Olaf Ahlers

The cellular and molecular basis of hyperthermia

In oncology, the term hyperthermia refers to the treatment of malignant diseases by administering heat in various ways. Hyperthermia is usually applied as an adjunct to an already established treatment modality (especially radiotherapy and chemotherapy), where tumor temperatures in the range of 40-43 degrees C are aspired. In several clinical phase-III trials, an improvement of both local control and survival rates have been demonstrated by adding local/regional hyperthermia to radiotherapy in patients with locally advanced or recurrent superficial and pelvic tumors. In addition, interstitial hyperthermia, hyperthermic chemoperfusion, and whole-body hyperthermia (WBH) are under clinical investigation, and some positive comparative trials have already been completed. In parallel to clinical research, several aspects of heat action have been examined in numerous pre-clinical studies since the 1970s. However, an unequivocal identification of the mechanisms leading to favorable clinical results of hyperthermia have not yet been identified for various reasons. This manuscript deals with discussions concerning the direct cytotoxic effect of heat, heat-induced alterations of the tumor microenvironment, synergism of heat in conjunction with radiation and drugs, as well as, the presumed cellular effects of hyperthermia including the expression of heat-shock proteins (HSP), induction and regulation of apoptosis, signal transduction, and modulation of drug resistance by hyperthermia.

DCL-Hb for trauma patients with severe hemorrhagic shock: the European "On-Scene" Multicenter Study

ObjectiveA major cause of death in patients with severe hemorrhagic shock following trauma is the subsequent occurrence of multiple organ failure due to tissue hypoxia. Early administration of an oxygen carrier may reduce the occurrence of organ failures and improve survival. It may also reduce the need of blood products.Design and settingProspective multicenter study in a university clinic.Patients121 patients with severe hemorrhagic shock.InterventionsPatients were randomly assigned on-scene to receive either up to 1000xa0ml of a 10% diaspirin cross-linked hemoglobin (DCLHb) solution or the study centers standard therapy.Measurements and resultsDemographic and physiological characteristics of the two treatment groups at baseline were comparable. Organ failures and survival rates until day 5 and day 28 showed no significant differences. The sponsor therefore terminated this trial prematurely after an interim evaluation of the data indicated no evidence of efficacy to offset concerns raised about the safety of DCLHb. Median volumes of cumulative blood products administered on 1 (1595 vs. 3716xa0ml) and 7xa0days (3139 vs. 4746xa0ml) after admission were lower in the DCLHb group.ConclusionsThe early application of an oxygen carrier (DCLHb) to patients with severe hemorrhagic shock following trauma had no significant effect on the occurrence of organ failure or on 5- and 28-day survival in this abbreviated trial. However, early infusion of up to 1000xa0ml DCLHb reduces the need for blood products without changing morbidity or survival.

Impact of bolus application of low-dose hydrocortisone on glycemic control in septic shock patients.

ObjectiveTo determine whether glycemic control is less feasible when hydrocortisone is given as axa0bolus compared with continuous application in septic shock patients.DesignObservational prospective pilot study.SettingFourteen-bed surgical university hospital ICU.PatientsSixteen consecutive patients with septic shock receiving axa0continuous infusion of 200u202fmg hydrocortisone/day and an infusion regime of insulin keeping blood glucose below 150u202fmg/dl.InterventionBlood glucose and insulin infusion were adjusted to steady state before intervention. At baseline, the continuous hydrocortisone infusion was replaced with axa0single bolus of 50u202fmg hydrocortisone. During axa0subsequent 6-h period, blood glucose was monitored hourly and insulin infusion was kept constant. Afterwards, hydrocortisone application and adjustment of blood glucose was resumed according to standard treatment.ResultsMean blood glucose in steady state at baseline immediately prior to intervention was 128u202fmg/dl (range 114–141u202fmg/dl; 95% confidence interval). After bolus injection of hydrocortisone, blood glucose increased significantly within 6u202fh with peak levels of 154u202fmg/dl (range 132–178u202fmg/dl; pu202f<u202f0.01). Blood glucose returned to baseline with restoration of continuous hydrocortisone infusion. There were marked inter-individual variations with peak glucose values up to 254u202fmg/dl, but no significant difference in intra-individual glucose variability before and after bolus injection of hydrocortisone.ConclusionsBolus injections of hydrocortisone may induce significant increases of blood glucose in patients with septic shock. The individual response is highly variable and we speculate that repetitive boluses would induce marked undulation of blood glucose. In terms of glycemic-control strategies, axa0continuous infusion of hydrocortisone seems to be preferable.

Whole body hyperthermia: a secure procedure for patients with various malignancies?

Objective: To establish the safety of systemic Cancer Multistep Therapy (sCMT) including whole body hyperthermia, by means of hemodynamic, laboratory and clinical investigations. Design: Prospective study. Setting: University clinic. Patients: 12 patients with various cancers (with sCMT), a second group of 20 patients with colorectal carcinoma treated with chemotherapy (without sCMT). Interventions: 25 treatments with sCMT for 60 min at 41.8 °C (including chemotherapy) were given in addition to induced hyperoxemia and hyperglycemia under general anesthesia. Measurements and results: Invasive monitoring of systemic and pulmonary hemodynamics as well as pulmonary gas exchange was used at 37 °C, 40 °C, 41.8 °C and 39 °C. In addition, laboratory parameters were measured before and within 4 days of therapy. At 41.8 °C, invasive monitoring showed characteristic signs of hyperdynamic circulation. In addition, right-to-left shunt, oxygen consumption, oxygen delivery and lactate levels were significantly different from pretreatment values. At the end of therapy, lactate levels and the extravascular lung water index increased, whereas all other parameters showed a clear tendency to return to initial values. Within the first day after sCMT, we measured a slight but significant reversible increase in serum creatinine compared to pretreatment values, but found no significant alterations of other chemical parameters. Between the sCMT group and controls, there was only a temporary significant difference in aspartate aminotransferase levels 2 days after therapy. Conclusions: sCMT, including whole body hyperthermia, accompanied by suitable anesthesiological management and monitoring, does not lead to any serious or sustained organ dysfunction and can therefore be regarded as a safe therapy.

Anaesthesiological experiences with whole body hyperthermia

Objective : In order to investigate the safety of whole body hyperthermia (WBH) within the context of systemic Cancer Multistep Therapy (sCMT) in patients with disseminated malignancies, cardiopulmonary changes and various organ functions were examined. Methods and procedures : Fifty-seven sCMT treatments were performed in 22 patients. WBH with a plateau phase of 1 h at 41.8°C was induced by an IRATHERM 2000 device. Cardiopulmonary parameters were measured at 37, 40, 41.8 and 39°C by use of a pulmonary artery catheter, femoral oxymetry and a radial artery catheter. Organ functions of the liver, kidney, cardiovascular and central nervous system were evaluated before and after treatment. Results : Compared with the initial values, significant alterations were found of most cardiopulmonary parameters in the sense of hypercirculation at 41.8°C. With the exception of extra vascular lung water index, all parameters showed a clear tendency towards the pre-treatment levels at 39°C. In eight out of 57 sCMT treatments, reversible organ dysfunctions were observed. Comparison of radial and femoral arterial blood pressure showed significantly different values at 40 and 41.8°C. Conclusions : WBH induces cardiovascular stress, but by careful selection of patients and appropriate anaesthesiological monitoring it can be performed safely using general anaesthesia. This enables further evaluation of WBH in multimodal treatment concepts.

Whole body hyperthermia induces apoptosis in subpopulations of blood lymphocytes

Whole Body Hyperthermia (WBH) has been shown to induce alterations of lymphocyte subpopulations in peripheral blood: T-cells decrease and NK-cells increase in number in the course of this therapy. As elevated temperature induces programmed cell death in healthy lymphocytes in vitro, we intended to determine the role of lymphocyte apoptosis in WBH by measuring the rate of apoptosis in blood lymphocytes in the course of this treatment. Blood was taken from cancer patients, treated with whole body hyperthermia and chemotherapy, before, during and the day after treatment. Apoptosis rates of the whole lymphocyte population, as well as, of B-, T-, CD4 + -T-, CD8 + -T-, and Natural-Killer (NK)-cell-subpopulations were determined by staining with AnnexinV-FITC and FACS flow analysis. A significant rise of apoptosis in the whole lymphocyte population, in CD4 + -T- and in CD8 + -T-cells occurred during treatment. In contrast, an elevated rate of apoptosis in NK-cells was observed 20 hours after termination of WBH. These differences were similar when the cells were incubated at 37 degrees C for 24 hours. Our results suggest, that apoptosis is one reason for the previously described decrease of T-cells during WBH and of NK-cells after WBH, and that the hyperthermia-related apoptosis-inducing mechanism is different in T-cells and NK-cells.

Intraoperative fresh-frozen plasma versus human albumin in craniofacial surgery − A pilot study comparing coagulation profiles in infants younger than 12 months

The transfusion of fresh-frozen plasma (FFP) is suggested to minimize dilution coagulopathy when applied instead of colloids during paediatric craniofacial surgery (pCFS). We prospectively compared plasmatic haemostaseologic function between volume replacement with FFPs versus human albumin (HA) in a pilot study. Thirty infants with primary craniosynostosis were scheduled for pCFS. In 15 of those, FFPs were available from the identical donor as for packed red blood cells (pRBC), and were thus employed for intraoperative volume replacement. The remaining 15 infants were infused with HA-5% instead. Haemoglobin(Hb)-values, global coagulation parameters (activated partial thromboplastin time-aPTT; prothrombin time-PT), selected clotting factors (F) (VIII, XI, XIII), antithrombin-AT, fibrinolytic factors (fibrinogen; plasminogen; alpha2-antiplasmin-alpha2A), and activation parameters (thrombin-antithrombin-complex-TAT; plasmin-antiplasmin-complex-PAP; D-dimers) were assessed and compared between both groups after induction of anaesthesia, before transfusion of pRBC, and at the end of surgery. Patients and treatment characteristics were balanced between both groups. Prolongation of aPTT and decreases of PT, FXI, FXIII, AT3, and fibrinolytic factors were more pronounced in the HA-group. Increases in F VIII activity, activation parameters, and the course of Hb-values were similar among both groups. There was no difference regarding clinical endpoints (peri-/postoperative pRBC-transfusions, postoperative blood loss). In conclusion, the application of HA was associated with a more distinct dilution of procoagulant factors, AT3, and fibrinolytic factors than the use of FFPs. However, the course of activation markers suggested a similar extent of clotting and fibrinolytic activation with the use of both transfusion regimens, and there were no differences with regard to clinical endpoints.

Der Tauchunfall – Präklinische und klinische Behandlungsstrategien

The diving accident is a rare incident for an emergency physician which requires special physical and patho-physiological knowledge. With increasing recreational activities and the fascination of diving also for older persons diving accidents are expected to occur more often. There can be several reasons for diving accidents such as the ignorance of the physics of diving, a trauma under water as well as internistical illnesses like heart attach, stroke or hypoglycaemia. The therapy of the underlying illness should not be left aside while dealing with the patient. The careful rescue and the immobilisation are most important for the initial therapy. The patient should receive oxygen, if possible via a demand valve, until a hyperbaric chamber is reached. There is no specific medical therapy for decompression illness. It is very important that a pre-information is sent to the closest hyperbaric chamber as soon as possible since often the chamber needs some time to be properly prepared for usage. In order to receive information regarding the depth where the diving incident occured, the duration of the diving trip and the decompression stops, it is important to secure the diving computer of the victim for the hyperbaric chamber. Also outside diving, decompression illness can occur, for example working in a tunnel under hyperbaric conditions. These accidents have to be treated according to the same guidelines.