Ann Thorac Surg 1999;67:804-809
© 1999 The Society of Thoracic Surgeons
Original Articles
Cardiovascular effects of induced hypothermia after lung transplantation
Leif T. Eriksson, MDa,
Roger Roscher, MDb,
Richard Ingemansson, MD, PhDc,
Stig Steen, MD, PhDc
a Department of Respiratory Medicine, University Hospital, Lund, Sweden
b Department of Anesthesiology and Intensive Care, University Hospital, Lund, Sweden
c Department of Cardiothoracic Surgery, University Hospital, Lund, Sweden
Accepted for publication August 14, 1998.
Address reprint requests to Dr Steen, Department of Cardiothoracic Surgery, University Hospital, S-221 85 Lund, Sweden
 |
Abstract
|
|---|
Background. Induced hypothermia may be used to reduce metabolism in acute respiratory failure. Hypothermia is accompanied by an increase in pulmonary vascular resistance, as also seen in the early period after lung transplantation. It was our concern that the combination of the two would lead to an increased workload on the right ventricle.
Methods. To test this hypothesis we induced hypothermia to 32°C in two groups of pigs. In one group we performed left single-lung transplantation combined with right pulmectomy (TRANSP group); in the other group, only right pulmectomy was performed (PULMEC group).
Results. During hypothermia, there was a significant increase in both groups in pulmonary vascular resistance (TRANSP group, 77%, p < 0.05; PULMEC group, 54%, p < 0.05) and a significant decrease in cardiac output (TRANSP group, 41%, p < 0.05; PULMEC group, 34% p < 0.05). Mean pulmonary artery pressure was unchanged, and the work done by the right ventricle was reduced (TRANSP group, 39%, p < 0.05; PULMEC group, 31%).
Conclusions. Induced hypothermia to 32°C after lung transplantation resulted in a significant decrease in the work done by the right ventricle despite a significant increase in pulmonary vascular resistance.
|
Introduction
|
|---|
Lung transplantation has evolved over the past 15 years as a treatment option in severe lung disease [1]. Survival has improved, and many centers now show a 1-year survival rate of more than 80% [2], approaching the survival rate for heart transplantation [3].
Early graft failure remains a significant cause of death and accounts for approximately 25% of all deaths in the first 30 days after lung transplantation [3]. The cause of the graft failure is often multifactorial, including long cardiopulmonary bypass time, ischemia–reperfusion syndrome, bacterial infection, acute rejection, and technical problems with the atrial anastomosis. All these factors are potentially reversible. The main problem is to sustain the patient until a diagnosis is made and treatment has been effective.
Treatment options when conventional intensive care fails include retransplantation and extracorporeal membrane oxygenation (ECMO). Retransplantation is not an option in most cases, mainly because of the shortage of donors, and extracorporeal membrane oxygenation has high complication and mortality rates [4, 5]. An alternative treatment of critical respiratory failure, previously described by our group [6], is to induce hypothermia and thereby reduce oxygen consumption and carbon dioxide production. During hypothermia there is an increase in both pulmonary and systemic vascular resistance [7], and during the early postoperative period after lung transplantation, increased pulmonary vascular resistance is often seen, partly because of impaired pulmonary artery endothelium-dependent relaxation [8].
The aim of the present study was to investigate whether the combination of lung transplantation and hypothermia would lead to an excessive increase in pulmonary vascular resistance, jeopardizing the function of the right ventricle.
To test this hypothesis we induced hypothermia to 32°C in two groups of pigs. In one group left single-lung transplantation was combined with right pulmectomy (TRANSP group), thus having animals 100% dependent on transplanted lung tissue for their survival. In the other group only right pulmectomy was performed (PULMEC group). Both groups were studied 24 hours after the operation to rule out immediate postoperative influences from circulating vasoactive substances such as thromboxane and prostacycline, which are seen in the first postoperative hours after lung transplantation but which stabilize after 24 hours [9].
|
Material and methods
|
|---|
Sixteen domestic pigs with a mean weight of 55 kg (range, 52 to 61 kg) were used in this study (5 donor, 5 recipient, and 6 control pigs). The study was approved by the Ethical Committee for Experimental Animal Research, Lund University. The animals were cared for in compliance with the "Guide for the Care and Use of Laboratory Animals" (NIH publication 85-23, revised 1985).
Anesthesia
Anesthesia was induced with ketamine chloride (Ketalar, Parke-Davis, Morris Plains, NJ) intramuscularly at a dosage of 30 mg/kg. Atropine (1 mg) and sodium thiopental (Penthotal, Abbot Scandinavia AB, Sweden) (5 to 10 mg/kg) were given intravenously before tracheostomy and pancuronium bromide (Pavulon, Organon Teknika, Boxtel, the Netherlands), at a dose of 0.13 mg/kg, at the moment of tracheostomy. Anesthesia and muscle relaxation were maintained with a continuous infusion of ketamine chloride (8 mL · kg-1 · h-1), midazolam (Dormicum, Roche, Basel, Switzerland) (0.03 mL · kg-1 · h-1), and pancuronium bromide (0.3 mL · kg-1 · h-1) in 10% glucose (0.5 mL · kg-1 · h-1). The fluid supply during the 24-hour observation period was kept constant in all animals and consisted of 720 mL of 10% glucose (ie, anesthetic infusion given at 30 mL/h), 400 mL of saline for cardiac output measurements, and 1,000 mL of 4% human albumin. After the observation period, standard Ringer’s solution with 25-mg glucose/mL (Pharmacia, Stockholm, Sweden) with the addition of potassium chloride to a concentration of 20 mmol/L was given as a continuous infusion at a rate of 3.3 mL/h during the rest of the experiment in addition to the anesthetic infusion.
Volume-controlled ventilation was initiated with a Servo-ventilator 900B (Siemens Elema, Sweden). A constant fraction of inspired oxygen of 0.5 and a positive end-expiratory pressure of 5 cm H2O were maintained during the first 24-hour observation period.
Operation
Donor pigs
A median sternotomy was performed, and both pleural spaces were entered. After inspection of the lungs and placement of a needle probe in the right lung for temperature measurement, ventricular fibrillation was induced by ligation of the left coronary artery, and topical cooling of the lungs was obtained by pouring cold saline over the lungs, which were allowed to collapse spontaneously by disconnecting the ventilator. After 6 hours of storage in this way at 6 to 8°C, the left lung was harvested and transplanted into a prepared recipient pig.
Transplantation group
Right thoracotomy was performed through the seventh intercostal space, followed by surgical preparation for a later pulmectomy on this side. Left thoracotomy was performed through the sixth intercostal space, followed by a left pulmectomy. The left lung from the donor pig was transplanted into the recipient. A catheter for pressure measurement was placed in the left atrium, and a flow probe was placed around the left pulmonary artery (Transonic System Inc, Ithaca, NY). After preliminary closure of the left thoracotomy, a right lung pulmectomy was performed, and the right thoracotomy closed. The pig was then placed with the left (transplanted) side up, and the lung was inspected to ascertain that no atelectasis was present before closure of the left thoracotomy. The ventilator settings were not changed.
Pulmectomy group
Anesthesia and monitoring were accomplished as described for the animals undergoing transplantation. Right thoracotomy was performed through the seventh intercostal space, and a right pulmectomy was performed. Left thoracotomy was performed through the sixth intercostal space. A catheter for pressure measurement was placed in the left atrium, and a blood flow probe was placed around the left pulmonary artery. Blood flow was continuously monitored with a transonic flowmeter, as in the animals undergoing transplantation, and during the observation period the animals were kept with the left side up.
Blood gases
Arterial and venous blood gases (ABL 500; Radiometer, Copenhagen, Denmark) and oxygen saturation (OSM3, adjusted for pig mode; Radiometer, Copenhagen, Denmark) were analyzed at 37°C and are presented at this temperature.
Calculation of right and left ventricular work
Right and left ventricular work were calculated according to the following formulas:
where RVW = right ventricular work; LVW = left ventricular work; MPAP = mean pulmonary artery pressure; CVP = central venous pressure; MAP = mean arterial pressure; LAP = left arterial pressure; CO = cardiac output; and k = constant for conversion to Joules.
Experimental protocol
All animals were observed for 24 hours to ensure a stable clinical state before the study began. After the 24-hour observation period, normothermic baseline measurements were done. The animals were then immersed in cold water (10°C). Central blood temperature was monitored with the termistor of the pulmonary artery catheter, and at a core temperature of 35°C the immersion was stopped. After another 90 minutes, the core temperature stabilized at 32°C (range, 31.3 to 32.7°C). Hemodynamic measurements were performed with a fraction of inspired oxygen of 0.5, and the gas exchange measurements were performed on air at a fraction of inspired oxygen of 0.21. Ventilation was reduced during hypothermia with the intention to keep the arterial carbon dioxide tension, measured at 37°C, constant.
Statistical analysis
Wilcoxon’s test for paired data was used to compare data during normothermia and hypothermia in the respective groups. Results are reported as mean ± standard error of the mean. P < 0.05 was considered significant.
|
Results
|
|---|
All animals survived the surgical procedures without difficulty and were in a stable condition 24 hours after operation, before they were exposed to hypothermia, and all animals survived the hypothermic regimen. The temperature was reduced from 38.3 ± 0.4°C to 32.1 ± 0.2°C in the PULMEC group and from 38.5 ± 0.7°C to 32.0 ± 0.5°C in the TRANSP group. Hypothermia resulted in a decrease in carbon dioxide production from 295 ± 28 to 154 ± 4 mL/min in the PULMEC group, a reduction by 48%.
Hemodynamics variables
Hemodynamic variables are presented in Table 1. As can be seen, cardiac output and heart rate were reduced during hypothermia. With an unchanged mean pulmonary artery pressure, this reduction in cardiac output and heart rate resulted in an increased pulmonary vascular resistance. Pulmonary vascular resistance for the individual animals in both groups is shown in Figure 1. Mean arterial pressure and systemic vascular resistance were both increased during hypothermia.
View larger version (20K):
[in this window]
[in a new window]
|
Fig 1. Pulmonary vascular resistance (PVR) during normothermia (38°C) and hypothermia (32°C) for the individual animals. Mean values are indicated by circles and thick line. (PULMEC = right lung pulmectomy; TRANSP = left single-lung transplantation and right lung pulmectomy.)
|
|
Right and left ventricular work
The work done by the right ventricle was reduced during hypothermia. The reduction was statistically significant in the TRANSP group. The magnitude of mean reduction in right ventricular work in the PULMEC group was similar to that in the TRANSP group (31% and 39%, respectively; p < 0.05) However, 1 of 6 animals in the PULMEC group showed an increase in right ventricular work during hypothermia, making the reduction not statistically significant. Right ventricular work for the individual animals is shown in Figure 2. The work done by the left ventricle did not change significantly, even though there was a tendency toward a reduction. Left ventricular work is shown in Figure 3.
View larger version (21K):
[in this window]
[in a new window]
|
Fig 2. Right ventricular work during normothermia (38°C) and hypothermia (32°C) for the individual animals. Mean values are indicated by circles and thick line. (PULMEC = right lung pulmectomy; TRANSP = left single-lung transplantation and right lung pulmectomy.)
|
|
View larger version (20K):
[in this window]
[in a new window]
|
Fig 3. Left ventricular work during normothermia (38°C) and hypothermia (32°C) for the individual animals. Mean values are indicated by circles and thick line. (PULMEC = right lung pulmectomy; TRANSP = Left single-lung transplantation and right lung pulmectomy.)
|
|
Gas exchange variables
Gas exchange variables are shown in Table 2. All animals in both groups except 1 in the TRANSP group showed better oxygenation in hypothermia, making the changes in arterial oxygen tension and arterial and venous oxygen saturation statistically significant in the PULMEC group but not in the TRANSP group. The PULMEC group was slightly hyperventilated and showed a significantly lower arterial carbon dioxide tension during hypothermia; however, the pH did not change.
Blood chemistry
Blood chemistry values are shown in Table 3. The hemoglobin value was significantly higher during hypothermia in both groups. Serum potassium levels decreased in all animals during hypothermia, whereas sodium and ionized calcium levels remained unchanged.
|
Comment
|
|---|
The most straightforward therapy that should be tried first to diminish pulmonary vascular resistance is inhalation of nitric oxide, which we have shown to be effective in transplanted lungs [10]. The more the pulmonary endothelium is injured, the better the vasodilatory effect of inhaled nitric oxide [11]. The beneficial effects of nitric oxide have also been shown in clinical studies [12, 13]. However, not every patient responds to nitric oxide treatment, and in this case other methods to sustain the patient until treatment has been effective are needed. The rationale for inducing hypothermia in acute respiratory failure is to reduce the metabolic rate and thereby also reduce oxygen consumption and carbon dioxide production. Induced hypothermia is not just a question of lowering the body temperature but is a regime consisting of heavy sedation, complete muscle relaxation, and buffering to a pH higher than 7.2 when necessary, in combination with hypothermia. If sedation and muscle relaxation are incomplete, increased sympathetic activity may lead to an increased metabolism despite a reduced body temperature [14]. So far we have used this strategy successfully in 2 patients who developed acute respiratory failure with hypoxia, hypercapnia, and acidosis after lung transplantation despite a fraction of inspired oxygen of 1.0 and high airway pressures. Both patients could be stabilized and eventually rewarmed and were subsequently discharged from the hospital in good clinical condition, with normal arterial blood gases [15]. We have also used this regimen in 4 patients with adult respiratory distress syndrome, referred to us for extracorporeal membrane oxygenation treatment. All 4 patients recovered without the need for extracorporeal membrane oxygenation (unpublished results).
A common finding in studies on induced hypothermia has been an increase in pulmonary vascular resistance [7], and because this is also the case in the early postoperative period after lung transplantation [8], it was our concern that the combination of the two—hypothermia and lung transplantation—would prove detrimental to right ventricular function.
In the TRANSP group we found a higher pulmonary vascular resistance at normothermic baseline and a more marked increase during hypothermia than in the PULMEC group. Mean pulmonary artery pressure was higher at normothermic baseline in the TRANSP group but remained unchanged during hypothermia in both groups.
The unchanged mean pulmonary pressure in combination with the reduced cardiac output and heart rate actually led to a decrease in the work done by the right ventricle, which was statistically significant in the TRANSP group. It can be speculated that the increase in pulmonary vascular resistance is a physiologic response to the reduced cardiac output aiming at preserving a good ventilation/perfusion distribution analogous to the hypoxic vasoconstriction seen in airway disease.
The work done by the left ventricle did not change significantly despite a marked increase in systemic vascular resistance.
The metabolic changes induced by lowering body temperature from 38° to 32°C were a reduction in carbon dioxide production of 6% to 8% per degree centrigrade, as would be expected from previous studies [16]. The increased arterial and mixed venous oxygen tension and the constant pH are indications that the oxygen balance is improved in hypothermia.
Our intention was to keep arterial carbon dioxide tension constant during the experiment. This strategy was not succesful in the PULMEC group, where arterial carbon dioxide tension was significantly reduced during hypothermia. We do not think that this had a major impact on the hemodynamic results because pH remained unchanged, and vascular tone is more related to pH than arterial carbon dioxide tension itself [17]. The increase in hemoglobin concentration during hypothermia in the pig has been ascribed to release of red blood cells from the spleen caused by increased sympathetic tone [18]. Increased hematocrit has also been described in infants during hypothermia [19].
The hypokalemia seen is a common finding in hypothermia, but potassium should only be added to cover measured losses, otherwise dangerous hyperkalemia can be seen on rewarming [20]. The explanation for the hypokalemia is a potassium shift from the extracellular to the intracellular compartment, presumably caused by increased sympathetic tone during hypothermia [21].
Induced hypothermia should be used with caution in patients with pulmonary hypertension who experience respiratory failure before transplantation, and if it is used it should be used with close monitoring of central hemodynamic variables, especially if it is combined with inotropic drugs [22].
In conclusion, we showed that induced hypothermia to 32°C leads to increased pulmonary vascular resistance, but the reduction in cardiac output and heart rate maintains a constant mean pulmonary artery pressure, with the consequence that the work done by the right ventricle is significantly reduced.
|
Acknowledgments
|
|---|
This study was supported by the Swedish Heart-Lung Foundation.
|
References
|
|---|
-
Trulock E.P. Lung transplantation. Am J Respir Crit Care Med 1997;155:789-818.[Medline]
-
Davis R.D., Pasque M.K. Pulmonary transplantation. Ann Surg 1995;221:14-28.[Medline]
-
Hosenpud J.D., Bennett L.E., Keck B.M., Fiol B., Novick R.J. The Registry of the International Society for Heart and Lung Transplantation: fourteenth official report—1997. J Heart Lung Transplant 1997;16:691-712.[Medline]
-
Whyte R.I., Deeb M.G., McCurry K.R., Andersson H.L., Bolling S.F., Bartlett R.H. Extracorporeal life support after heart or lung transplantation. Ann Thorac Surg 1994;58:754-759.[Abstract]
-
Glassman L.R., Keenan R.J., Fabrizio M.C., et al. Extracorporeal membrane oxygenation as an adjunct treatment for primary graft failure in adult lung transplant recipients. J Thorac Cardiovasc Surg 1995;110:723-727.[Abstract/Free Full Text]
-
Wetterberg T., Steen S. Combined use of hypothermia and buffering in the treatment of critical respiratory failure. Acta Anaesthesiol Scand 1992;36:490-492.[Medline]
-
Kornberger E., Mair P., Hörmann C., Braun U., Bucchardi H. Hemodynamics and oxygen metabolism in the pig during long-term hypothermia: comparison of 2 pH strategies. Resuscitation 1995;30:43-50.[Medline]
-
Kimblad P.O., Sjöberg T., Steen S. Pulmonary vascular resistance after lung transplantation related to endothelial function. Ann Thorac Surg 1994;58:416-420.[Abstract]
-
Kimblad P.O., Gréen K., Sjöberg T., Steen S. Prostanoid release after lung transplantation. J Heart Lung Transplant 1996;15:999-1004.[Medline]
-
Lindberg L., Sjöberg T., Ingemansson R., Steen S. Inhalation of nitric oxide after lung transplantation. Ann Thorac Surg 1996;61:956-962.[Abstract/Free Full Text]
-
Lindberg L., Kimblad P.O., Sjöberg T., Ingemansson R., Steen S. Inhaled nitric oxide reveals and attenuates endothelial dysfunction after lung transplantation. Ann Thorac Surg 1996;62:1639-1643.[Abstract/Free Full Text]
-
Adatia I., Lillihei C., Arnold J.H., et al. Inhaled nitric oxide in the treatment of postoperative graft dysfunction after lung transplantation. Ann Thorac Surg 1994;57:1311-1318.[Abstract]
-
Date H., Triantafillou A.N., Trulock E.P., Sohl M.S., Cooper J.D., Patterson G.A. Inhaled nitric oxide reduces human lung allograft dysfunction. J Thorac Cardiovasc Surg 1996;111:913-919.[Abstract/Free Full Text]
-
Dill D.B., Forbes W.H. Respiratory and metabolic effects of hypothermia. Am J Physiol 1941;132:685-697.[Free Full Text]
-
Eriksson L., Steen S. Induced hypothermia in acute respiratory failure after lung transplantation. Ann Thorac Surg 1998;65:827-829.[Abstract/Free Full Text]
-
Wetterberg T., Sjöberg T., Steen S. Effects of hypothermia in hypercapnia and hypercapnic hypoxemia. Acta Anaesthesiol Scand 1993;37:296-302.[Medline]
-
Feihl F., Perret C. Permissive hypercapnia. How permissive should we be?. Am J Respir Crit Care Med 1994;150:1722-1737.[Medline]
-
Hannon J.P., Bossone C.A., Rodkey W.G. Splenic cell sequestration and blood volume measurements in conscious pigs. Am J Physiol 1985;248:R293-R301.
-
Chen R.Y., Wicks A.E., Chien S. Hemoconcentration induced by surface hypothermia in infants. J Thorac Cardiovasc Surg 1980;80:236-241.[Abstract]
-
Koht A., Cane R., Cerullo L.J. Serum potassium levels during prolonged hypothermia. Intensive Care Med 1983;9:275-277.[Medline]
-
Silva P., Spokes K. Sympathetic system in potassium homeostasis. Am J Physiol 1981;241:F151-F155.[Medline]
-
Roscher R., Ingemansson R., Wetterberg T., Algotsson L., Sjöberg T., Steen S. Contradictory effects of dopamine at 32°C in pigs anesthetized with ketamine. Acta Anaesthesiol Scand 1997;41:1213-1217.[Medline]
Top
Abstract
Introduction
