Clinical review: Influence of vasoactive and other therapies on intestinal and hepatic circulations in patients with septic shock

The organs of the hepatosplanchnic system are considered to play a key role in the development of multiorgan failure during septic shock. Impaired oxygenation of the intestinal mucosa can lead to disruption of the intestinal barrier, which may promote a vicious cycle of inflammatory response, increased oxygen demand and inadequate oxygen supply. Standard septic shock therapy includes supportive treatment such as fluid resuscitation, administration of vasopressors (adrenergic and nonadrenergic drugs), and respiratory and renal support. These therapies may have beneficial or detrimental effects not only on systemic haemodynamics but also on splanchnic haemodynamics, at both the macrocirculatory and microcirculatory levels. This clinical review focuses on the splanchnic haemodynamic and metabolic effects of standard therapies used in patients with septic shock, as well as on the recently described nonconventional therapies such as vasopressin, prostacyclin and N-acetyl cysteine.
Introduction
Research interest has focused on the intestinal and hepatic circulations in various models of shock, and particularly in septic shock. The splanchnic area is reported to be the 'motor' of multiple organ failure [1] and the 'canary' of the body [2]. In fact, because of its peculiar vascular anatomy, the hepatosplanchnic area is jeopardized during septic shock, which may potentially lead to a vicious circle of inflammatory responses, culminating in multiple organ failure syndrome.
The present clinical review briefly discusses the splanchnic vascular anatomy and focuses on the different therapeutic approaches that have been proposed to promote perfusion of the gastrointestinal tract during resuscitation of patients with septic shock. When possible and reasonable, we propose therapeutic recommendations.
References were obtained from Medline database (from the earliest records to 2003). We used the following keywords: gastric mucosal pH or pHi, splanchnic, haemodynamics, microcirculation, sepsis, septic shock, vasoactive drugs, dobutamine, dopamine, norepinephrine, epinephrine, dopexamine vasopressin, terlipressin, prostacyclin, N-acetyl cysteine, dialysis and haemofiltration. We also reviewed the reference lists of all available review articles and primary studies to identify references not found in computerized searches. We placed emphasis on prospective, randomized, controlled clinical trials.
Anatomy of hepatosplanchnic vascular bed
The splanchnic vasculature includes both serial and parallel vascular beds (Fig. 1). The gut is perfused by the coeliac trunk and mesenteric arteries, and is drained via the portal system. The liver has a unique and special blood supply that includes both arterial (the common hepatic artery) and venous (the portal vein) inflow. The portal vein supplies 75–80% of the liver blood flow and the hepatic artery supplies 20–25%. Physiologically, there is an interdependent response with a compensatory blood flow between the portal vein and the hepatic artery called the hepatic arterial buffer response [3]. The hepatosplanchnic blood flow accounts for 25–30% of the cardiac output [4], and the regional oxygen extraction is slightly higher than the whole body oxygen extraction. During sepsis or septic shock, splanchnic oxygen extraction is increased compared with nonseptic patients (44% versus 30%), which leads to an increase in the hepatic venous/mixed venous haemoglobin oxygen saturation gradient [4]. In clinical practice it is generally not possible to determine portal venous flow in isolation, and measurements are taken from the hepatosplanchnic region as a whole. The flow is estimated at bedside by the method of primed, constant infusion of indocyanine green (ICG) with hepatic venous catheterization [5].
The intestinal villus is supplied by a single, unbranched arterial vessel that arborizes at the villus tip into a network of surface capillaries drained by a central villus vein. This anatomical arrangement allows countercurrent exchange and shunting of diffusible molecules such as oxygen, and hypoxia may occur at the tip of the villus even during moderate decreases in macrocirculatory flow [6]. In addition, intestinal villi perfusion is highly heterogeneous, as suggested by the wide range of intestinal surface oxygen saturation [7].
In patients with sepsis, splanchnic blood flow usually increases in proportion to cardiac output [8] and is associated with decreased hepatic vein oxygen haemoglobin saturation. Two different interpretations are possible: first, the increase in splanchnic blood flow is insufficient to meet the increased oxygen consumption; and second, hepatic arterial blood flow is reduced as a consequence of the hepatic arterial buffer response. The latter hypothesis is supported by the observations of De Backer and coworkers [9], who demonstrated that there is usually no net lactate production from the hepatosplanchnic area. In addition, the observation that splanchnic blood flow is increased does not rule out an impairment in microvascular blood flow [10-12] or the presence of cytopathic hypoxia [13].
In normal conditions the partial carbon dioxide tension (PCO2) gap, which is defined as the difference between mucosal PCO2 measured with a tonometer and arterial PCO2, is low. In case of inadequate mucosal blood flow, whether tissue hypoxia is present or not, the PCO2 gap increases. Levy and coworkers [14] recently reported that a PCO2 gap greater than 20 mmHg was associated with poor outcome in patients with septic shock. Unfortunately, there is no apparent correlation between PCO2 gap and global or regional haemodynamic measurements in septic patients [15] because the PCO2 gap mirrors both variations in microvascular flow [10] and in carbon dioxide metabolism [16]. For these reasons variations in PCO2 gap must be interpreted with caution.
Therapeutic strategies
Fluid challenge
The mainstay of supportive treatment in patients with severe sepsis or septic shock is maintenance of adequate fluid balance, titration of appropriate oxygen delivery, and adequate perfusion pressure [17]. Hypovolaemia is a common clinical occurrence in intensive care medicine and results from several mechanisms such as fluid loss, haemorrhage, vasoplegia and capillary leak syndrome. This explains why fluid replacement therapy is a key component in the treatment of severe sepsis and septic shock. Although there is no consensus regarding the ideal type of fluid replacement, colloids are efficient in this indication [18].
There are few clinical studies focusing on the effects of colloids on splanchnic haemodynamics. In a randomized study conducted in patients with sepsis, Boldt and coworkers [19] assessed the effects on tonometric gastric mucosal acidosis of hydroxyethyl starch and albumin targeted to maintain pulmonary artery occlusion pressure between 12 and 18 mmHg. In hydroxyethyl starch treated patients cardiac index, oxygen delivery and consumption increased, and gastric intramucosal pH (pHi) remained stable whereas it decreased in albumin treated patients. In three other studies [20-22] conducted in patients with sepsis and septic shock, fluid challenges performed with hydroxyethyl starch neither altered the PCO2 gap nor influenced splanchnic haemodynamics. Moreover, a randomized comparison of hydroxyethyl starch and gelatin in haemodynamically stable septic patients revealed a beneficial effect of gelatin on the PCO2 gap [20]. These studies suggested no better effect of one colloid over the others on splanchnic haemodynamics, and the use of colloids must be weighed against their side effects [23].
Red blood cell transfusions are commonly used in intensive care units (ICUs) to enhance systemic oxygen delivery. However, proof of improved utilization of oxygen by peripheral tissues, especially in the splanchnic area, is lacking. Silverman and Tuma [24] reported the absence of improved gastric pHi with red blood cell transfusions in 21 septic patients. Moreover, there is an inverse association between the change in gastric pHi and the age of the transfused blood [25]. Finally, a recent report in 15 septic patients showed that red blood cell transfusion failed to improve oxygen utilization measured either using Fick's equation or by indirect calorimetry, and gastric pHi remained unaltered [26].
Adrenergic drugs
The choice of vasoactive drugs in sepsis and septic shock is controversial. There is no evidence that any one vasoactive drug is more effective or safer than any other. Larger trials are needed to elucidate existing clinically significant differences in morbidity and mortality. A multicentre trial, which is currently ongoing, is comparing the effects of epinephrine with a combination of a fixed dose of dobutamine in addition to norepinephrine.
Dopamine alone or versus norepinephrine (Table 1)
The infusion of low-dose dopamine (defined as a dose lower than 5 μg/kg per min administered to normotensive patients) may not improve gut mucosal perfusion. In fact, Nevière and coworkers [27] showed that low-dose dopamine decreased gut mucosal blood flow in septic patients. Furthermore, other investigators [27-30] reported that either pHi or PCO2 gap were unchanged in patients with sepsis treated with low-dose dopamine. The effects on liver blood flow may also be variable; Maynard and coworkers [30] observed that dopamine did not affect ICG clearance and monoethylglycinexylidide (MEGX) formation from lidocaine. Interestingly, the effects of dopamine on splanchnic blood flow may differ according to basal splanchnic perfusion. Low-dose dopamine increased splanchnic blood flow that was low at baseline (seven patients) but not when splanchnic perfusion was preserved (four patients) [28]. The very small number of patients in each group limited these observations. Recently, Jakob and coworkers [31] reported that dopamine administration titrated to achieve a 25% increase in cardiac output induced a significant increase in splanchnic blood flow from 0.9 to 1.1 l/min per m2, which was associated with a significant reduction in splanchnic oxygen consumption.
The results are even more controversial when dopamine is used at higher doses to restore blood pressure. Ruokonen and coworkers [32] observed that dopamine increased splanchnic blood flow and metabolism in some but not all patients with septic shock. In some patients, the same group of investigators [33] also observed an increase in hepatic vein oxygen saturation, suggesting an improvement in the balance between oxygen supply and demand during dopamine administration. However, in a pilot study, Marik and Mohedin [34] reported that dopamine administered at doses up to 25 μg/kg per min even decreased pHi. Given the very small number of patients included in these studies, no definite conclusions can be drawn regarding the effects of dopamine on splanchnic blood flow in septic patients.
Comparison of the effects of norepinephrine and dopamine is difficult because norepinephrine is often combined with dobutamine, and study results are conflicting. Ruokonen and coworkers [32] reported unpredictable effects on splanchnic blood flow in patients with septic shock with norepinephrine, whereas dopamine induced a consistent increase in splanchnic blood flow. By contrast, in the randomized study reported by Marik and Mohedin [34], conducted in 20 septic patients with hyperdynamic septic shock, dopamine was reported to induce a decrease in pHi when compared with norepinephrine. More recently, De Backer and coworkers [35] reported the effects of dopamine, norepinephrine and epinephrine on the splanchnic circulation in moderate and in severe septic shock, and the main results are as follows. In moderate septic shock cardiac index was similar in dopamine-treated and norepinephrine-treated patients, and higher in epinephrine-treated patients, whereas splanchnic blood flow was the same with the three drugs. The gradient between mixed venous and hepatic venous oxygen saturation gradient was the lowest with dopamine, while PCO2 gaps were identical. In patients with moresevere septic shock cardiac index was greater and splanchnic blood flow lower with epinephrine than with dopamine and epinephrine; mixed venous and hepatic venous oxygen saturation gradient was greater with epinephrine, whereas PCO2 gap remained unaltered by any of the treatments.
Given the available data (summarized in Table 1), no definite conclusions can be drawn regarding differences between dopamine and norepinephrine on splanchnic blood flow and metabolism in patients with septic shock.
Dobutamine alone or combined with norepinephrine versus epinephrine (Tables 2 and 3)
In patients with sepsis, a retrospective study conducted by Silverman and coworkers [24] identified a beneficial effect of dobutamine infusion on pHi [24]. Two years later Gutierrez and coworkers [36] reported an increase in pHi with dobutamine infusion in patients with sepsis syndrome who initially had low pHi. This beneficial effect, confirmed in other studies [37-39], was not related to an increase in splanchnic blood flow induced by dobutamine [39,40]. Creteur and colleagues [41] reported that dobutamine decreased the PCO2 gap in septic patients with a high gradient between the mixed venous and hepatic vein oxygen saturation (>20%), whereas PCO2 gap was not affected in patients when this gradient was less than 20%. This suggests that patients with the most severe alterations in hepatosplanchnic blood flow are also prone to decreased mucosal perfusion.
Dobutamine usually, but not without exception, increases splanchnic perfusion [40-42]. The effects on splanchnic metabolism are more variable [39] and may depend on the adequacy of splanchnic perfusion at baseline. In patients with septic shock, De Backer and coworkers [43] reported that splanchnic oxygen consumption increased during dobutamine administration only in patients with an increased gradient between hepatic venous and mixed venous oxygen saturation.
Combinations of dobutamine and other catecholamines have often been studied, in particular in association with norepinephrine for its effects on β-receptors, with the aim of modulating hepatosplanchnic haemodynamics. Indeed, in patients with sepsis, changing from norepinephrine (α-agonist and β-agonist) to phenylephrine (pure α-agonist), titrated to produce similar global haemodynamic measurements, led to a decrease in splanchnic blood flow, splanchnic oxygen delivery and gastric pHi. These changes were associated with decreased rates of liver lactate uptake and glucose production [44].
Whether dobutamine has a specific effect on the splanchnic circulation is still debated. In a cross-over study conducted in eight patients with septic shock, Meier-Hellmann and coworkers [45] showed that epinephrine caused lower splanchnic flow and oxygen uptake, lower gastric pHi, and higher hepatic vein lactate concentration than did the combination of dobutamine and norepinephrine. Duranteau and coworkers [11] compared the effects of epinephrine, norepinephrine and the combination of norepinephrine and dobutamine in patients with septic shock on gastric mucosal flow, as assessed using a laser Doppler technique. Epinephrine and dobutamine–norepinephrine led to a significant increase in gastric mucosal flow as compared with norepinephrine alone, but these findings were not corroborated by those reported by Seguin and coworkers [46]. Moreover, in patients with septic shock resistant to dopamine, the combination of norepinephrine and dobutamine, in comparison with epinephrine alone, restored gastric pHi more quickly and limited the increase in arterial lactate concentration. However, there was no difference in gastric mucosal PCO2 gradients between groups at 24 hours of treatment [38].
The preferential effect of dobutamine on splanchnic blood flow was not confirmed by Reinelt and coworkers [42], who studied the effects of dobutamine on fractional splanchnic flow and hepatic glucose production in septic patients resuscitated adequately with fluid and norepinephrine. Their results showed a parallel increase in splanchnic blood flow and cardiac index, unaltered splanchnic oxygen consumption and decreased rate of endogenous production of hepatic glucose. These findings suggest that splanchnic blood flow is increased in well resuscitated septic patients, and that a dobutamine test is able to reveal a oxygen delivery/consumption dependency [41,43] but it cannot exclude intraorgan blood flow redistribution at the microcirculatory level. The inadequacy of blood flow distribution is mirrored by the absence of correlation between splanchnic blood flow and the PCO2 gap.
Reported data on the effects of dobutamine and norepinephrine on splanchnic haemodynamics are summarized in Tables 2 and 3, respectively.
Recommendations regarding use of adrenergic drugs
We suggest that both dopamine and norepinephrine can be given to septic shock patients as first-line catecholamine drugs but that their use must be weighed against the undesired neuroendocrine side effects of dopamine [45]. Epinephrine should be reserved for use as rescue therapy. If norepinephrine is chosen as the first agent, then the addition of dobutamine may be considered.
Dopexamine
Dopexamine hydrochloride is a dopamine analogue with vasodilating effects that may be useful in improving splanchnic microcirculation in septic shock. Twenty-five ventilated patients with systemic inflammatory response syndrome were randomly assigned to receive either a 2-hour infusion of dopexamine (1 mg/kg per min) or of dopamine (2.5 μg/kg per min) after baseline measurements of gastric pHi, MEGX formation from lidocaine and ICG disappearance rate. Dopexamine had no effects on systemic measurements but it significantly increased pHi and ICG plasma disappearance, suggesting a selective increase in splanchnic blood flow and improved hepatic function, as indicated by increased MEGX concentration [30]. A previous study from the same group showed that dopexamine at higher doses (4–6 μg/kg per min) raised gastric pHi together with a nonsignificant increase in ICG clearance [47]. Temmesfeld-Wollbrück and coworkers [7] employed reflectance spectrophotometry for direct assessment of the microvascular haemoglobin saturation and haemoglobin concentration in the gastric mucosa in patients with septic shock. Compared with healthy control individuals, patients with septic shock exhibited a reduced microvascular haemoglobin saturation with a wide distribution and with tailing of the histogram to severely hypoxic values in spite of high whole body oxygen delivery. This microvascular disturbance was associated with reduced microvascular haemoglobin concentration and a lower gastric pHi. Short-term infusion of 2 μg/kg per min dopexamine in 10 patients with septic shock increased both microvascular haemoglobin saturation and concentration, whereas whole body oxygen uptake and gastric pHi remained unaltered.
Other investigators did not confirm these beneficial effects. Hannemann and coworkers [48] reported the effect of incremental doses (0.5–4 μg/kg per min) dopexamine on splanchnic circulation in 12 patients with severe sepsis haemodynamically controlled with fluid challenge and dobutamine. Splanchnic blood flow increased proportionally to cardiac output but dopexamine lowered gastric pHi in a dose-dependent manner in all patients [49]. Finally, in 12 septic shock patients haemodynamically controlled with norepinephrine, dopexamine titrated to increase cardiac output by 25% [50] increased median splanchnic blood flow whereas the fractional splanchnic blood flow was significantly reduced, and none of global or regional oxygen exchange or PCO2 was altered. In addition, those investigators found no influence of dopexamine on metabolic parameters either [51]. Given these discrepancies, it is reasonable to recommend further investigations into dopexamine before it may be routinely used in septic shock.
Other vasoactive drugs
Vasopressin and terlipressin
Physiologically, vasopressin (a nonapeptide that is released from the neurohypophysis) plays a minor role in blood pressure regulation. Clinical data revealed that the initially very high plasma concentrations of vasopressin decrease during prolonged sepsis [52].
In the past few years clinical studies showed that blood pressure can be rapidly restored in septic shock using vasopressin, but this is mainly at the expense of cardiac output [53]. Nevertheless, in 2000 the American Heart Association and International Liaison Committee on Resuscitation recommended (grade IIB) continuous vasopressin infusion in refractory septic shock [54]. However, the effects of vasopressin on regional (i.e. splanchnic) blood flow are discussed controversially.
In 1997, Landry and coworkers [52] reported on the continuous infusion of vasopressin (1.8–3.0 IU/hours) in five patients with septic shock. In all patients, blood pressure was rapidly restored and urine output increased in three. Patel and coworkers [55] randomly assigned 24 patients with septic shock to a double-blind 4-hour infusion of norepinephrine or vasopressin, and open-label vasopressors were titrated to maintain blood pressure. Although norepinephrine dosage could be significantly lowered in the vasopressin group, blood pressure and cardiac index were maintained in both groups. Urine output did not change in the norepinephrine group but increased substantially in the vasopressin group. Similarly, creatinine clearance did not change in the norepinephrine group but increased by 75% in the vasopressin group. Finally, gastric mucosal PCO2 gradient did not change significantly in either group.
Recent results from Klinzing and coworkers [56], however, indicate that vasopressin may lead to a different blood flow distribution pattern in the splanchnic area as compared with norepinephrine. In 12 patients with septic shock, vasopressin was administered at a dose of 0.06–1.8 IU/min to replace norepinephrine completely. As a result, cardiac index and systemic oxygen uptake decreased significantly. Total splanchnic blood flow tended to decrease, while splanchnic blood flow expressed as percentage of cardiac output as well as the PCO2 gap were doubled [56]. By contrast, the increase in gastric PCO2 gap suggests that blood flow may have been redistributed away from the mucosa, and therefore it does not appear beneficial to directly replace norepinephrine with vasopressin in septic shock. Clinical data also suggest that low-dose vasopressin (0.04 IU/min) to compensate for endogenous deficiency could be a beneficial strategy [57-60], as was recently demonstrated by Dünser and coworkers [61], who randomly assigned 48 patients with catecholamine-resistant vasodilatory shock to receive a combined infusion of vasopressin and norepinephrine or norepinephrine alone. Vasopressin-treated patients had significantly lower heart rate, norepinephrine requirement and incidence of new onset tachyarrhythmias. Mean arterial pressure, cardiac index and stroke volume were significantly greater, and the PCO2 gap was significantly lower in patients treated with this combination. However, these patients also presented with a significant increase in plasma bilirubin concentration, suggesting an impaired liver blood flow and/or a depressed hepatic function mediated by vasopressin.
More recently, terlipressin (glycinpressin), a long-acting vasopressin analogue, was proposed as a treatment for septic shock. O'Brien and coworkers [62] reported their clinical experience with terlipressin (1–2 mg) as rescue treatment in eight patients with refractory septic shock. Those investigators reported a rapid and 24 hour lasting stabilization in blood pressure, with a significant reduction in norepinephrine but a significant decrease in cardiac index. In that study, seven patients required renal replacement therapy and four patients died during their stay in the ICU. However, optimism regarding these findings must be tempered somewhat [63], in particular because detrimental effects on splanchnic blood flow have been described. Auzinger and coworkers [64] studied seven patients with catecholamine-refractory septic shock and subsequent infusion of terlipressin using gastric tonometry. During the 24-hour intervention period, terlipressin was administered as an intermittent bolus (1–3 mg). Although no changes occurred in lactate levels, the PCO2 gap progressively increased over 72 hours.
Both vasopressin and terlipressin are potent vasoconstrictors and both are able to restore blood pressure in vasodilatory or septic shock. However, the effects on splanchnic blood flow are not yet fully elucidated. Clearly, adequacy of volume resuscitation is a major prerequisite for maintenance of microcirculatory blood flow. The currently available data suggest that both substances administered to compensate for endogenous vasopressin deficiency may be beneficial. Although the armamentarium for treatment of septic shock is enriched by such substances, it remains unclear whether administration during septic shock decreases morbidity or improves survival, and further research is warranted.
Enoximone
Modulation of the cytokine response by catecholamines might be a mechanism by which decreased morbidity and mortality are achieved with supranormal oxygen delivery in high-risk surgical patients [65]. Phosphodiesterase III inhibitors have positive inotropic, vasodilating and anti-inflamatory properties, and they may avoid the development of tolerance to catecholamines as a result of β-receptor desensitization.
In a prospective, double-blind study [66], 44 patients with septic shock and conventional resuscitation were randomly assigned to receive dobutamine or enoximone to maximize left ventricular stroke work index. At 12 and 48 hours after baseline measurements, liver blood flow was assessed with hepatic venous catheterization, liver function was derived from appearance in plasma of MEGX, and release of tumour necrosis factor-α was determined to assess the severity of ischaemia/reperfusion injuries. There was a similar increase in cardiac index, systemic oxygen delivery and consumption, and liver blood flow in the two groups. Fractional splanchnic blood flow decreased slightly but significantly in dobutamine-treated patients, whereas it remained unchanged in enoximone-treated patients. In the latter group liver oxygen consumption and MEGX kinetics were significantly higher at 12 hours but not at 48 hours. The release of hepatic tumour necrosis factor-α after 12 hours of dobutamine treatment was twice as high (P < 0.05) as during enoximone treatment, suggesting a faster anti-inflammatory effect of enoximone. These interesting findings on hepatosplanchnic effects of phosphodiesterase III inhibitors were not confirmed by other studies, and further investigations are needed if these agents are to be recommended for routine clinical use.
Prostacyclin
Prostacyclin or its stable analogue iloprost are vasodilator substances with platelet aggregation inhibiting and cytoprotective properties. Administration of prostacyclin by the intravenous route was shown to increase oxygen delivery and consumption in septic patients [67] and to improve gastric pHi [68], as did aerosolized prostacyclin in patients with septic shock and pulmonary hypertension treated with epinephrine or norepinephrine [69]. Finally, Lehmann and coworkers [70] reported restored plasma ICG clearance without harmful effect on systemic haemodynamics in patients with septic shock treated with iloprost.
More recently Kiefer and colleagues [71] reported the hepatosplanchnic effects of iloprost in 11 patients with septic shock requiring norepinephrine. Iloprost was incrementally infused to increase cardiac index by 15%, which significantly increased splanchnic blood flow in parallel, without a major fall in mean arterial pressure. Iloprost induced a decrease in endogenous glucose production rate without change in the hepatic clearance of the glucose precursors alanine, pyruvate and lactate. Similarly, the PCO2 gap was not altered. The authors avoided mean arterial pressure drop by careful exclusion of hypovolaemia before inclusion, but still the increment in iloprost doses was limited by the decrease in arterial partial oxygen tension, which raises many questions in patients with acute respiratory distress syndrome. These interesting findings on hepatosplanchnic effects of such vasodilators need further investigation before these agents may be recommended for routine clinical use [72].
Nitroglycerin
Opening the microcirculation using a vasodilator is an alternative approach for treatment of the jeopardized microcirculation in patients with sepsis or septic shock. Data reported by Sprock and coworkers [73] suggest that the use of intravenous nitroglycerin results in improved sublingual microvascular flow, as assessed by orthogonal polarization spectral imaging. However, one cannot assume that the sublingual microcirculation necessarily behaves like the whole splanchnic microcirculation does.
N-acetyl cysteine
N-acetyl cysteine (NAC) administration was associated with a decrease in gastric pHi in septic patients [74,75] and prevented the decrease in pHi in septic patients under hyperoxic stress [76]. In a randomized, double-blind study conducted in septic shock patients, NAC given within the first 24 hours after admission to the ICU was shown to improve cardiac index and splanchnic blood flow and MEGX concentration, and to decrease gastric mucosal PCO2 gap, whereas it did not influence fractional splanchnic blood flow [75]. Nevertheless, these positive effects of NAC on the splanchnic circulation must be balanced against several negative studies. Indeed, NAC was reported to depress cardiac performance in septic patients [77], and it even worsened mortality rate when it was given more than 24 hours after hospital admission [78]. Is NAC a 'double edged sword'? This question should be answered before its use in daily practice can be recommended.
Extracorporeal renal support
Publications related to this topic are scarce. In 11 critically ill patients mechanically ventilated and treated with inotropic support, intermittent dialysis increased the PCO2 gap [79]. In contrast, in two recent studies conducted in patients with acute renal failure [80] and septic shock [81], the PCO2 gap remained unaltered whereas cardiac index and stroke volume, as well as splanchnic blood flow, transiently decreased [80]. Although improved cardiovascular stability during continuous veno-venous haemofiltration in comparison with intermittent dialysis has been demonstrated in retrospective studies [82], the superiority of continuous haemofiltration over hemodialysis on splanchnic circulation has not been proven [81].
Conclusion
In this review we summarize different, and potentially opposing, approaches to management of splanchnic circulation in patients with septic shock. However, in these studies the measurements were focused on the effect of the drug on splanchnic blood flow or a surrogate such as the PCO2 gap, but none of these studies reported convincing results with respect to mortality and/or morbidity.
Competing interests
None declared.
Abbreviations
ICG = indocyanine green; ICU = intensive care unit; MEGX = monoethylglycinexylidide; NAC = N-acetyl cysteine; PCO2 = partial carbon dioxide tension; pHi = intramucosal pH.

septic shock
supportive treatment
adrenergic drugs
splanchnic circulation
nonconventional treatments


Rituximab therapy for chonic and refractory immune thrombocytopenic purpura: a long-term follow-up analysis

The aim of this study was to evaluate the long-term response to rituximab in patients with chronic and refractory immune thrombocytopenic purpura (ITP). Adults with ITP fail to respond to conventional therapies in almost 30% of cases, developing a refractory disease. Rituximab has been successfully used in these patients. We used rituximab at 375 mg/m2, IV, weekly for a total of four doses in 18 adult patients. Complete remission (CR) was considered if the platelet count was >100 × 109/l, partial remission (PR) if platelets were >50 × 109/l, minimal response (MR) if the platelet count was >30 × 109/l and <50 × 109/l, and no response if platelet count remained unchanged. Response was classified as sustained (SR) when it was stable for a minimum of 6 months. Median age was 43.5 years (range, 17 to 70). Median platelet count at baseline was 12.5 × 109/l (range, 3.0 to 26.3). CR was achieved in five patients (28%), PR in five (28%), MR in four (22%), and two patients were classified as therapeutic failures (11%). Two additional patients were lost to follow-up. The median time between rituximab therapy and response was 14 weeks (range, 4 to 32). SR was achieved in 12 patients (67%). There were no severe adverse events during rituximab therapy. During follow-up (median, 26 months; range, 12 to 59), no other immunosuppressive drugs were used. In conclusion, rituximab therapy is effective and safe in adult patients with chronic and refractory ITP. Overall response rate achieved is high, long term, and with no risk of adverse events.
Introduction
In immune thrombocytopenic purpura (ITP), platelets are coated with an IgG autoantibody that prompts its premature destruction and, as a result, different grades of peripheral thrombocytopenia and clinical bleeding become evident [5, 23]. Steroids are the first-line treatment for acute ITP. In case of failure to steroids, splenectomy induces a 70 to 80% response rate [10]. However, almost 30% of adults with ITP fail to respond to conventional therapies [steroids, IV immunoglobulin (IVIg), splenectomy, or immunosuppressive drugs] and, eventually, they develop a chronic refractory disease [5, 12, 23]. Refractory patients are defined as those who failed standard-dose steroids and splenectomy, requiring further treatment due to unsafe platelet counts (<30 × 109/l) or clinical bleeding. These patients are unlikely to be cured, although spontaneous remissions sometimes occur [17]. If a patient becomes refractory, some alternatives are available such as danazol, dapsone, azathioprine, high-dose steroids, or chemotherapy combinations like CHOP regimen. However, these options are not quite useful because if response is achieved it is but for a brief period and sustained responses are scarce [23]. Hematopoietic stem cell transplantation has been occasionally used in some cases, but this option represents a high-risk procedure [14]. At the end, these patients may respond poorly to subsequent therapy, may have significant morbidity from the disease and its treatment (bleeding and infections secondary to immunosuppressive therapy), and the mortality rate at 10 years may rise up to 20% [5, 11]. On the other hand, these patients have higher hemorrhagic risk imposed by trauma or surgery. Therefore, new treatment strategies for these patients are needed.
Rituximab is an anti-CD20 chimeric murine-human monoclonal antibody. CD20 is a B-lymphocyte membrane protein absent on other normal cells. This monoclonal IgG-kappa antibody is used in non-Hodgkin lymphomas because it induces apoptosis or direct lysis of B cells [19]. In ITP, B cells are responsible of autoantibody production and the subsequent platelet opsonization that allows its destruction. Therefore, if B cell clones are eliminated, thrombocytopenia could be reverted.
There are some reports informing that rituximab is useful in refractory ITP showing a high overall response rate, with complete remission (CR) and partial remission (PR) rates ranging from 48 to 54% [4, 8, 9, 18, 20–22]. We report herein our long-term experience with rituximab therapy in chronic and refractory ITP.
Materials and methods
In a 5-year period, we prospectively administered rituximab to all patients with chronic and refractory ITP who were unresponsive to prednisone, azathioprine, vincristine, danazol, and high-dose dexametasone, among other therapies, including those unsuccessfully splenectomized. Patients must have a platelet count of <30 × 109/l to be considered for this therapy.
Rituximab was given in doses of 375 mg/m2, diluted in 500 ml 5% dextrose–water solution in a 4-h continuous IV infusion. This regimen was indicated weekly for four doses after prophylactic application of antipyretic and antihistamine premedication administered 30 min before rituximab infusion (paracetamol, 500 mg, PO; diphenhydramine, 30 mg, PO; and hydrocortisone, 100 mg, IV). Outpatient follow-up was scheduled monthly for 6 months. Long-term follow-up was performed every 2 months.
Response was classified as complete (CR) if the platelet count was >100 × 109/l, partial (PR) if platelet count >50 × 109/l, minimal response (MR) if platelet count was <50 × 109/l and >30 × 109/l, and no response (NR) if there was no change from the baseline platelet count. Response was sustained (SR) when it was maintained for a minimum of 6 months.
Numerical variables were expressed using the median and range number. The probability to achieve more than 50 × 109/l and 100 × 109/l platelets and the median time from response to end of follow-up was calculated using the Kaplan and Meier method.
Before starting treatment, all patients signed an informed consent authorization. The procedures done in this protocol were in accordance with the Helsinki Declaration of 1975. The protocol was approved by the Ethics Committee of the participating hospitals.
Results
Eighteen patients were candidates for this therapy, and all of them were suitable for evaluation because they received the planned four doses of rituximab. Patient characteristics and response to rituximab are shown in Table 1. Median age for the whole group was 43.5 years (range, 17 to 70). Median platelet count at baseline was 12.5 × 109/l (range, 3.0 to 26.3). Median follow-up was 26 months (range, 12 to 59). Mean number of treatment regimens received before rituximab was 5.5 (range, 3 to 8). Fifteen patients (83%) had failed to splenectomy.
Table 1Patient characteristics and outcomesPatient/age/genderEvolutiona (months)Previous treatmentsPC at baseline (×109/l)PC at 12 months (×109/l)Time to response (weeks)Response typeSR1/42/F37P, S, Az, D, IFN3.014624CRYes2/43/F84P, S, Az, D, IFN, V5.012324CRYes3/30/F48P, S, Az, D, IFN, V12.534. 516MRYes4b/27/F38P, S, Az, D, IFN24.47816PRbYesb5/70/M60P, Az, D, V7.8NRNRNRNo6/43/F96P, S, Az, D, IFN, V10.137.78MRYes7/53/F96P, S, Az, D, IFN, V12.55412PRYes8/36/F264P, S, Az, D, IFN, V, OE, IVIg5.030.64MRYes9/17/F38P, S, Az, D, IFN, V, OE6.51294CRYes10/57/F26P, Az, D8.3648PRYes11/36/F25P, S, Az, D, IFN, V7.04920MRNo12/63/F120P, Az, D, V26.3NRNRNRNo13/53/F348P, De, D, S, Az22.01128CRYes14/22/F266P, S, D, IFN, IVIg12.66712PRNo15/56/F137P, D, S, Az18.42234CRYes16/35/F38P, D, Az, S23.211.40NRNo17/52/F41P, D, S16.551.94PRYes18/24/F60O, D, S24.0NRNRNRNoPC Platelet count, P prednisone, S splenectomy, Az azathioprine, D danazol, IFN interferon alpha 2b, V vincristine, De dexamethasone, OE opsonized erythrocytesaTime from ITP diagnosis to rituximab therapybA second course of rituximab was given.
CR was achieved in five patients (28%), PR was obtained in another five (28%), MR was seen in four (22%) patients, and two patients were considered treatment failures (11%). Two patients were lost to follow-up (11%). Ten patients (55%) achieved >50 × 109/l platelets. Median time from the first rituximab dose to achievement of any response was 14 weeks (range, 4 to 32). Twelve patients (67%) showed SR beyond the sixth month of follow-up. As expected from the results depicted in Table 1, we were unable to find any correlation between the ITP duration and the type of response to rituximab. Figure 1 shows the median platelet counts during follow-up in three different groups of patients classified according to their pattern of response (CR, PR, and MR). The median time to achieve >50 × 109/l platelets was 5 months (95%CI = 0.5 to 11.6 months), and the median time to achieve >100 × 109/l platelets was not reached (Fig. 2). One patient relapsed 22 months after the first course of rituximab. She received steroids for another 14 months; she did not obtain response, and a second course of rituximab was given using the regimen described previously. She achieved a new PR 6 months after stopping therapy. After 22 months of follow-up, PR still remains in this patient.
Fig. 1Platelet count achieved after first dose of rituximab (time 0 first dose of rituximab). Diamonds, CR; ovals, PR; triangles, MRFig. 2Time required to obtain platelet counts >50 × 109/l (a) or >100 × 109/l (b) after first dose of rituximab in adult patients with chronic and refractory ITP
Median time of response duration was 54 months (95%CI = 15–93 months) for patients with CR, 18 months (95%CI = 8–28 months) for patients with partial response, and 12 months (95%CI = 7–17 months) for those individuals with minimal response. Difference was statistically significant between patients in CR vs those achieving PR or MR (p < 0.05). No difference was observed between PR and MR (Fig. 3).
Fig. 3Median duration of response for patients who achieved complete remission (CR; 54 months, 95%CI = 15–93 months), partial remission (PR; 18 months, 95%CI = 8–28 months), or minor response (MR; 12 months, 95%CI = 7–17 months)
Side effects related to the first dose of rituximab such as fever, chills, and respiratory symptoms were common (8 out of 18 patients, 43%). There were no severe adverse events during drug administration. Neither hemorrhagic events nor infections were recorded. Neutropenia, an occasional long-term side effect of rituximab therapy, was never recorded in our group of patients (Fig. 4). In fact, the lower neutrophil count recorded during the study was 1.3 × 109/l in patient 7 after 6 weeks of treatment with rituximab. No patient needed additional immunosuppressive therapy other than rituximab. During the whole follow-up period, no other illnesses have been recorded in this group of patients.
Fig. 4Mean (squares), maximum (diamonds), and minimum (triangles) neutrophil counts through the follow-up of patients receiving rituximab for chronic and refractory ITP
Discussion
Because almost 30% of individuals with ITP do not respond to the first- and second-line therapies, they live with low platelet counts, a situation that carries a high risk of hemorrhage and, eventually, a short life expectancy. It has been largely demonstrated that ITP with persistent low platelet counts carries a grave prognosis [6, 13]. Efforts to increase the platelet count to at least 30 × 109/l include IVIg, anti-D immunoglobulin, cyclophosphamide, polychemotherapy such as the CHOP regimen, thrombopoietin, interleukin-11, dapsone, alpha interferon, plasma exchange, and bone marrow transplantation [23]. Using these therapies, the response rate is low and the patient is exposed to unnecessary risks [10]. When the first ITP patient successfully treated with rituximab was informed, it drew the attention of physicians because this regimen offered high response rate and low toxicity. In subsequent reports, researchers have found similar results.
The aim of this study was to evaluate the response rate achieved in 18 patients with chronic and refractory ITP after rituximab treatment as well as the evolution of these patients to learn about the possible long-term side effects associated with the use of this drug, information that is almost inexistent in the literature. We observed 12 favorable responses (67%) and at least a stable clinical evolution in two additional patients (11%), for a global response rate of 78%. Based on the characteristics of the evolution of our group of patients, we may emphasize some points of interest: (1) Response rate obtained was quite satisfactory considering the history of chronicity and refractoriness of the patients; (2) the monoclonal antibody was well tolerated and caused only mild allergic reactions that could be easily managed with antihistaminics and paracetamol; (3) most of the patients achieve SR; and (4) increase of platelet count was not always immediate (median time to response = 14 weeks), a fact that slightly disagrees with previous reports that found shorter time to response (3 to 8 weeks; Table 2) [4, 8, 20]. In fact, in a recent systematic review about the efficacy of rituximab in adult patients with ITP, it was found that median time to response was 5.5 weeks (ranges 2 to 18 weeks) [2]. We do not have an explanation for this discrepancy. After a careful analysis, we did not find significant differences between the results obtained in the systematic review and our results in terms of the variables that may affect the time to response to rituximab, namely, age, sex, previous use of corticosteroids, number of treatments before rituximab, rituximab dose and schedule, period between diagnosis and rituximab administration, duration of ITP before rituximab, and pretreatment platelet counts. Although splenectomy may not be a significant predictor of response to rituximab as previously suggested [2, 4, 8], it should be noted that 83% of the patients included in our report had had splenectomy as compared with 50.5% of the patients in the systematic review. Therefore, history of splenectomy seems to be the only factor related to a different time to response to rituximab in our series.
Table 2Patterns of response in patients with chronic and refractory ITP (from [1, 6, 18])ReferenceNumber of patientsOR (%)CR (%)PR (%)Median time to response (weeks)Mayo clinic1250428?USA–Italy575331228Denmark353318152–8Peru22684027?Mexico1856282814OR Overall response, CR complete response, PR partial response
Of course, we have no data about all possible variables influencing the pattern of response to rituximab. For example, we do not show information about B-cell counts and platelet autoantibodies before and after rituximab therapy, two variables that may influence the response as observed in other trials. The expected therapeutic effect of rituximab is a reduction in specific platelet-associated autoantibodies and the consequent increase in platelet counts. Although rituximab has not been always associated with a reduced load of platelet autoantibodies and most of the publications reporting this effect are small series of cases [1], the high overall response rate obtained in our study allows us to believe that rituximab effectively decreased the B-cell counts as well as the levels of platelet autoantibodies.
Three patterns of response to rituximab have been proposed: early (before the fourth dose of rituximab), intermediate (7 to 11 weeks after rituximab), and delayed (>13 weeks after rituximab) [8]. In our study, the probability to achieve a platelet count >50 × 109/l occurred at a median of 5 months, so we speculate that the complete inhibition of antibody formation and restoration of platelet counts with rituximab may occur after at least 5 months (95%CI = 0.5 to 11.6 months) from the first dose of the antibody (Fig. 2). However, some patients may achieve a quite delayed response (as long as 1 year after therapy), a situation in which it is important to wait a reasonable time period before another treatment is planned.
A previous report informed the results obtained in patients treated with the same regimen as we used [4]. After a median follow-up of 47 weeks, the authors observed a lower overall response rate of 44% (CR = 18%, PR = 15%, MR = 10%); most of the responses were sustained. They observed two response patterns: (1) an early-response group in which responses appeared within the first 2 weeks after the first dose of rituximab; (2) a late-response group characterized by an increase in platelets several weeks after rituximab. Finally, after a median follow-up of 72.5 weeks, the response rate was 54% with a majority of SR [8]. In a prospective trial performed in pediatric patients with chronic ITP, treatment with rituximab produced an increase of >50 × 109/l platelets in 11 of 36 children (31%) [3]. Median time to response was 1 week (range, 1 to 7 weeks); however, a 6% incidence of serum sickness was observed. More recently, one of the largest experiences in ITP patients treated with rituximab was published [15]. An increase of >50 × 109/l platelets was observed in 55% of the patients (CR = 46%, SR = 35%). The only predictive factor for SR was to achieve CR. Patients who were treated more intensively (more than three different treatments) and those with a longer ITP duration (>10 years from diagnosis) had the worse response. In this study, non-splenectomized patients had a higher early response rate than those splenectomized. Although some of these results are similar to those reported in our study, we believe that contrasting results seen in our study are partially explained by differences in the inclusion and response criteria used, in the evolution time of the disease, and in the number and type of treatments given before rituximab.
As early relapses may be seen in ITP patients treated with rituximab and because re-treatment with this monoclonal antibody offers good results [16], this drug has been used as a long-term maintenance treatment. Based on long-lasting remissions achieved using one or two doses of rituximab [7] and the results of late responders, we feel that a single dose of 375 mg/m2 every 6 months could be an alternative for this purpose.
On the other hand, because of the mechanism of action of rituximab and its interference with the immune system, we searched for possible long-term complications associated with its use, namely, neoplasias, chronic infections, or autoimmune diseases. Immune status is a major concern in patients treated with rituximab being the induction of low CD20+ counts and hypogammaglobulinemia (specifically low levels of immunoglobulin M), two previously reported secondary effects. Although we do not have data about these two immunological variables, the lack of severe infectious diseases during the long-term follow-up of our patients allows us to speculate that no severe immune abnormalities were developed in our series. As we previously stated, during the follow-up period, no associated illnesses or pathological phenomena were observed. To our knowledge, this seems to be the first report about the lack of long-term complications associated with rituximab.
In conclusion, rituximab is a long-term, safe, and effective alternative treatment of chronic and refractory ITP patients. Prospective randomized clinical trials are needed to elucidate the efficacy of the drug in comparison to splenectomy in early stages of the disease

rituximab
refractory itp
anti-cd20
chronic itp


Joint-action coordination in transferring objects

Here we report a study of joint-action coordination in transferring objects. Fourteen dyads were asked to repeatedly reposition a cylinder in a shared workspace without using dialogue. Variations in task constraints concerned the size of the two target regions in which the cylinder had to be (re)positioned and the size and weight of the transferred cylinder. Movements of the wrist, index finger and thumb of both actors were recorded by means of a 3D motion-tracking system. Data analyses focused on the interpersonal transfer of lifting-height and movement-speed variations. Whereas the analyses of variance did not reveal any interpersonal transfer effects targeted data comparisons demonstrated that the actor who fetched the cylinder from where the other actor had put it was systematically less surprised by cylinder-weight changes than the actor who was first confronted with such changes. In addition, a moderate, accuracy-constraint independent adaptation to each other’s movement speed was found. The current findings suggest that motor resonance plays only a moderate role in collaborative motor control and confirm the independency between sensorimotor and cognitive processing of action-related information.
Introduction
Given the strong inclination that people have towards behavioral mimicry when they are jointly involved in walking or speaking (Chartrand and Bargh 1999; Lakin et al. 2003), can we also demonstrate co-actors adopting each other’s movement patterns in the simple task of transferring objects? If an object relevant for my own actions is placed in front of me at a high speed, shall I then automatically pick it up and transfer it also with a high speed or will I stick to my own, preferred speed? Furthermore, will an observer be sensitive to the height of the movement trajectory with which an object is placed within reach as a potential cue of that object’s weight?
Detailed questions surrounding the potential transfer of movement kinematics in a shared action sequence as specified above have not yet been systematically investigated (cf. Sebanz et al. 2006). The little work that has been done in this area was limited to unintentional synchronization of arm movements in pendulum swinging (Schmidt and O’Brien 1997), incidental entrainment of leg movements when dyads solve a puzzle through dialogue (Shockley et al. 2003), and the kinematic characteristics of cooperative versus competitive grasping movements (Georgiou et al. 2007).
A recent model of joint action by Oztop et al. (2005) that makes relevant claims regarding joint-action coordination in sequential task performance presumes that when a person observes someone else’s actions she automatically will activate her own action system not only to understand the behavior of the actor being observed (Rizzolatti and Craighero 2004) but also to infer that actor’s intentions (cf. Wolpert et al. 2003; Iacoboni et al. 2005). The example Oztop et al. (2005) mentioned in this context concerns the implied meaning that is conveyed by the specific way in which people may handle a tool. For example, whereas holding a hammer with a usual grip around its handle is very likely to signal the intent of hammering, holding the hammer with a power grip around its face communicates the intention to handing over the tool to someone else rather than start hammering with it oneself. Of course, which semantics are primed by the way in which a tool is handled will depend on the shared knowledge of how the tool is used for the general purpose it was designed for (see also Cuijpers et al. 2006).
In the present study we were neither interested in what a particular act might convey to an observer in terms of action semantics (Oztop et al. 2005) nor how cooperative or competitive contexts are differentially reflected in the prehension kinematics of dyads (Georgiou et al. 2007). Instead, we focused on the extent to which an observer in her subsequent movements is influenced by specific kinematic features of a co-actor’s movements bringing the object within reach. Since the participants in the present study were asked to perform complementary acts rather than identical ones this research question is therefore only indirectly related to topics like behavioral mimicry and imitation (Koski et al. 2003).
Our reasoning about the possible transfer of kinematic movement parameters from one actor to another was that if during action observation people internally simulate the movements that they observe (Gallese and Goldman 1998; Rizzolatti and Craighero 2004), then the kinematic features of these simulated movements might as well be re-used for a related, self-generated movement that, in time, closely follows the observed one even when this future movement is complementary in nature. Economizing on parameter remapping costs formed the basis of this expectation (cf. Rosenbaum et al. 1986).
As regards inference making we were interested in the extent to which people derive the weight of an object when seeing someone else picking up and transporting the object. A similar matter has been investigated in an fMRI study by Grezes et al. (2004) but their experiment was primarily designed to find the brain correlates of action observation in the context of deception. To this end these researchers used pictures of an accomplice lifting boxes as if they were heavy or when they were actually heavy. In the present study, however, deceit was not the issue of investigation. Moreover, the object-weight dependent variations in movement kinematics were more subtle than in the Grezes et al. (2004) study and related studies on box lifting by Hamilton et al. (2007) and Kingma et al. (2005) as we will explain next.
To gain further insight into the extent to which task-dependent kinematic variations affect the subsequent complementary actions of a co-actor, we exploited two widely investigated motor-control paradigms, viz. the speed-accuracy trade-off (Fitts 1954; Fitts and Peterson 1964) and size–weight illusion (Charpentier 1891). Figure 1 depicts the transportation task that we used for this purpose. First, one of the two actors—the ‘putting-actor’—was asked to pick up a vertically positioned cylinder from a nearby location on the table and to put that cylinder into a circular-shaped target area in the middle of the table, i.e., within reach for the other actor. Subsequently, the other actor—the ‘fetching-actor’—was asked to fetch the cylinder from where the putting-actor had left it, and to reposition it, also in a circular-shaped, nearby target area. The fetching-actor was instructed not to pick up the cylinder before the putting-actor had released it.
Fig. 1Top view of experimental setup depicting the experimental task. The dashed squares represent the starting areas for the (right) hand movements of both actors. At the filled circle a cylinder was positioned which had to be picked up by the putting-actor, repositioned in the central circular target area where the fetching-actor was to pick it up and place it in the target circle in the vicinity of her own starting area
Three task variables were manipulated, viz. the size of the target areas in which the actors were to successively reposition the cylinder and the size and weight of the to-be-transported cylinder. The size of the target areas was expected to modulate the actors’ movement-speed and the size and weight properties of the cylinders were thought to affect the height with which the actors would lift the cylinders during transport. Before elaborating on our rationale it is important to mention that task conditions were kept constant within trial blocks of three repetitions to examine how quickly the dyads adapted to the between trial-block changes in the experimental conditions. All factors other than the repetition factor were randomized across the trial series and dyads, and at the start of each trial block the participants were unaware of the experimental conditions of that particular block (see “Method”).
Two types of potential transfer of movement kinematics were foreseen in our experimental task. First, it was expected that an incorrectly anticipated weight of a to-be-picked up cylinder would be reflected in the height with which an actor would lift that cylinder (cf. Grezes et al. 2004). A lighter than expected cylinder was assumed to be lifted higher than a heavier one and vice versa, i.e., a heavier than expected cylinder was assumed to be lifted less high than a lighter one. Furthermore, if the fetching-actor would infer the weight of the cylinder that was transported by the putting-actor by observing her movements, then the fetching-actor was expected to have a more precise initial estimate of the weight of the to-be-transported cylinder than the putting-actor. The degree to which any surprise effect due to a wrongly anticipated object weight would transfer from the putting-actor to the fetching-actor thus formed a test as to whether or not the fetching-actor had actually inferred the cylinder weight. In repetitions two and three of each trial block both actors could rely, of course, on their sensorimotor memory (see Nowak and Hermsdorfer 2003) as regards the object weight since in these trials they already had handled that particular cylinder in the previous (two) trial(s) of the trial block.
To investigate the predicted object-weight dependent interpersonal kinematic transfer effects, we factorially combined two cylinder weights (light vs. heavy) with two cylinder sizes (small vs. large) yielding four cylinders. The size–weight illusion that results from this particular combination of object features reflects the fact that people perceive a smaller of two equally-massed objects as heavier. For one of the suggested explanations of this illusion, we refer to Flanagan and Beltzner (2000). The size–weight illusion is so prominent that it also yields its typical effects when wielding a small and a large object of equal weight in the left and right hand simultaneously suggesting the distorted perception is due to sensory invariants rather than inferences (Amazeen and Turvey 1996). Irrespective of any size–weight illusion effects, we expected the cylinder-weight variations to result in larger between trial adaptation effects on the height with which the participants would lift the cylinders than the cylinder-size variations (Gordon et al. 1991a, b). We thus examined the extent to which the weight of an object carried from one position to another would be inferred by an observer. If the observer, i.e., the fetching-actor, would not infer the weight of the transferred cylinder, then the surprise-effect expressed in the lifting height of the fetching-actor should be equally large as that in the putting-actor. Conversely, should the fetching-actor correctly infer the weight of the object by observing the putting-actor lifting and repositioning the cylinder, then the fetching-actor should be able to anticipate the cylinder’s weight better and not show such large surprise effects as the putting-actor would.
A second manipulation targeted the extent to which the two actors would adopt each other’s movement speed in the face of variations of movement-accuracy constraints. If merely by observing someone else’s movements, one would be inclined to adopt a similar speed in a subsequent complementary movement, then confronting two actors with different target area sizes was expected to modulate their speed differently than when the actors would be confronted with these target areas individually. The rationale here was based on Fitts’ law, which states that one’s movement speed systematically varies with the size of the target area (Fitts 1954; Fitts and Peterson 1964; Mottet et al. 2001). The smaller the target area to reach for, the lower the movement speed due to the higher accuracy demands that are associated with small target areas. In the present study we manipulated the target area sizes of the first and the second actor separately, where the size was either small (diameter of 9 cm) or large (diameter of 18 cm). If both actors had identical (either small or large) target area sizes, their movement speeds were most likely to become similar under the assumption that there would be a strong tendency to adopt each others’ speed. If this tendency of movement speed transfer was strong enough, then violations of Fitts’ law in the fetching-actor could be expected under conditions in which the two actors were confronted with dissimilar target area sizes.
In sum, in the present study consisting of a sequential motor task involving two actors we tested whether lifting height—a parameter that potentially could reveal an object’s weight—would be picked up by an observing co-actor and determine her subsequent handling of that object and whether she would be inclined to adapt her speed to the observed speed, or, alternatively, whether the interpersonal transfer of kinematic parameters would be incidental in nature, i.e., unrelated to the task constraints with which the individuals of the dyad were confronted.
Method
Participants
Fourteen right-handed adult dyads participated in the experiment. Their ages ranged from 18 to 30 years; mean age was 22 ± 2 years. The 28 participants, 22 females and 6 males, formed 8 female dyads and 6 dyads of mixed gender. They received either course credits or payment (6 euros per hour) for their participation. Each participant signed an informed consent form. The study was approved by the local ethics committee and performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.
Materials
A Microsoft Windows-2000 controlled PC was used to control the stimulus events and data collection. Two synchronized 3D infrared motion-tracking systems (Optotrak™, Northern Digital, Waterloo, Canada) were used to record the displacements of the wrist, thumb and index finger of the right hand of the two actors. Three infrared-light emitting diodes (IREDs) were used per participant. The IREDs were fixated on the wrist joint and the distal phalanxes of the index finger and thumb of the right arm of the participants. The IRED-position data were sampled at a rate of 100 Hz with accuracy better than 0.2 mm in X, Y and Z directions. Each participant wore a pair of earphones through which a repetitive sound was presented at approximately 60 dB throughout the experiment. This prevented the participants from speaking to each other and hearing any task-related noise, e.g., due to the cylinders making contact with the tabletop at completion of the transport phases. Each participant also wore a facial mask to avoid communication by means of facial cues. The participants were seated comfortably at opposite sides of a table on top of which a 1-cm thick marble plate was placed to prevent any object-weight information being conveyed from one actor to the other by means of vibrations via the table surface.
Four cylinders of 25 cm height were used, two with a diameter of 2.5 cm and two with a diameter of 6.5 cm. Two cylinders had a lightweight of 230 g and two cylinders had a weight of 835 g. To avoid any potential confounding between the effects of cylinder and target-area size all cylinders were given a 4-mm thick, circular base of 8 cm in diameter. This ensured that the thin and thick cylinders had the same size support base and could be repositioned in a comparable stable way which was a factor that also could contribute to the accuracy constraints since the participants were asked to place the cylinders on small and large circular target areas that were clearly marked on the table surface.
Procedure and task
The experiment consisted of three sections. In the first section one of the two participants performed 48 single-actor control trials consisting of picking up and repositioning in random order, but blocked (three repetitions per block), the four cylinders without the presence of the other participant. In the second section, the other participant performed 48 single-actor control trials, also alone. In the third section the two participants of the dyad performed 96 joint-action experimental trials. The 48 control trials per participant resulted from three blocked replications (n = 3) of each of the factorial combinations of the factors size of starting area (small vs. large), size of target area (small vs. large), cylinder weight (light vs. heavy) and cylinder size (small vs. large). The number of joint-action experimental trials was twice the number of single-actor control trials. In the joint-action experimental trials each participant was given in half the trials the role of putting the cylinder in the centre of the table, and in the other half of the trials the role of fetching the cylinder from the centre of the table (see Fig. 1). The role was randomly assigned to the trial blocks of three repetitions.
In their control trials the participants of dyads 1–9 (arbitrary numbered) performed the fetch-part of the experimental task, i.e., at the start of their control trials they were confronted with a cylinder that was placed in the middle of the table and their task was to pick it up and place it in the area which was closest to their own starting position. Dyads 10–14 performed in their control trials the put-part of the experimental task, i.e., at the start of each trial they found the cylinder on the area closest to themselves and they were instructed to put the cylinder in the target area at the centre of the table. The data analyses showed that there were no systematic differences between the two groups of dyads as far as the targeted research questions concerned so the comparisons with the control trial data will not be addressed further in the remainder of this paper.
The experiment was conducted by two experimenters who sat behind the participants. Each experimenter had a clear view on a separate computer screen which displayed information that specified the experimental conditions of every trial. In-between trials the participants were asked to close their eyes. After both participants had closed their eyes, the experimenters put the appropriate target pads on the table as well as the appropriate cylinder in the starting area of the putting-actor. Then, the two experimenters simultaneously tapped the participants on their lower arm, which indicated that they could open their eyes to start performing the trial. At the same time one of the experimenters started the movement recording.
The standard event sequence in a joint-action experimental trial was as follows. At the start of each trial one of the two actors, i.e., the putting-actor, found in a location close to the starting position of the right hand a cylinder that had to be picked up and moved to the target area in the centre of the tabletop (see Fig. 1). Only after the putting-actor had released the cylinder was the fetching-actor allowed to pick up the cylinder and to reposition it in a target area adjacent to her. The action sequence was to be completed within 8 s during which the displacements of the wrist and finger IREDs on both actors were sampled at a rate of 100 Hz. After every 48 trials, or whenever they asked, the participants were offered a 10-min break.
Data analysis
The raw IRED position data were smoothed with a second-order, low-pass Butterworth filter with a cut-off frequency of 8 Hz. Subsequently, the position data were segmented on the basis of the tangential velocity–time functions of the IREDs on the wrists of the two actors (see top-left graph in Fig. 2).
Fig. 2Kinematics derived from position data of infrared-light emitting diode (IRED) on tip of the thumb, tip of the index finger and wrist as obtained in a prototypical trial. Green (light grey) functions are from the putting-actor, red (dark grey) functions are from the fetching-actor. The top-left graph shows the tangential wrist-velocity time functions, the top-right graph a 3D rendering of finger-thumb displacements, the bottom-left graph shows the aperture-time functions, and the bottom-right graph shows the height (in cm above the table surface) of the midpoint between the thumb and index-finger IREDs
The movement sequence of each actor was segmented into three intervals, the first interval corresponding to grasping the cylinder starting with the right hand in the home-position on the edge of the table and ending with finger and thumb making contact with the object, the second interval corresponding to the transportation of the cylinder to the target area (see put and fetch legends in Fig. 2), and the third interval corresponding to the participant’s hand returning to the home-position. The intervals were detected by a semi-automatic search procedure for relevant local minima in the tangential velocity profiles of the wrist movements. The time indexes thus found could be adjusted with an interactive computer program using a cross-hair whenever the experimenter considered the segmentation inaccurate.
Following segmentation, the data analyses focused on the displacements of the IREDs located on the tip of the thumb and index finger of each of the two actors. The top-right graph of Fig. 2 shows a 3D-graph of the typical finger–thumb displacements of the putting-actor (in green or light grey) and the fetching-actor (in red or dark grey). The three cylinders were added to this graph post hoc to indicate the phasing of the displayed movement patterns. The bottom-left graph of Fig. 2 shows the aperture-time functions of both actors. This figure was used to inspect the grasping behavior of the participants. Systematic aperture overshoots just prior to object contact and upon object release were visually checked by the experimenter to verify whether the task of each actor was performed as requested.
The bottom-right graph of Fig. 2 shows the height in the Z-dimension (perpendicular to the table surface) of the midpoint between the 3D positions of the IREDs on the thumb and index finger of each actor. This parameter reflected the surprise effects due to unexpected between-trial cylinder-weight changes on the lifting height, which was defined as the difference in the vertical position of the midpoint between the tips of the digits at the time of grasping the cylinder and the maximum height realized during transportation. In the second interval of each of the three-segment movement patterns, i.e., the green function for the putting-actor and the red function for the fetching-actor, this lifting height reflected the height with which the participants lifted the cylinder while transporting it to their target area.
The maximum lifting height (in cm) and the mean tangential wrist speed (in cm/s) realized by each actor during cylinder transport were used for further analyses. Statistical evaluation of the data consisted of repeated measures ANOVAs of which the designs are described in the relevant paragraphs in the results section or targeted t tests to evaluate specific hypotheses in more detail.
Results
Effects of cylinder properties
Figure 3 shows the means and standard errors of the lifting heights realized by the putter and fetcher as a function of cylinder mass, cylinder size and the repetition factor. Table 1 summarizes the results of the repeated measures ANOVA that was conducted to evaluate these effects with a factorial design consisting of the within-dyad factors 2 roles (put vs. fetch) × 2 object masses (light vs. heavy) × 2 object sizes (small vs. large diameter) × 3 repetitions. As expected, the light cylinders were lifted higher than the heavy ones [F(1,13) = 86.5, P < 0.001]. This effect interacted with object size [F(1,13) = 14.4, P < 0.01] in line with the size–weight illusion. For the light cylinders it was the smaller one that was lifted higher than the larger one. For the two heavy cylinders, it was the larger one that was lifted higher than the smaller one. The interaction between object mass and object size on lifting height—reflecting the size–weight illusion effect—was most pronounced in repetition 1 as confirmed by the first-order interaction between object mass and repetition [F(2,26) = 123.8, P < 0.001] but remained present in repetitions 2 and 3 as reflected by the second-order interaction between object mass, object size and repetition [F(2,26) = 3.78, P < 0.05], confirming the robustness of the size–weight illusion.
Fig. 3Means and standard errors of the lifting height (in cm) as a function of role (putting vs. fetching), object diameter (small vs. large) and object weight (light vs. heavy) for repetitions 1, 2 and 3 separatelyTable 1Results of repeated measures Anova on the lifting height according to a 2 role (putting vs. fetching) × 2 object mass (230 vs. 835 g) × 2 object sizes (2.5 vs. 6.5 cm in diameter) × 3 repetitions factorial designFactordfFPRole1,13<1NSObject mass1,1386.5<0.001Object size1,137.1<0.05Repetition2,2658.0<0.001Role × object mass1,13<1NSRole × object size1,131.3NSObject mass × object size1,1314.4<0.01Role × object mass × object size1,13<1NSRole × repetition2,26<1NSObject mass × repetition2,26123.8<0.001Role × object mass × repetition2,26<1NSObject size × repetition2,263.67<0.05Role × object size × repetition2,26<1NSObject mass × object size × repetition2,263.78<0.05Role × object mass × object size × repetition2,26<1NS
No main effect or interaction of role (put vs. fetch) was found (all Fs < 1), which was not unexpected since cylinder-weight increases and decreases were expected to have counteracting effects on the lifting heights by the putter and fetcher if any interpersonal transfer would take place at all. Targeted paired t tests confirmed that there were systematic interpersonal transfer effects of lifting height between putter and fetcher as will be described next.
A detailed time-series analysis of the lifting heights which the dyads realized indicated that the fetching-actor benefited from movement observation. The results of this analysis are shown in Fig. 4. In those cases in which from one trial block to the next the cylinder’s weight changed from heavy to light and the putting-actor showed a ‘surprise’ effect as reflected by an increase of her lifting height between these two trials of, on average, 4.69 cm, the fetching-actor showed a similar surprise effect but to a smaller extent. This reduced surprise effect in the fetching-actor of, on average, 3.67 cm, is shown in the left-hand graph of Fig. 4. The incidence of this effect was relatively high. It happened in 88% of those trials (i.e., N = 99) in which a heavy-to-light cylinder-weight change occurred. A two-tailed t test comparing the lifting heights on trial i − 1 and trial i (being the third trial of each trial block and the first of the subsequent block, respectively) for the putting-actor revealed that her surprise effect was statistically significant [t(98) = 15.98, P < 0.01]. For the fetching-actor, the smaller surprise-effect was also statistically significant [t(98) = 13.54, P < 0.01]. A repeated measures ANOVA confirmed that the relevant interaction between role (putter vs. fetcher) and trial (i − 1 = heavy and i = light) was statistically significant [F(1,13) = 7.24, P < 0.05].
Fig. 4Means and standard errors of the lifting height (in cm) of the putting-actor and the fetching-actor. Left-hand graph: whenever the putting-actor showed a lifting-height increase from trial i − 1 to trial i due to an unexpected mass reduction between these trials, the fetching-actor also showed this surprise effect but less strong. Trials i − 1 were the third trials of the trial blocks; trials i were the first trials of the subsequent trial blocks. Right-hand graph: similarly, whenever the putting-actor showed a lifting-height decrease from trial i − 1 to trial i due to an unexpected mass increase between these trials, the fetching-actor also showed this surprise effect, but again, not as strong as the putting-actor did
We found a similar effect when focusing on those trial pairs in which the cylinder-weight changed from light to heavy and the putter showed a ‘surprise’ effect as reflected by a decrease of her lifting height between those trials. The results of this analysis are shown in the right-hand graph of Fig. 4. Whereas the putting-actor proved to lift the cylinder, on average, 2.21 cm less high when the cylinder turned heavier from trial i − 1 to trial i, the fetching-actor did so as well but, on average, for only 0.97 cm. The incidence of this phenomenon was at chance level, i.e., in 54% (N = 61) of the cases in which such a cylinder-weight change occurred in the experiment. A two-tailed t test comparing the lifting heights on trial i − 1 and trial i for the putting-actor and fetching-actor separately again revealed that the effects were statistically significant for both actors [t(60) = 12.08, P < 0.01, t(60) = 3.69, P < 0.01, respectively]. A repeated measures ANOVA confirmed that the relevant interaction between role (putter vs. fetcher) and trial (i − 1 = light and i = heavy) was statistically significant [F(1,13) = 31.08, P < 0.001].
The time-series analyses on light-to-heavy cylinder weight changes and vice versa were corroborated by the results of dyad-based linear regression analyses in which the lifting height of the putting-actor in the first trial of the trial blocks was used as predictor for that of the fetching-actor. In contrast to the repeated measures ANOVA, the regression analysis took into account lifting-height co-variations in both directions, i.e., increases as well as decreases. An example of these data is depicted in Fig. 5. The slopes of the resulting regression equations turned out to be smaller than 1.0 for all 14 dyads showing that the putting-actor was more surprised by a cylinder-weight change than the fetching-actor. For nine of the dyads the positive slope proved statistically significant (P < 0.05). On average, the slopes amounted to 0.43 (R2 = 0.25), indicating that the fetching-actors were less surprised by any cylinder-weight change than the putting-actors.
Fig. 5Example of the linear regression analysis between the lifting-height data generated by the putter and fetcher of 1 of the 14 dyads participating in the study. The data concern the first trial within trial blocks of three repetitions of the experimental conditions. The regression analyses revealed the robustness of the observed reduction of the size–weight illusion due to movement observation in the dyads studied. The dashed line with slope = 1 represents the situation in which the lifting height of the fetcher would equal that of the putter
Effects of target-area size variations
Figure 6 shows the average effects on the mean tangential wrist velocity of the putting and fetching-actors as a function of the manipulations of the size of the target regions where the cylinders had to be placed. The second part of the sequential action under study, i.e., fetching the cylinder from the middle of the table, proved for no apparent reason overall to be performed somewhat slower than the first part, i.e., putting the cylinder in the middle of the table. The performance speeds of the participants were independently tuned to the sizes of the target areas with which the actors were confronted. In line with Fitts’ law, small target areas elicited low speeds and large ones yielded high speeds. This relationship applied to both actors whether or not they were confronted with similar or dissimilar accuracy constraints. Table 2 summarizes the repeated measures ANOVA to evaluate these effects with a 2 roles (put vs. fetch) × 2 sizes of putting target region (‘putting-size’; small vs. large) × 2 sizes of fetching target region (‘fetching-size’; small vs. large) factorial design. The absence of the first-order interaction between putting-size and fetching-size (F < 1) and the second-order interaction between the factors role, putting-size and fetching-size confirm the robustness of these findings.
Fig. 6Means and standard errors of the mean wrist speed (in cm/s) as a function of role (putting vs. fetching) and target area size (S = Small, L = Large; p = put, f = fetch). The labels with subscript p reflect the size of the target area of the putting-actor and labels with subscript f reflect the size of the target area of the fetching-actorTable 2Results of repeated measures ANOVA on the mean wrist speed (in cm/s) according to a 2 role (putting vs. fetching) × 2 putting-size (small vs. large target area) × 2 fetching-size (small vs. large target area) factorial designFactordfFPRole1,1318.60<0.01Putting-size1,1375.07<0.001Fetching-size1,1333.90<0.001Role × putting-size1,1320.21<0.001Role × fetching-size1,1322.03<0.001Putting-size × fetching-size1,13<1NSRole × putting-size × fetching-size1,13<1NS
A trial-by-trial inspection of the speed changes of both actors revealed, however, a moderate degree of performance-speed adaptation by the fetching-actor to that of the putting-actor. Figure 7 shows the results of this analysis. If from one trial to the next the size of the target areas remained constant for both actors but the putting-actor increased her performance speed for some reason, the fetching-actor followed this incidental speed increase of the putting-actor only partially as shown in the left-hand graph of Fig. 7. The incidence of this co-variation in performance speed between the two actors was below chance level, i.e., it happened in 34% (N = 150) of the cases in which the phenomenon could theoretically occur. Nevertheless, the changes in speed were, in both actors, statistically significant [t(149 = 7.63, P < 0.02 and t(149) = 5.95, P < 0.01, two-tailed, for the putting-actor and fetching-actor, respectively).
Fig. 7Means and standard errors of the wrist speed (in cm/s) of the putting-actor and the fetching-actor. Left-hand graph: whenever the putting-actor showed a task-unrelated speed increase from trial i − 1 to trial i, the fetching-actor also showed such a speed increase. The trials involved concerned the second and third trials of the trial blocks in which no task conditions changed. Right-hand graph: similarly, whenever the putting-actor showed a task-unrelated speed decrease from trial i − 1 to trial i, the fetching-actor followed this speed decrease
The reverse co-variation of performance speeds happened slightly more often. The right-hand graph of Fig. 7 shows that whenever the putting-actor reduced her movement speed from trial i - 1 to trial i during which the size of the target regions remained constant, the fetching-actor again partially followed this speed decrease. This co-variation in speed occurred in 42% (N = 186) of the cases in which this effect could occur. For the putting-actor and fetching-actor the speed decreases that were isolated here were again both statistically significant [t(185) = 5.95, P < 0.01 and t(185) = 3.32, P < 0.01, two-tailed, respectively].
Linear regression analyses in which the mean wrist speeds of the putting-actor as observed in the second and third trials of the trial blocks were used as predictor for that of the fetching-actor confirmed the just described results. The slopes of the regression equations proved positive for 12 of the 14 dyads indicating that the fetching-actor followed the speed changes of the putting-actor in direction but only partially in size. For 10 of the 14 dyads the positive correlations proved statistically significant (P < .05). R2s in these analyses ranged between 0 and 0.33 (mean R2 was 0.11) indicating the target-size independent speed relationship between the two actors was weak.
Combined effects of size–weight illusion and speed-accuracy trade-off
An inspection of the combined effects of the three task constraints that were manipulated revealed that even though on average the heavier cylinders were transported at a systematically lower speed than the lighter cylinders (mean = 43.78 cm/s; SD = 8.37 cm/s for the light cylinders and M = 38.14 cm/s; SD = 7.06 cm/s for the heavy cylinders), the speed variations due to the variations in the size and weight of the cylinders did not differentially affect the movement-speed variations as a result of the target-area size variations. Lifting-height variations due to the spatial accuracy-constraint manipulations were marginal (<2 mm) and also did not systematically influence the lifting-height variations due to the size-illusion effect.
Discussion
The present study examined the extent to which at the level of movement kinematics a transfer of performance parameters takes place between co-actors involved in transferring objects. The results of the main analyses that we conducted to assess the effect sizes of the experimental manipulations were largely negative. Object-mass variations induced lifting-height variations of equal size in both actors. Target-region size based speed variations also did not show interpersonal transfer. These results suggest that in sequential joint actions the tuning to each others movement parameters is absent and thus demonstrate the limits of automatic movement simulation by observation as suggested by mirror-neuron theories (Gallese and Goldman 1998; Gallese et al. 2004; Rizzolatti and Craighero 2004). However, it remains to be seen whether the mirror-neuron system represents observed actions with a precision that allows for direct imitation. This does not appear to be the case in macaque monkeys. One could claim that any hypothetical system in general could infer the goals/intentions of observed movements without explicitly representing, say, the speed of the movement.
More detailed analyses of incidental interpersonal transfer effects indicated that the situation was more complex than that. When focusing on the effects of between-trial cylinder-weight changes, the actor who was confronted with such changes first showed a systematically larger surprise-effect than the actor who was asked to transport the cylinder after the first actor had done so. A key finding here was that through the realized trajectory height during object transportation, the object mass was picked up by movement observation and integrated into the observer’s movement plan. Our prediction was therefore confirmed, i.e., the movements of an actor are likely to affect a subsequent, complementary movement generated by an observer.
Regarding the size of the effects it proved that the object property mass was, via lifting height, a more prominent factor determining task performance of the co-actors than movement speed. The linear regression analyses of the between-trial lifting-height changes due to cylinder-mass changes yielded larger proportions of explained variance when correlating the behavior of the fetching-actor with that of the putting-actor than the comparable analyses involving the incidental speed changes. With respect to goals and means of task performance, the dominance of object-mass over target-width makes sense given that the object is more likely to function as a goal in the task of handing over objects than the movements needed to perform such a task (Cuijpers et al. 2006). In a similar vein, the different sizes of the effects of object mass and movement speed could be taken to provide support for the importance of goal-inference making in collaborative joint action over and above a quasi-automatic, direct-matching based process of movement imitation or ‘motor resonance’ (Flanagan and Johansson 2003; Iacoboni et al. 1999; Koski et al. 2003) (Fig. 8).
Fig. 8Example of the linear regression analysis between the wrist-speed data generated by the putter and fetcher of 1 of the 14 dyads participating in the study. The data concern the second and third trials within trial blocks of three repetitions of the experimental conditions. The regression analyzes revealed the robustness of the observed, task-constraint independent covariation of movement speed between the two actors. The dashed line with slope = 1 represents the situation in which the wrist speed of the fetcher would equal that of the putter
Our interpretation of the current results does rely, of course, on the validity of both the weight-change effects and the co-variation of the actors’ movement speeds. It could be argued that the fetcher’s movement speed covaried with that of the putter due to a non-specific, visually primed increase in attention rather than the direct consequence of perceiving the putter’s object-transportation movements. However, attentional mechanisms are an unlikely explanation for our observations since the only visual cue that could have increased the attention in the fetcher was the putter’s movement speed. Whether the object-weight related adaptation in the fetcher to the observed movement of the putter was due to the inference of the weight of the object or to the observed kinematics per se, also remains a matter of discussion. If it was the former, then motor resonance (i.e., mirror-neuron system) may not be responsible for a direct transfer of the kinematics parameters.
The effects of the object and the accuracy constraints differ in one fundamental aspect. The expected information transfer for the object is valid for the programming of the movement, while any hypothesized transfer of speed, by simple copying the observed movement to reduce dimensionality violates Fitts’ law. This implies that our hypothesis about the transfer of speed was either not valid or that the effect is intrinsically short lived because the duration of the effect is overruled by intrapersonal constraints. In other words, while the information about weight change is very relevant for movement programming, the examined speed changes were not.
Apparently, movements that are being observed in a joint-action task can be used for multiple purposes. First, the observation might lead to internal simulation in order to understand the behavior that is being observed (Rizzolatti and Craighero 2004). Second, the internally simulated movements might provide clues as to the intentions associated with the observed behavior (Oztop et al. 2005; Wolpert et al. 2003; Iacoboni et al. 2005). Third, the observed movements might form the basis for prediction as to what an actor might do in the near future (Csibra 2005). Fourth, observed movements might provide clues about the task constraints at hand. In the present experiment, lifting height was such a parameter that indicated to the observer the weight of the cylinder that was transported. Fifth, observed movements may provide a global scaling parameter of ones own future actions, specifically if these actions are complementary to those performed by the actor that is being observed. Further research into the factors that determine the relative importance of these various roles which action observation may play in joint action is clearly needed.
Our study also suggests that kinematic parameters picked up during movement observation may even affect a subsequent movement that is performed in a workspace that is totally differently oriented than the workspace of the actor being observed. This finding extends the findings of the recent study by Van Schie et al. (2004) who showed that action observation activates cortical motor areas as if the observer had performed the task herself, i.e., when an observer who is facing an actor sees that actor move with her right hand the right cortical motor areas of the observer become activated indicating that the observer would have executed the task with her left hand. These findings suggest that movement simulation is egocentric and viewpoint-dependent.
Our demonstration of interpersonal action coordination in complementary joint action was restricted to the successive transportation of a cylinder by two actors. The movements preceding and succeeding the actual transportation of the cylinder could also have been scrutinized for signs of action coordination. However, the amplitudes of these movements by the two actors were hardly comparable. Moreover, the dyads involved in this study showed, not surprisingly, also the tendency to wanting to start task performance simultaneously. The preference of people to adopt either in-phase or out-of-phase timing patterns is not only prevalent in individual, inter-limb coordination tasks but also when people perform tasks together (Schmidt and O’Brien 1997; Shockley et al. 2003). These tendencies clearly co-exist alongside the casual transfer of kinematic movement parameters in dyadic action sequences.

coordination
grasping
joint action
size–weight illusion
fitts’ law