Drop In Core Temperature Research Articles

The thermal benefit of prewarming in children

Background: It has been suggested that warming patients before induction of anaesthesia (prewarming) reduces the drop in core temperature (Tcore) normally associated with the induction of anaesthesia [1]. It may also reduce the incidence of surgical wound infection [2, 3]. Neither the ideal ambient temperature (Tambient), nor the duration necessary to achieve these aims, is established for adults or children. Since drops in Tcore can take some time to reverse with intra‐operative heating [4], there may be benefit in starting off at a higher Tcore. We therefore conducted a prospective randomized clinical study to assess the impact of prewarming on Tcore behaviour after induction of anaesthesia in children.Aims: We aimed to quantify the impact of prewarming vs standard ambient temperature on core temperature behaviour after induction of anaesthesia in children.Methods: Prospective clinical study with randomization to either 26°C or 21°C ambient temperature. Well children scheduled for elective surgery where presurgical anaesthetic duration exceeded 20 mins. Continuous oesophageal temperature monitoring until operative procedure commenced.Results: There were 30 children in each group. Those in the prewarmed group had significantly higher initial Tcore, a reduced drop in their Tcore and a longer time to reach the same fall in Tcore.Conclusions: The demonstrated differences are considered clinically insignificant. When the surgical procedure is short or when convective heating is available and will last for at least 45 mins, there is no clinically important ‘thermal advantage’ in prewarming. This is independent of age, weight, height and body surface area.References1 Sessler DI, McGuire J, Moayeri A, Hynson JM. Isoflurane‐induced vasodilation minimally increases cutaneous heat loss. Anesthesiology 1991; 74: 226–232.2 Melling AC, Baqar A, Scott EM, Leaper DJ. Effects of preoperative warming on the incidence of wound infection after clean surgery: a randomized controlled trial The Lancet 2001; 358(15): 876–880.3 Kurz A, Sessler DI, Lenhardt R. Perioperative normothermia to reduce the incidence of surgical‐wound infection and shorten hospitalization. New Engl J Med 1996; 334: 1209–1215.4 Cassey J, Armstrong P, Smith GE, Farrell PT. The safety and effectiveness of a modified convection heating system for children during anesthesia. Pediatr Anesth 2006; 16: 654–662.

Understanding post-operative temperature drop in cardiac surgery: a mathematical model

A mathematical model is presented to understand heat transfer processes during the cooling and re-warming of patients during cardiac surgery. Our compartmental model is able to account for many of the qualitative features observed in the cooling of various regions of the body including the central core containing the majority of organs, the rectal region containing the intestines and the outer peripheral region of skin and muscle. In particular, we focus on the issue of afterdrop: a drop in core temperature following patient re-warming, which can lead to serious post-operative complications. Model results for a typical cooling and re-warming procedure during surgery are in qualitative agreement with experimental data in producing the afterdrop effect and the observed dynamical variation in temperature between the core, rectal and peripheral regions. The influence of heat transfer processes and the volume of each compartmental region on the afterdrop effect is discussed. We find that excess fat on the peripheral and rectal regions leads to an increase in the afterdrop effect. Our model predicts that, by allowing constant re-warming after the core temperature has been raised, the afterdrop effect will be reduced.

Circadian rhythm of wrist temperature in normal-living subjects: A candidate of new index of the circadian system

Most circadian rhythms are under the control of a major pacemaker located in the hypothalamic suprachiasmatic nucleus. Some of these rhythms, called marker rhythms, serve to characterize the timing of the internal temporal order. A marker rhythm, (e.g., one used in chronotherapy) has to be periodic and easy to measure over long periods using non-invasive methods. The most frequent reference variables for human chronotherapy include salivary melatonin or cortisol, urinary 6-sulfatoximelatonin, actimetry and core body temperature (CBT). Recent evidence suggests that sleepiness may be more closely linked to increased peripheral skin temperature than to a core temperature drop, and that distal skin temperature seems to be correlated and phase-advanced with respect to CBT, suggesting that heat loss from the extremities may drive the circadian CBT rhythm. The aim of the present study was to evaluate whether the wrist skin temperature rhythm could be used as a possible index of the human circadian system. To this end, wrist skin temperature (WT1), as determined by a wireless data logger in healthy normal living subjects, was correlated with sleep-wake diaries and oral temperature (OT) recordings. WT and sleep habits were studied in 99 university students. Each subject wore a wireless iButton sensor attached to the inner side of a sport wristband. Our results show that the WT rhythm exhibits an inverse phase relationship with OT, and it is phase-advanced by 60 min with respect to OT. WT started to increase in association to bed time and dropped sharply after awakening. A secondary WT increase, independent of feeding, was observed in the early afternoon. In conclusion, WT wireless recording can be considered a reliable procedure to evaluate circadian rhythmicity, and an index to establish and follow the effects of chronotherapy in normal living subjects.

Full recovery of an avalanche victim with profound hypothermia and prolonged cardiac arrest treated by extracorporeal re-warming

Survival of hypothermic avalanche victims with cardiac arrest is rare. This report describes full recovery of a 29-year-old backcountry skier completely buried for 100 min at 3.0m (9.8 ft) depth. On extrication he was unconscious, but breathing spontaneously into an air pocket; core body temperature measured 22.0 degrees C (71.6 degrees F). He was intubated and ventilated on site. Ventricular fibrillation commenced during helicopter transportation, whereby chest compression was lacking for 15 min. At the nearest hospital continuous cardiopulmonary resuscitation was initiated, but defibrillation failed. Tympanic core body temperature measurement confirmed life-threatening hypothermia of 21.7 degrees C (71.1 degrees F) and serum K(+) was 4.3 mmol/l, necessitating transferral to a hospital with cardiopulmonary bypass facilities. Defibrillation finally succeeded following re-warming, by femoral veno-arterial bypass, to 34.5 degrees C (94.1 degrees F). Total duration of cardiac arrest was 150 min. The patient developed pulmonary oedema, treated by extracorporeal membrane oxygenation, but progressed well and was discharged from hospital on day 17, fit to resume professional and social activities. Follow-up cerebral magnetic resonance imaging 2 years after avalanche burial demonstrated only minimal changes attributable to unrelated, prior cranial trauma. Extensive neurological and psychological investigations gave excellent results. This report confirms previous literature that an air pocket with patent airways is essential for survival of a completely buried avalanche victim after 35 min and endorses the recommended management strategies of the International Commission for Mountain Emergency Medicine ICAR MEDCOM. In particular, all hypothermic victims extricated with an air pocket and free airways must be treated optimistically, even despite prolonged cardiac arrest. This remarkable case documents the fastest drop in core temperature ever recorded during snow burial, namely 9.0 degrees C (16.2 degrees F)/h, and the second-lowest reversible core temperature in avalanche literature.

A model to predict patient temperature during cardiac surgery

A core temperature drop after cardiac surgery slows down the patient's recuperation process. In order to minimize the amount of the so-called afterdrop, more knowledge is needed about the impaired thermoregulatory system during anesthesia and the effect of different protocols on temperature distribution. Therefore, a computer model has been developed that describes heat transfer during cardiac surgery. The model consists of three parts: (1) a passive part, which gives a simplified description of the human geometry and the passive heat transfer processes, (2) an active part that takes into account the thermoregulatory system as a function of the amount of anesthesia and (3) submodels, through which it is possible to adjust the boundary conditions. The validity of the new model was tested by comparing the model results to the measurement results of three surgical procedures. A good resemblance was found between simulation results and the experiments. Next, a model application was shown. A parameter study was performed to study the effect of different temperature protocols on afterdrop. It was shown that the effectiveness of forced-air heating is larger than the benefits resulting from increased environmental temperature or usage of a circulating water mattress. Ultimately, the model could be used to develop a monitoring decision system that advises clinicians what temperature protocol will be best for the patient.

The effect of irrigation fluid temperature on core body temperature in arthroscopic shoulder surgery

The purpose of this study was to investigate the relationship between irrigation fluid temperature and core body temperature in patients undergoing arthroscopic shoulder surgery. Twenty-four consecutive patients undergoing arthroscopic subacromial decompression were allocated to receive irrigation fluid at either room temperature (22 degrees C) or warmed to 36 degrees C. There were no statistically significant differences between the two groups in any of the preoperative parameters. Core temperature was monitored throughout surgery. The maximum drop in core temperature for each patient was calculated. The mean maximum drop in the room temperature group was 1.67 degrees C (95% CI 1.33-1.97) and 0.33 degrees C (95% CI 0.17-0.49) in the warmed fluid group (P < 0.001). Further to this the drop in core temperature in the room temperature group was maintained throughout surgery whereas normothermia resumed by 30 min in the warmed fluid group. We thus conclude that core temperature may be influenced by irrigation fluid temperature and recommend that fluid be warmed to 36 degrees C.

Seasonal acclimation in cardiac activity: Mammals vs. fish

The dominance of vagal tonus over cardiac sympathetic tone is accentuated on acute cold exposure of mammals to a core temperature of 25 °C, leading to a bradycardia appropriate for the reduction in metabolic rate. When investigated by Power Spectral Analysis, changes in heart rate variability (HRV) can be seen as a decrease in the ratio of low frequency to high frequency (LF:HF) power in rats. In hamsters this only occurs after a period of cold acclimation to an environmental temperature of 4 °C, whilst maintaining core temperature. Interestingly, despite ∼30% cardiac hypertrophy on chronic cold exposure, the power output of acclimated hamster hearts (either rate-pressure product, or dP/dt) is less than those from euthermic controls, although less temperature-sensitive. Acclimation of common carp to similar environmental temperatures leads to a commensurate drop in core temperature, with a similar degree of cardiac hypertrophy. In this case, heart rate varied directly with oxygen consumption, although HR decreased and HRV increased in a non-linear manner between 25 and 5 °C on chronic exposure. Interestingly, acute changes in temperature resulted in a decrease in vagal tone on warming, but no significant change on cooling. Pharmacological blockade shows both chronic and acute responses to be dominated by cholinergic influences, with little role for adrenergic control. Supported by NERC.

Meperidine and skin surface warming additively reduce the shivering threshold: a volunteer study

IntroductionMild therapeutic hypothermia has been shown to improve outcome for patients after cardiac arrest and may be beneficial for ischaemic stroke and myocardial ischaemia patients. However, in the awake patient, even a small decrease of core temperature provokes vigorous autonomic reactions–vasoconstriction and shivering–which both inhibit efficient core cooling. Meperidine and skin warming each linearly lower vasoconstriction and shivering thresholds. We tested whether a combination of skin warming and a medium dose of meperidine additively would reduce the shivering threshold to below 34°C without producing significant sedation or respiratory depression.MethodsEight healthy volunteers participated on four study days: (1) control, (2) skin warming (with forced air and warming mattress), (3) meperidine (target plasma level: 0.9 μg/ml), and (4) skin warming plus meperidine (target plasma level: 0.9 μg/ml). Volunteers were cooled with 4°C cold Ringer lactate infused over a central venous catheter (rate ≈ 2.4°C/hour core temperature drop). Shivering threshold was identified by an increase of oxygen consumption (+20% of baseline). Sedation was assessed with the Observer's Assessment of Alertness/Sedation scale.ResultsControl shivering threshold was 35.5°C ± 0.2°C. Skin warming reduced the shivering threshold to 34.9°C ± 0.5°C (p = 0.01). Meperidine reduced the shivering threshold to 34.2°C ± 0.3°C (p < 0.01). The combination of meperidine and skin warming reduced the shivering threshold to 33.8°C ± 0.2°C (p < 0.01). There were no synergistic or antagonistic effects of meperidine and skin warming (p = 0.59). Only very mild sedation occurred on meperidine days.ConclusionA combination of meperidine and skin surface warming reduced the shivering threshold to 33.8°C ± 0.2°C via an additive interaction and produced only very mild sedation and no respiratory toxicity.

The Pre-Optic Anterior Hypothalamus (POAH) partially mediates the hypothermic response to hemorrhage in rats

Two sets of experiments were performed to characterize the role of the Pre-Optic Area of the Anterior Hypothalamus (POAH) in the decrease in set point and hypothermia that follows severe hemorrhage. In the first set, lidocaine or artificial cerebrospinal fluid (ACSF) was microinjected into the POAH of rats at the time of hemorrhage. Lidocaine microinjection attenuated the hemorrhagic hypothermia by approximately 50%. The mean drop in core temperature (Tc) following hemorrhage was 1.5 °C with ACSF microinjection ( N = 6), 0.70 °C ( N = 6) with lidocaine, and 1.77 °C ( N = 6) after sham microinjection. This partial attenuation of the hemorrhagic hypothermic response indicates that an intact POAH is necessary for at least some of the hypothermia following hemorrhage. In the second experimental set, hypothalamic tissue temperature (Thyp) was modulated in an attempt to alter the hemorrhagic hypothermic response. Bilateral closed-ended cannulas were inserted into the POAH. One cannula consisted of a water-perfused thermode to change local tissue temperature. The other housed a thermocouple to measure local temperature. The effectiveness of the thermode was first confirmed in conscious rats, evidenced by an inverse deflection in Tc upon Thyp modulation. Then, the POAH region was either heated, cooled, or sham perfused following hemorrhage. The mean drop in Tc following hemorrhage was 2.16 °C ( N = 5) with hypothalamic heating, 1.35 °C ( N = 5) with cooling, and 1.44 °C ( N = 5) following the sham perfusion control. Heating of the POAH significantly exacerbated the hemorrhagic hypothermic response. These data further suggest that the POAH is at least partially responsible for mediating hemorrhagic hypothermia.

Hypothermia in mice tested in Morris water maze

The Morris water maze, one of the most common behavioral tasks to assess learning and memory in rodents, exposes the animals to cold water for a few minutes. Unlike rats, young healthy mice can become severely hypothermic during the task. Five swims of 45 s in 20 °C water with 30 s between the trials was enough to cause up to 9 °C drop in the rectal temperature. The decline in core temperature was accompanied by slowing of the swimming speed. Moreover, the effect was dependent on the sex and genotype of the mice, such that females were more susceptible to hypothermia than males and transgenic mice carrying Alzheimer-associated APP and PS1 mutations more vulnerable than their nontransgenic littermates. Raising the water temperature from 20 to 24 °C alleviated the hypothermia, but did not remove the significant drop in core temperature when using 30-s inter-trial interval. However, increasing the break from 30 s to 13 min removed the net cooling effect of five trials on the core temperature and swimming speed. We conclude that the currently most common water maze protocol renders mice hypothermic, which may confound the test results, especially when transgenic female mice are used. We recommend monitoring of the swimming speed on a trial-by-trial basis and using longer inter-trial intervals.

A new method of continuous venovenous rewarming

Purpose Hypothermia is a significant problem in medicine and is part of a deadly triad, including hypothermia, acidosis, and coagulopathy. Multiple methods of rewarming are used to treat moderate hypothermia. The purpose of this study was to compare the effectiveness of continuous venovenous rewarming (CVVR) using the FMS 2000 (Belmont Instrument Corp., Billerica, Massachusetts) in conjunction with external rewarming techniques versus external rewarming alone in the porcine model. Methods Ten subject animals, each weighing approximately 40 kg, were evenly divided and randomly assigned to either a control group using external rewarming techniques alone or the CVVR group utilizing the FMS 2000 in addition to the external rewarming techniques used in the control group. Hypothermia was induced in the swine model using cold water immersion to achieve a core temperature of 30°C. Both esophageal and rectal temperature probes were used to monitor and record core body temperatures every 15 minutes during the experiment. Each study animal was then rewarmed until a core temperature of at least 37°C was recorded in both the esophageal and rectal probes. The animals were observed clinically for 3 days after the study. Results The average time required to rewarm the control group was 253 minutes, compared with 113 minutes in the CVVR group. After 30 minutes of rewarming, the difference between the 2 groups with respect to core temperature was statistically significant (p = 0.002). A drop in core temperature after the initiation of rewarming, or after-drop, was noted in the control group animals, but not in the CVVR group. This difference was statistically significant after 15 minutes of rewarming (p = 0.015) Conclusions Venovenous rewarming utilizing the FMS 2000 fluid management system is more effective than is standard therapy alone for rewarming in the moderately hypothermic porcine model. This finding may prove clinically useful in the treatment of patients suffering from moderate hypothermia.

Part 8: Advanced Challenges in Resuscitation

Part 8: Advanced Challenges in Resuscitation

Factors limiting cold-water swimming distance while wearing personal floatation devices.

The influence of body adiposity, arm skinfold thickness, aerobic capacity, and cooling rate were studied in a mock survival swimming situation conducted in water at around 14 degrees C. Seventeen adult participants wore personal floatation devices on top of seasonal clothing and were asked to swim as far as they could, as if attempting to reach shore following an accidental immersion in cold water. Triceps and patellar skinfold thickness showed a significant correlation with distance covered (r = 0.70 and 0.56, respectively), while abdominal skinfold and percent body fat showed no significant correlation. Maximum oxygen consumption (VO2max) was not significantly related to distance covered. There was a negative correlation between body cooling rate during the swimming period and distance covered. A multiple stepwise regression analysis, however, indicated that the only significant contributor to variance in the distance covered was the triceps skinfold thickness (r2 = 0.49). It was concluded that for a healthy subject accidentally immersed in cold water, triceps skinfold thickness is a stronger predictor of the swimming distance covered than body adiposity, VO2max, or the drop in core temperature.

Reduced oxygen consumption precedes the drop in body core temperature caused by hemorrhage in rats.

This study examines the early time course in core temperature change and oxygen consumption at 4 levels of hemorrhage. Chronically instrumented rats were acclimatized to a respirometry chamber for 30 min. The rats were briefly (10 min) removed from the chamber for a fixed volume hemorrhage of 0 mL/kg (sham), 8 mL/kg, 16 mL/kg, 24 mL/kg, or 32 mL/kg. Rats were then returned to the chamber, and oxygen consumption and body core temperature were monitored for the next 2 h. Oxygen consumption (control 1.26 mL O2/g/h) fell significantly 5 min after hemorrhage in all but the sham and 8 mL/kg hemorrhage groups, with the decrease proportional to the hemorrhage volume. The 32 mL/kg hemorrhage group showed the greatest decrease, to 0.47 mL O2/g/h. Body core temperature (control 37.5 degrees C) fell more gradually, declining to 35.6 degrees C 110 min after the 24 mL/kg hemorrhage, and to 33.2 degrees C at 6 h after the 32 mL/kg hemorrhage. In the 16 mL/kg hemorrhage group, oxygen consumption fell significantly by 5 min after hemorrhage, but a drop in body temperature was not seen until 25 min after hemorrhage. The data from this study indicate that the drop in core temperature does not cause the observed decrease in oxygen consumption. In fact, the timing and magnitude of the drop in oxygen consumption indicate that the reduced metabolic rate may mediate the hemorrhage-induced drop in body core temperature in conscious rats.

Controversies of Labor Epidural Analgesia

Controversies of Labor Epidural Analgesia

The role of irrigation in the development of hypothermia during laparoscopic surgery

OBJECTIVES: Our purpose was to determine the incidence and etiology of hypothermia during laparoscopic surgery and to evaluate the role of irrigation fluid temperature. STUDY DESIGN: A prospective randomized study was performed of 35 women undergoing operative laparoscopy under general anesthesia who received surgical irrigation fluid either at ambient temperature or warmed to 39° C. The core body temperature was determined with use of both an esophageal sensor and a tympanic membrane sensor and was expressed as the change from baseline. Additional data collected included age, height, weight, amount of irrigation fluid and intravenous fluid used, room temperature, length of anesthesia, and amount of carbon dioxide used for pneumoperitoneum. RESULTS: Hypothermia occurred in 94% of all patients, with no difference in incidence between the groups. The minimal core temperature was lower in the ambient temperature group (−1.7° ± 0.2° C) than in the warmed fluid group (−1.0° ± 0.2° C). Of the variables measured, length of anesthesia and the amount of ambient temperature fluid alone explained the drop in core temperature. CONCLUSION: Hypothermia is extremely common in laparoscopic surgery and is related to the length of anesthesia and the use of ambient temperature irrigation fluid. The use of warmed irrigation fluid can decrease, but not eliminate, this drop in core temperature.(Am J Obstet Gynecol 1997;176:598-602.

Controlled Composting of Paper Pulp Sludge Using the Aerated Static Pile Method

The UK paper industry is searching for alternatives to landfilling for the 700,000 tonnes of sludge that is produced every year. This project examines the feasibility of composting paper pulp sludge using the, relatively low cost, aerated static pile method. Recycled paper sludge from the de-inking plants and primary and secondary sludge from the wastewater treatment, mixed with chicken manure and green waste at an 8:2:1 volume ratio, were composted in two 2.2m × 1.5m × 5m piles. The raw material had low heavy metal contamination, meeting European requirements for sludge application to land. The characteristic temperature profile of the ASP using temperature feedback control was observed, with a core temperature drop by day 12. Changes in the compost chemical characteristics and its stability, as assessed by respiration, indicated that the aeration period did not need to extend over two weeks. During this period more than 30 percent of the initial volatile solids content was decomposed, and the respiration rate dropped by more than 80 percent, to 0.8 mg O2/g VS/hr. However, phytotoxicity, as assessed by cress germination, may take some what longer to disappear and subsequent storage of the material without aeration could improve its quality. This suggests a composting strategy of a two weeks aeration phase, and a further four to five weeks maturation.

Infradian alteration of circadian rhythms in owl monkeys ( Aotus lemurinus griseimembra): An effect of estrous?

Long-term recordings of locomotor activity, feeding activity and core temperature carried out in 7 male and 7 female adult owl monkeys ( Aotus lemurinus griseimembra) revealed sex-specific infradian alterations in the level of these circadian functions when the monkeys were housed under lighting conditions which neither inhibited nor enhanced (i.e., “masked,”) their circadian activity rhythms. Such nonmasking lighting conditions were: constant dim light (LL) at 0.1–0.5 Ix, photoperiods consisting of 0.5 h light (L) at 80 lx and 23.5 h darkness (D) at 0.5 lx, and skeleton photoperiods consisting of two 80-lux light pulses of 0.5 h applied at intervals of 12:12 h and 9:15 h, respectively. In 5 of the female and none of the male owl monkeys, the amount of locomotor activity per day or per circadian cycle, increased at an average interval of 14.0 ± 2.3 days to 198.4 ± 48.2%, while the feeding activity was concomitantly reduced to 53.7 ± 11.2%, and the core temperature level dropped by 0.3 ± 0.1°C, as compared to the respective preceding level of these parameters. The period of this infradian periodicity superimposed on the circadian rhythms corresponds approximately to the ovarian cycle length of Aotus (6,7). As food deprivation for one day resulted in a statistically significant increase in locomotor activity and a decrease in core temperature, the infradian (ovarian cyclic) drop in core temperature is probably the result of reduced food intake. The infradian rise in activity and the decrease in food intake might be an effect of the ovarian cyclic variation in estrogen level.

Effects of age and gender on brown fat and skeletal muscle metabolic responses to cold in F344 rats.

Older male Fischer 344 (F344) rats do not maintain core temperature as well as do older females during cold exposure. To elucidate factors contributing to the decreased thermoregulatory ability of older males, the metabolic potentials of interscapular brown adipose tissue (IBAT) and skeletal muscle were evaluated at rest (26 degrees C) and during 4 h of cold (6 degrees C) in male and female F344 rats, aged 6, 12, and 26 mo. Compared with 26-mo-old females, cold-exposed 26-mo-old males exhibited a greater drop in core temperature and lower amounts of IBAT mitochondrial uncoupling protein (UCP) and IBAT thyroxine 5'-deiodinase (T5'D) activity. Unlike females, 26-mo-old males showed no cold-induced increase in total IBAT UCP or T5'D activity. In contrast, plasma norepinephrine was higher in cold-exposed 26-mo-old males vs. females, whereas plasma insulin and thyroxine did not differ with gender. Skeletal muscle oxidative capacity (measured by citrate synthase activity) and carbohydrate availability (measured by muscle glycogen and plasma glucose levels) did not differ between the 26-mo-old males and females. Our data suggest that altered regulation of IBAT UCP levels during cold exposure of aged rats, due at least in part to attenuated cold-induced IBAT T5'D activity, contributes to the gender difference in thermoregulatory ability of older males vs. females.

Additive hypothermic effects of cocaine and nicardipine in guinea-pigs

1. 1. This study investigated the thermoregulatory effects of cocaine combined with two reported antidotal treatments for acute cocaine overdosage, calcium channel blocker therapy and cold ambient temperatures. 2. 2. Cocaine and nicardipine alone lowered the core temperature of female guinea-pigs (ambient temperature, 5°C) which resulted in a drop in core temperature of approximately 2°C at their highest respective doses (40 mg/kg and 50 mg/kg). 3. 3. Nicardipine administration 30 min prior to cocaine caused an almost 2-fold drop in temperature (3.75°C) relative to either drug alone. 4. 4. The data suggest that cocaine and nicardipine produce hypothermia by different, but additive, mechanisms.