Hyperthermia

Objectives: To optimize volume therapy during induced whole-body hyperthermia (WBH) [less than or equal to] 42.2[degrees]C, pulmonary capillary wedge pressure (PCWP) and intrathoracic blood volume index (ITBVI) were compared as goal parameters.

Design: Prospective clinical study.

Setting: ICU at university hospital.

Patients: Twenty-three patients with metastatic cancers.

Interventions: Radiant WBH in combination with induced hyperglycemia, hyperoxemia, and chemotherapy was applied. Volume therapy was directed to the PCWP (group A, 8 to 12 mm Hg [20 treatments]), or to ITBVI (group B, 800 to 1,100 mL/[m.sup.2] [19 treatments]) following a standardized protocol. Goals other than PCWP and ITBVI were cardiac index of > 3.5 L/min/[m.sup.2] and mean arterial pressure of > 55 mm Hg.

Measurements and results: In addition to the primary goals PCWP and ITBVI, at defined temperatures, central venous pressure (CVP), extravascular lung water index, the number of infusions, and packed RBCs, as well as serum lactate level, norepinephrine dosage, and levels of liver enzymes, bilirubin, creatinine, and urea were measured. Patients in group A received a significantly greater mean ([+ or -] SD) amount of crystalloids compared to those in group B (6,175 [+ or -] 656 vs 3,947 [+ or -] 375 mL, respectively) and required significantly lower dosages of vasoconstrictors compared with patients in group B. Except for the lower values of CVP in patients in group A during hyperthermia, all of the other hemodynamic and laboratory parameters showed no significant differences between the groups or stayed in a normal range.

Conclusion: PCWP and ITBVI are useful parameters to assess preload in induced WBH. Differences in crystalloids and vasopressor dosages may suggest an appropriate ITBVI of > 1,100 mL/[m.sup.2] for patients with good cardiopulmonary health under such extremely hypercirculatory conditions.

Key words: extravascular lung water index; goal-directed volume therapy; intrathoracic blood volume index; pulmonary capillary wedge pressure; whole-body hyperthermia

Abbreviations: CI = cardiac index; CVP = central venous pressure; EVLWI = extravascular lung water index ITBVI = intrathoracic blood volume index; MAP = mean arterial pressure; PCWP = pulmonary capillary wedge pressure; WBH = whole-body hyperthermia.

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Whole-body hyperthermia (WBH) with a body core temperature of [less than or equal to] 42.2[degrees]C is used for the treatment of patients with disseminated malignancies in Europe and the United States. WBH using radiant heat devices has been shown in phase I/II trials (1) to be feasible with an acceptable toxicity, but this procedure leads to extreme physical stress and extensive changes of systemic hemodynamics, as well as pulmonary hemodynamics. A drastic increase in heart rate, cardiac index (CI), and pulmonary artery pressure, as well as a drop in systemic and pulmonary vascular resistance and mean arterial pressure (MAP), has been round. (2-4) A decrease in systemic vascular resistance in WBH is induced by an extreme peripheral vasodilation, especially by radiant heat devices using percutaneous heating. Therefore, the cutaneous perfusion during hyperthermia increased drastically leading to a cutaneous perfusion of approximately 6 to 8 L/min with a corresponding decrease in cardiac preload and total peripheral resistance. (5) In addition to vasodilation in patients experiencing WBH, polyuria and evaporation lead to large fluid losses and require a differentiated volume management, which has not been investigated in therapeutic hyperthermic conditions up to now. Indeed, an appropriate intravascular volume for the maintenance of cardiac output and sufficient MAP has been detected as a prerequisite for the secure clinical performance of WBH. (6) Furthermore, the simultaneous application of cytostatic drugs in combination with induced hyperglycemia for the acidification and sensitization of cancer cells may be associated with various organ dysfunctions and may require a sufficient intravascular volume. (7,8)

Up to now it is still unclear which kind of monitoring technique should be used to monitor cardiac preload during WBH. The hemodynamics in patients experiencing WBH appear to be comparable with other hyperdynamic circulatory conditions like sepsis or septic shock, as well as to the condition of critically ill patients. Under these conditions, there has been a focus on research to detect a reliable indicator of intravascular fluid status. (9-12)

The aim of this study was to assess the clinical efficiency of volume management during WBH at [less than or equal to] 42.2[degrees]C using either pulmonary capillary wedge pressure (PCWP) or the intrathoracic blood volume index (ITBVI). An additional objective was to evaluate the differences in organ function parameters between both strategies for monitoring cardiac preload in a goal-directed protocol.

MATERIALS AND METHODS

Patients

This prospective clinical study of 39 WBH treatments was performed in patients with various metastatic cancers (for patient characteristics see Table 1). All of the patients received one or two treatments with WBH in the course of a phase I/II study that evaluated the feasibility and toxicity of WBH. Within 2 weeks before the first WBH, all of the patients underwent an extensive anesthesiologic evaluation, involving resting and exercise electrocardiography, transthoracic echocardiography, lung function examination, chest radiograph, cranial CT scan, and laboratory controls including thyroid function parameters, as described previously. (3) Findings in these investigations within the normal range were a precondition for therapy with WBH. The study was approved by the local review board for ethics and included obtaining the informed consent of all patients prior to treatment.

WBH

WBH was provided by using an infrared system (IRATHERM 2000; von Ardenne Institut; Dresden, Germany), as described elsewhere. (13) After a heating period of approximately 2 to 3 h, a core temperature of 41.8 to 42.2[degrees]C was maintained in the plateau phase for 60 min. After completing the plateau phase, the patients cooled passively.

In this setting, WBH was applied in combination with induced hyperglycemia (blood glucose level, > 400 mg/dL) by the infusion of approximately 5 g/kg body weight glucose, hyperoxemia (Pa[O.sub.2], >250 mm Hg) by ventilation with an inspiratory fraction of oxygen of 0.5, and disease-specific chemotherapy. (6) During the treatment, patients were intubated and mechanically ventilated in a volume-controlled mode under total IV anesthesia.

Study Algorithm

In all of the study patients, hemodynamic management was established based on a standardized algorithm (Fig 1). Therapeutic goals for patients in both groups consisted of a CI of > 3.5 L/min/[m.sup.2], a MAP of > 55 mm Hg, and a defined preload level determined according to the study group. Basically, the patients received 1.5 mL/kg/h crystalloids (Jonosteril; Fresenius Medical Care; Bad Homburg, Germany). Hyperglycemia was achieved by the infusion of glucose 50% (Glucosteril 50%; Fresenius Medical Care). To preserve the hemoglobin levels, > 9 g/dL packed RBCs were administered.

[FIGURE 1 OMITTED]

If CI and MAP were not attained, the first volume was replaced up to a defined preload level. For that, colloids were administered up to a colloid-osmotic pressure of 18 mm Hg (Hes 6%; Fresenius [maximum dose, 33 mL/kg/d]) followed by an infusion of crystalloids. A CI of < 3.5 L/min/[m.sup.2] was an indication for dobutamine, and if the MAP rose to < 55 mm Hg, norepinephrine was infused (Fig 1).

Study Groups and Monitoring

For group A, during 20 treatments, fluid management was guided by a pulmonary artery catheter for the measurement of PCWP, central venous pressure (CVP), and CI using the thermodye-dilution technique (Edwards Swan-Ganz-Catheter Model 744H [7.5F]; Baxter Healthcare Corporation; Irvine, CA). For the technique, the volume was replaced up to a PCWP of 8 to 12 mm Hg.

For group B, over a period of 10 months in 19 WBH treatments, we tested the application of ITBVI instead of PCWP as a surrogate parameter for cardiac preload; that is, a pulmonary artery catheter was not placed in these patients. The other target values regarding CI and MAP were not changed. In this group, we inserted a femoral artery catheter (Pulsiocath 4F, PV 2024L, COLD-Z021; Pulsion Medical Systems; Munich, Germany) using the transpulmonary thermo-dye-dilution technique to measure ITBVI and CI in combination with a central venous line for the measurement of CVP.

In all of the patients, the measurement of MAP was performed invasively in the radial artery (20-G Catheter; Leader Cath; Vygon, France), and the extravascular lung water index (EVLWI) was determined using a transpulmonary double-indicator dilution technique (Pulsiocath 4F, PV 2024L, COLD-Z021; Pulsion Medical Systems).

Measurement

PCWP, ITBVI, CI, MAP, CVP, and EVLWI, as well as levels of blood glucose, lactate, hemoglobin, and dosages of norepinephrine were measured at standardized temperatures during WBH (ie, body core temperature, 37, 40, 42, and 39[degrees]C). In addition, minute ventilation, respiratory rate, peak inspiratory pressure, and positive end-expiratory pressure were also measured at the same temperatures. Furthermore, the amount of crystalloids, colloids, glucose 50%, and packed RBCs, and the level of diuresis were measured cumulatively at the end of treatment. Laboratory tests included those for alanine amino-transferase, aspartate aminotransferase, bilirubin, alkaline phosphatase, [gamma]-glutamyltransferase, creatinine, and urea. Blood samples were drawn before and 24 h after the initiation of WBH.

Statistical Analysis

All of the data were processed using statistical software (SPSS, version 11.0; SPSS Inc; Chicago, IL). Results are presented as the mean [+ or -] SEM. The differences between the two treatment groups were tested for significance using the Mann-Whitney U test for quantitative ordinal parameters and the Fisher exact test for qualitative nominal parameters. Significance was assumed at a two-tailed p value of < 0.05. Spearman correlation coefficients between PCWP and CVP, as well as ITBVI and CVP, were calculated. The differences in CI were not analyzed because of the different measurement techniques used.

RESULTS

With regard to age, weight, height, and gender, there were no significant differences between both treatment groups (Table 1). In all of the patients, a CI of > 3.5 L/min/[m.sup.2] was observed at all of the temperature levels without any administration of dobutamine. A comparison of the treatment groups revealed no differences with regard to the infusion of colloids, glucose 50%, and packed RBCs (Table 2), as well as diuresis (group A, 3,143 [+ or -] 267 mL per treatment; group B, 2,533 [+ or -] 232 mL per treatment). In addition, the ventilation parameters showed no differences between the groups (Table 3).

Patients in group A required a significantly higher amount of crystalloids to maintain a PCWP of 8 to 12 mm Hg but obtained a significantly lower dosage of norepinephrine at 40, 42, and 39[degrees]C in comparison with the ITBVI-guided group (Tables 2, 3). CVP was significantly higher in group Bat 40 and 42[degrees]C (Table 3). In addition, we found a correlation coefficient between CVP and PCWP of 0.67 in group A, as well as a correlation coefficient between CVP and ITBVI of 0.52 in group B. Moreover, we found that CI, EVLWI, and the serum level of lactate increased during the course of WBH treatment, but these alterations were not significantly different between the treatment groups (Table 3).

With regard to pretreatment and posttreatment laboratory parameters, no significant differences between the groups could be observed, except for creatinine level (Table 4). Therefore, creatinine, urea, and bilirubin levels remained in the normal range. Slightly elevated pretreatment levels of alkaline phosphatase and [gamma]-glutamyltransferase decreased, and alanine aminotransferase and aspartate aminotransferase levels increased slightly on the first day after WBH in comparison with pretreatment levels.

After the completion of treatment, all of the patients were extubated and transferred to an intermediate tare unit. With the above-mentioned protocol, all of the treatments could be performed without clinical problems. In addition, there was no need for circulatory support during the early postinterventional phase; that is, the administration of catecholamines or volume replacement was not necessary.

DISCUSSION

This study was performed to compare two different methods of monitoring cardiac preload and to investigate their usefulness for the guidance of volume replacement in extreme WBH. We hypothesized that PGWP and ITBVI for the estimation of cardiac preload are equivalent under these hypercirculatory conditions. Our results show that preload monitoring by PCWP, representing the cardiac filling pressure, resulted in a significantly higher number of infusions in comparison with the ITBVI, which is a reliable indicator for volume status. Correspondingly, the dosages of vasoconstrictors required to restore a sufficient mean arterial pressure were higher in the ITBVI-guided group. Despite these differences, both techniques, PCWP and ITBVI measurement, were effective in achieving the predefined therapeutic goals with regard to CI and MAP.

In interpreting our results, it has to be considered that all of the patients treated in this protocol were able to increase their cardiac output to excessively high levels without any necessity for the administration of inotropic agents because of their healthy cardiopulmonary state. These observations clarified the idea that a reduced cardiac function represents a major exclusion criterion for this kind of treatment. (1) The clinical situation during WBH regarding MAP, CI, and the necessity of vasoconstrictor administration, however, may raise suggestions to patients experiencing septic shock, which is accompanied by multiple organ dysfunctions. (14) Indeed, in therapeutic hyperthermia, organ dysfunctions have been reported. (7) Organ dysfunctions may develop first because of neutropenic sepsis in patients who have been treated with dose-intensive chemotherapy or partly because of a redistribution of blood flow (eg, from the splanchnic region to the cutaneous system). (1,15) In this context, it has to be pointed out that suitable anesthesiologic monitoring including the measurement of systemic and pulmonary hemodynamics may help to prevent significant organ dysfunctions during or immediately after treatment with WBH. (3)

Lactate levels, which are usually used in detecting metabolic disorders, were significantly increased in our patients in comparison with initial values, but this parameter might not be assumed to be reliable for the reflection of circulatory shock or hypoxemia under conditions of induced hyperglycemia. (16,17) Instead, it reflects the successful acidification of tissues by hyperglycemia that is part of the concept to sensitize cancer cells to chemotherapeutic agents. (18) Measurements of all of the laboratory parameters for the identification of organ dysfunctions showed slight differences between pretreatment and post-treatment levels, but this is considered to be clinically irrelevant. Except for creatinine, there were no statistically significant differences between the treatment groups. Only serum creatinine levels were statistically different between groups, but all of the values stayed within the normal range and had no effect on the clinical need for additional treatments.

We measured EVLWI as an excellent clinical tool to detect developing pulmonary edema and to assess pulmonary function. (19) Despite the administration of high amounts of infusions and a significant increase of EVLWI in the course of WBH treatment in both groups, EVLWI values did not differ between the groups, and all of the patients could be extubated at the end of treatment.

Despite the existence of randomized controlled trials demonstrating the low benefit and even harm caused by the use of a pulmonary artery catheter in critically ill patients, (10,11) we applied this device in this special setting in which we expected a hyperdynamic circulation that is mostly unknown in details. Furthermore, the hemodynamic data that were available during WBH mostly referred to previous studies (2) in which nonradiative heating procedures were applied. In the literature, there is a lack of investigations regarding volume therapy or comparisons of different techniques for monitoring cardiac preload during WBH. In critically ill patients, volume parameters such as ITBVI have been demonstrated in numerous studies (9,20) as reliable parameters of intravascular volume status and cardiac preload in comparison with PCWP or CVP. Therefore, variables such as ITBVI have been shown to guide volume expansion more efficiently than cardiac filling pressures. (21) To our knowledge, no data for ITBVI in patients with induced extreme WBH are available yet.

In this study, fluid management by ITBVI led to significantly higher doses of norepinephrine assuming an intravascular volume deficit and favoring the application of supranormal values of ITBVI, as has been reported in patients with septic shock. (9,22) In additional studies, the effects of different supranormal ITBVI values on hemodynamics and clinical outcome parameters should be investigated in patients undergoing WBH. Nevertheless, a sufficient knowledge of hemodynamics is of major importance in patients who are being treated with extreme WBH, independent of the type of monitoring performed. Furthermore, in our study PCWP, as well as ITBVI, showed a moderate correlation with the CVP in the course of WBH treatment, and, therefore, volume management in healthy cardiac patients may even be performed by monitoring CVP as an objective of additional studies.

As one possible limitation of our study, it might be argued that no randomization was performed. Because our study was part of a phase I/II trial to investigate the feasibility and toxicity of treatment with WBH applied by a certain radiant heat device (Iratherm 2000; von Ardenne Institut), limited knowledge about systemic and pulmonary hemodynamics under these specific conditions led to the use of a pulmonary artery catheter in the initial phase of our phase I/II study. (3,13) Although during the past 5 years knowledge of the treatment of cancer patients with radiant-heat WBH has markedly increased because of the completion of phase II studies, WBH remains a challenge for intensivists and anesthesiologists as the first multicentric phase III trials have been initiated.

In conclusion, our data demonstrate that during WBH in healthy cardiac patients, PCWP and ITBVI are suitable parameters for fluid management. Monitoring preload during WBH with a pulmonary artery catheter is not routinely required, and supranormal levels of ITBVI are required to maintain intravascular volume status.

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* From the Departments of Anesthesiology and Critical Care Medicine (Drs. Deja, Ahlers, and Kerner) and Radiology (Dr. Wust), Medical Clinic for Hematology and Oncology (Drs. Hildebrandt and Riess), Charite Medical Center, Campus Virchow-Clinic, Humboldt-University, Berlin, Germany; and the Department of Anesthesiology Critical Care Medicine and Pain Management (Dr. Gerlach), Vivantes-Klinikum Neukolln, Berlin, Germany.

This study was supported by Deutsche Krebshilfe, Deutsche Forschungsgemeinschaft (SFB 273, Grako 331).

Manuscript received November 22, 2004; revision accepted January 25, 2005.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).

Correspondence to: Maria Deja, MD, Department of Anesthesiology and Critical Care Medicine, Charite Medical Center, Campus Virchow-Clinic, Augustenburger Platz 1, 13353 Berlin, Germany; e-mail: maria.deja@charite.ae

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