCO₂ at T1 between the groups. However, the frequency of DBDs with PaCO₂ levels within the reference range was 30.0% and 36.7% in the intervention and control group, respectively (P = .3); therefore, baseline PaCO₂ was not a confounding factor.

To the best of our knowledge, this is the first study indicating that disconnecting DBDs from optimal ventilation at ICU to suboptimal conditions during transfer harms the quality of lungs. Our results suggest that exposure of DBDs to suboptimal donor management conditions due to transport (for example, for transport in a hospital for imaging) does not allow proper maintenance of pulmonary function. During donor management in the ICU, many other factors may affect pulmonary function, including fluid overload, hemodynamic instability, endocrine failure, inflammatory response, arrhythmia, hypothermia, coagulopathy, and infection.^8,17 These confounders have to be considered during lung assessment with regard to suitability for transplant. Although our study design was a limitation for further analysis, our rather simplistic endpoint confirms that existing add-on complications can be avoided, including those related to disconnecting and reconnecting the ventilator during transport of a DBD and exposure to nonoptimal ventilation. Of note, some indirect conclusions can also be drawn, such as atelectasis development due to disconnection from the respirator during apnea test for the clinical diagnosis of brain death10 can be prevented when using an apnea test without disconnection from the respirator.

Although the central issue is to avoid harm to the lung by proper donor management, some controversy exists regarding whether a fixed PaO₂/FiO₂ ratio is helpful for lung donor selection. Botha and colleagues suggested that even PaO₂/FiO₂ ratios below 225 mm Hg should not serve as an exclusion criterion for critical lung grafts.¹⁸ In their report on 758 lung transplants, Thabut and colleauges¹⁹ found a higher relative risk of recipient mortality in grafts from donors with a PaO₂/FiO₂ ratio below 350 mm Hg. Conversely, according to the United Network for Organ Sharing database, lung transplant outcomes are more often related to recipient criteria rather than donor characteristics. However, transplant teams are likely to refuse organs with PaO₂/FiO₂ ratio < 300 mm Hg.¹² After donor transport and recruitment maneuvers, we found that the rate of DBDs that had PaO₂/FiO₂ ratios of < 350 mm Hg increased by 12.5%.

Luckraz and associates²⁰ analyzed 362 lung transplants and reported a higher 30-day mortality rate in recipients of donor grafts that had PaO₂/FiO₂ ratios ranging from 255 to 300 mm Hg. In contrast, Reyes and associates²¹ found that 18% of their lung donors had a PaO₂/FiO₂ ratio below 300 mm Hg; however, transplant outcomes in recipients were similar to those with donors having PaO₂/FiO₂ ratios above these values. Although controversy remains,²² we suggest a correlation between transplant outcome parameters (including airway and vascular parameters) and PaO₂/FiO₂ ratio; Okamoto and associates also emphasized the correction of PaO₂/FiO₂ ratio before transplant.²³

Among our 60 DBDs, 35 (58.3%) had PaO₂/FiO₂ ratio of < 300 mm Hg. The donor transfer process increased the number of donors with ratios of less than 300 mm Hg. At T2, 81.7% were in this range, whereas, after the recruitment maneuver, the percentage changed to 70%. Accordingly, as shown in Figure 2B, recruitment maneuver compensated the adverse effects of donor transfer between hospitals.

To improve oxygenation, Noiseux and associates24 suggested application of recruitment maneuvers. The group found that two-thirds of lungs in their study would be appropriate for transplant after recruitment maneuvers according to their protocol; however, the study lacked a control group. More recently, Mascia and associates16 showed that donor management with lung protective ventilation increased the number of lung grafts used for transplant. The PaO₂/FiO₂ ratio has been used to assess lung function; however, the direct relation between PaO₂/FiO₂ ratio and use of pulmonary grafts for transplant has not been investigated. Furthermore, in a study on patients with acute respiratory disorder, Barbas and associates found that performing a recruitment maneuver caused complete opening of the collapsed lungs and partial opening of the edematous lung tissue.²⁵ Paries and associates demonstrated that, although the mandatory apnea test for brain death diagnosis was responsible for regional atelectasis and reduced PaO₂/FiO₂ ratio due to airway disconnection, these complications were reversible with recruitment maneuvers.⁷

The incidence of adverse events related to inter- or intrahospital transport of patients varies from 20% to 79.8%. Various maneuvers have been recommended to decrease these events both before transporting and during transport.^26,27

We did not investigate several risks associated with recruitment maneuvers, including pulmonary barotrauma next to an atelectatic region. We also could not investigate whether the use of ventilators during transport equivalent to ventilators used in the ICU may mitigate the negative effect of transfer of DBDs. However, we suggest that clinicians should avoid unnecessary disconnections of airways, which could expose DBDs to suboptimal ICU therapy due to transfer problems.

Conclusions

We found that recruitment maneuvers were an effective method to increase the number of appropriate lungs for transplant. Targeted recruitment maneuvers reversed the reduced PaO₂/FiO₂ ratio in lungs from DBDs caused by issues related to transfer of donors from one place that necessitated temporary discon­nection from ventilation. Beyond strict adherence to donor management protocols, performing recruit­ment maneuvers could lessen the adverse respiratory effects resulting from such transfers. Recruitment maneuver after transfer improved gas exchange and increased the number of donors with PaO₂/FiO₂ ratios of > 300 mm Hg. We confirmed that transfer of donors between hospitals or other places reduced PaO₂ /FiO₂ ratio. It is important to note that, with regard to ABG criteria for pulmonary graft suitability, the recruitment maneuver prevents the loss of potential lung donors by improving the PaO₂ /FiO₂ ratio as a surrogate marker for proper gas exchange.

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