Blood volume and hemodynamics during treatment of major hemorrhage with Ringer solution, 5% albumin, and 20% albumin: a single-center randomized controlled trial.

BACKGROUND: Volume replacement with crystalloid fluid is the conventional treatment of hemorrhage. We challenged whether a standardized amount of 5% or 20% albumin could be a viable option to maintain the blood volume during surgery associated with major hemorrhage. Therefore, the aim of this study was to quantify and compare the plasma volume expansion properties of 5% albumin, 20% albumin, and Ringer-lactate, when infused during major surgery. METHODS: In this single-center randomized controlled trial, fluid replacement therapy to combat hypovolemia during the hemorrhagic phase of cystectomy was randomly allocated in 42 patients to receive either 5% albumin (12 mL/kg) or 20% albumin (3 mL/kg) over 30 min at the beginning of the hemorrhagic phase, both completed by a Ringer-lactate replacing blood loss in a 1:1 ratio, or Ringer-lactate alone to replace blood loss in a 3:1 ratio. Measurements of blood hemoglobin over 5 h were used to estimate the effectiveness of each fluid to expand the blood volume using the following regression equation: blood loss plus blood volume expansion = factor + volume of infused albumin + volume of infused Ringer-lactate. RESULTS: The median hemorrhage was 848 mL [IQR: 615-1145]. The regression equation showed that the Ringer-lactate solution expanded the plasma volume by 0.18 times the infused volume while the corresponding power of 5% and 20% albumin was 0.74 and 2.09, respectively. The Ringer-lactate only fluid program resulted in slight hypovolemia (mean, - 313 mL). The 5% and 20% albumin programs were more effective in filling the vascular system; this was evidenced by blood volume changes of only + 63 mL and - 44 mL, respectively, by long-lasting plasma volume expansion with median half time of 5.5 h and 4.8 h, respectively, and by an increase in the central venous pressure. CONCLUSION: The power to expand the plasma volume was 4 and almost 12 times greater for 5% albumin and 20% albumin than for Ringer-lactate, and the effect was sustained over 5 h. The clinical efficacy of albumin during major hemorrhage was quite similar to previous studies with no hemorrhage. TRIAL REGISTRATION: ClinicalTrials.gov NCT05391607, date of registration May 26, 2022.

Ventilatory efficiency as a prognostic factor for postoperative complications in patients undergoing elective major surgery: a systematic review.

BACKGROUND: Major surgery is associated with high complication rates. Several risk scores exist to assess individual patient risk before surgery but have limited precision. Novel prognostic factors can be included as additional building blocks in existing prediction models. A candidate prognostic factor, measured by cardiopulmonary exercise testing, is ventilatory efficiency (VE/VCO2). The aim of this systematic review was to summarise evidence regarding VE/VCO2 as a prognostic factor for postoperative complications in patients undergoing major surgery. METHODS: A medical library specialist developed the search strategy. No database-provided limits, considering study types, languages, publication years, or any other formal criteria were applied to any of the sources. Two reviewers assessed eligibility of each record and rated risk of bias in included studies. RESULTS: From 10,082 screened records, 65 studies were identified as eligible. We extracted adjusted associations from 32 studies and unadjusted from 33 studies. Risk of bias was a concern in the domains 'study confounding' and 'statistical analysis'. VE/VCO2 was reported as a prognostic factor for short-term complications after thoracic and abdominal surgery. VE/VCO2 was also reported as a prognostic factor for mid- to long-term mortality. Data-driven covariable selection was applied in 31 studies. Eighteen studies excluded VE/VCO2 from the final multivariable regression owing to data-driven model-building approaches. CONCLUSIONS: This systematic review identifies VE/VCO2 as a predictor for short-term complications after thoracic and abdominal surgery. However, the available data do not allow conclusions about clinical decision-making. Future studies should select covariables for adjustment a priori based on external knowledge. SYSTEMATIC REVIEW PROTOCOL: PROSPERO (CRD42022369944).

Outcomes reported in randomised trials of surgical prehabilitation: a scoping review.

BACKGROUND: Heterogeneity of reported outcomes can impact the certainty of evidence for prehabilitation. The objective of this scoping review was to systematically map outcomes and assessment tools used in trials of surgical prehabilitation. METHODS: MEDLINE, EMBASE, PsychInfo, Web of Science, CINAHL, and Cochrane were searched in February 2023. Randomised controlled trials of unimodal or multimodal prehabilitation interventions (nutrition, exercise, psychological support) lasting at least 7 days in adults undergoing elective surgery were included. Reported outcomes were classified according to the International Society for Pharmacoeconomics and Outcomes Research framework. RESULTS: We included 76 trials, mostly focused on abdominal or orthopaedic surgeries. A total of 50 different outcomes were identified, measured using 184 outcome assessment tools. Observer-reported outcomes were collected in 86% of trials (n=65), with hospital length of stay being most common. Performance outcomes were reported in 80% of trials (n=61), most commonly as exercise capacity assessed by cardiopulmonary exercise testing. Clinician-reported outcomes were included in 78% (n=59) of trials and most frequently included postoperative complications with Clavien-Dindo classification. Patient-reported outcomes were reported in 76% (n=58) of trials, with health-related quality of life using the 36- or 12-Item Short Form Survey being most prevalent. Biomarker outcomes were reported in 16% of trials (n=12) most commonly using inflammatory markers assessed with C-reactive protein. CONCLUSIONS: There is substantial heterogeneity in the reporting of outcomes and assessment tools across surgical prehabilitation trials. Identification of meaningful outcomes, and agreement on appropriate assessment tools, could inform the development of a prehabilitation core outcomes set to harmonise outcome reporting and facilitate meta-analyses.

Towards a common definition of surgical prehabilitation: a scoping review of randomised trials.

BACKGROUND: There is no universally accepted definition for surgical prehabilitation. The objectives of this scoping review were to (1) identify how surgical prehabilitation is defined across randomised controlled trials and (2) propose a common definition. METHODS: The final search was conducted in February 2023 using MEDLINE, Embase, PsycINFO, Web of Science, CINAHL, and Cochrane. We included randomised controlled trials (RCTs) of unimodal or multimodal prehabilitation interventions (nutrition, exercise, and psychological support) lasting at least 7 days in adults undergoing elective surgery. Qualitative data were analysed using summative content analysis. RESULTS: We identified 76 prehabilitation trials of patients undergoing abdominal (n=26, 34%), orthopaedic (n=20, 26%), thoracic (n=14, 18%), cardiac (n=7, 9%), spinal (n=4, 5%), and other (n=5, 7%) surgeries. Surgical prehabilitation was explicitly defined in more than half of these RCTs (n=42, 55%). Our findings consolidated the following definition: 'Prehabilitation is a process from diagnosis to surgery, consisting of one or more preoperative interventions of exercise, nutrition, psychological strategies and respiratory training, that aims to enhance functional capacity and physiological reserve to allow patients to withstand surgical stressors, improve postoperative outcomes, and facilitate recovery.' CONCLUSIONS: A common definition is the first step towards standardisation, which is needed to guide future high-quality research and advance the field of prehabilitation. The proposed definition should be further evaluated by international stakeholders to ensure that it is comprehensive and globally accepted.

Perioperative continuation of aspirin, oral anticoagulants or bridging with therapeutic low-molecular-weight heparin does not increase intraoperative blood loss and blood transfusion rate in cystectomy patients: an observational cohort study.

OBJECTIVE: To assess if uninterrupted anticoagulant agents' administration affects blood loss and blood transfusion during open radical cystectomy (RC) and urinary diversion. PATIENTS AND METHODS: We conducted an observational single-centre cohort study of a consecutive series of 1430 RC patients, between 2000 and 2020. Blood loss was depicted according to body weight and duration of surgery (mL/kg/h), and blood transfusion. The group 'with anticoagulant agents' was considered if surgery was performed with uninterrupted low-dose aspirin (ASS), oral anticoagulants (OAC) with an international normalised ratio (INR) goal of 2-2.5 or bridging with therapeutic low-molecular-weight heparin (LMWH). Outcomes were intraoperative blood loss, blood transfusion rate (separately analysed if administered within 24 h perioperatively or >24 h after surgery) and the 90-day major adverse cardiac events (MACE) rate. We used propensity score (PS)-matching analysis to adjust for imbalances between groups with or without anticoagulant agents. RESULTS: The PS-matched median (interquartile range [IQR]) blood loss was 2.10 (1.50-2.94) mL/kg/h in patients with anticoagulant agents vs 2.11 (1.47-2.94) mL/kg/h without anticoagulant agents (Padj > 0.99). The PS-matched blood transfusion rates were 26.2% vs 35.1% (Padj = 0.875) within 24 h perioperatively and 57.0% vs 55.0% (Padj = 0.680) if administered >24 h postoperatively. A sub-analysis of the three different anticoagulant agents could not detect any significance between ASS, OAC, or LMWH. The PS-matched incidence of MACE was 9.1% in the group with anticoagulant agents and 8.1% in those without anticoagulant agents (Padj > 0.99). Limitations include selection bias and retrospective analysis from prospectively assessed data. CONCLUSIONS: Perioperative continuation of ASS, uninterrupted OAC with low INR goal or bridging with LMWH had no impact on blood loss and transfusion rate in RC patients. Therefore, there might be no compulsory need for discontinuation of anticoagulant agents.

Strategies for optimal perioperative outcomes in gastric cancer.

Cancer and surgery represent a major stress on the human body. Any condition that prevents patients from tolerating the physiological stress is a risk factor for poor outcome. There is a need to identify these impairments early in the process with a simple screening, followed by assessments that provide a holistic picture of the patient. The proposed path of multimodal prehabilitation acts synergistically with enhanced recovery after surgery care to achieve optimal patient outcomes.

Plasma disappearance rate of albumin when infused as a 20% solution.

BACKGROUND: The transcapillary leakage of albumin is increased by inflammation and major surgery, but whether exogenous albumin also disappears faster is unclear. METHODS: An intravenous infusion of 3 mL/kg of 20% albumin was given over 30 min to 70 subjects consisting of 15 healthy volunteers, 15 post-burn patients, 15 patients who underwent surgery with minor bleeding, 10 who underwent surgery with major bleeding (mean, 1.1 L) and 15 postoperative patients. Blood Hb and plasma albumin were measured on 15 occasions over 5 h. The rate of albumin disappearance from the plasma was quantitated with population kinetic methodology and reported as the half-life (T1/2). RESULTS: No differences were observed for T1/2 between volunteers, post-burn patients, patients who underwent surgery with minor bleeding and postoperative patients. The T1/2 averaged 16.2 h, which corresponds to 3.8% of the amount infused per h. Two groups showed plasma concentrations of C-reactive protein of approximately 60 mg/L and still had a similarly long T1/2 for albumin. By contrast, patients undergoing surgery associated with major hemorrhage had a shorter T1/2, corresponding to 15% of the infused albumin per h. In addition, our analyses show that the T1/2 differ greatly depending on whether the calculations consider plasma volume changes and blood losses. CONCLUSION: The disappearance rate of the albumin in 20% preparations was low in volunteers, in patients with moderately severe inflammation, and in postoperative patients.

Impact of early postoperative creatinine increase on mid-term renal function after cystectomy.

OBJECTIVES: To determine whether early acute kidney injury affects mid-term renal function, to identify risk factors for impaired mid-term renal function, and to highlight the evolution of plasma creatinine and estimated glomerular filtration rate in the first 12 months after cystectomy and urinary diversion. METHODS: We conducted a single-center retrospective observational cohort study from 2000 to 2019. We included 900 consecutive patients undergoing cystectomy and urinary diversion. Patients with incomplete data and preoperative hemodialysis were excluded. Early acute kidney injury was defined as an increase in plasma creatinine of >50% or >26.5 µmol/L within 24 h after surgery. Multiple linear regression analysis was performed to model the association between risk factors and change in plasma creatinine and estimated glomerular filtration rate at 12 months. RESULTS: Early acute kidney injury was diagnosed in 183/900 patients (20.3%) and was associated with significant mid-term plasma creatinine increase compared to preoperative value (+10.0 µmol/L [95% confidence interval -1.5, 25.0] vs +4.0 µmol/L [-7.0, 13.0]; P < 0.001). Similarly, a significant estimated glomerular filtration rate change was found (-11.2 mL/min [95% confidence interval -19.8, 0.6] vs -4.9 mL/min [-15.6, 5.3]; P < 0.001). In the linear regression model, early acute kidney injury increased creatinine at 12 months by 9.8% (estimated glomerular filtration rate: decrease by 6.2 mL/min), male sex by 12.0%. Limitations include retrospective analysis from prospectively assessed data. CONCLUSIONS: Early acute kidney injury resulted in elevated plasma creatinine and decreased estimated glomerular filtration rate values 12 months postoperatively, albeit the clinical relevance remains questionable.

Intraoperative Intravascular Effect of Lactated Ringer's Solution and Hyperoncotic Albumin During Hemorrhage in Cystectomy Patients.

BACKGROUND: The intraoperative effect of 20% albumin on plasma volume during surgery involving major blood loss has not been explored extensively due to methodological difficulties. Crystalloids poorly expand the plasma volume, and using a colloid might then be a way to avoid fluid overload. As doubts have been raised about synthetic colloids, albumin solutions are currently used more extensively. This study presents a methodological development showing how plasma volume expansion can be studied in surgical settings with the coinfusion of 20% albumin and lactated Ringer's solution. METHODS: In this single-arm, single-center feasibility study, an intravenous (i.v.) infusion of 3 mL·kg·BW-1 of 20% albumin was administered over 30 minutes to 23 cystectomy patients during the bleeding phase in addition to lactated Ringer's solution to correct blood loss. Blood samples were measured at regular intervals over a period of 300 minutes to estimate the blood volume expansion resulting from simultaneous infusions of lactated Ringer's and 20% albumin solutions, using a regression equation and the area under the volume-time curve method. RESULTS: Mean hemorrhage was 974 mL (standard deviation [SD] ± 381). The regression method showed strong correlation (r2 = 0.58) between blood loss minus blood volume expansion and the independent effects of the infused volume of lactated Ringer's and 20% albumin solutions. The mean plasma volume expansion attributable to the infusion of lactated Ringer's solution amounted to 0.38 (95% confidence interval [CI], 0.31-0.49) of the infused volume; for the 20% albumin, it was 1.94 mL/mL (95% CI, 1.41-2.46 mL/mL) over 5 hours on average (regression method). The mean within-patient change was 0.20 mL/mL (± 0.06 mL/mL) for the lactated Ringer's solution and 2.20 mL/mL (±1.31 mL/mL) for the 20% albumin using the area under the volume-time curve method. CONCLUSIONS: Blood volume expansion averaged 1.9-2.2 times the infused volume of 20% albumin during surgery associated with hemorrhage of around 1000 mL. This effect was long standing and approximately 5 times stronger than for the lactated Ringer's solution. Twenty percent albumin boosts the plasma volume expansion of lactated Ringer's solution to as high as 40% of the infused volume on the average, which is an effect that lasts at least 5 hours.

Perioperative predictors of early surgical revision and flap-related complications after microvascular free tissue transfer in head and neck reconstructions: a retrospective observational series.

OBJECTIVES: The aim of this study was to determine the influence of perioperative fluid management and administration of vasopressors on early surgical revision and flap-related complications in free tissue transfer. MATERIALS AND METHODS: Intraoperative amount of fluid and of vasopressors, relevant perioperative parameters, and comorbidities were recorded in 131 patients undergoing head and neck microvascular reconstruction and compared with early surgical complications, defined as interventions requiring surgery after a flap-related complication, and/or other surgical problems in the operating room within 30 days after initial surgery. The relationship between perioperative variables for each revision category was determined using an optimized multiple logistic regression. RESULTS: The administration of diuretics (p=0.001) as a treatment for perioperative fluid overload and the type of flap (p=0.019) was associated with a higher risk of early surgical revisions. Perioperative fluid overload (p=0.039) is significantly related to flap-related complications. We found no effect of intraoperative administration of vasopressors on early surgical revisions (p=0.8) or on flap-related complications (norepinephrine p=0.6, dobutamine p=0.5). CONCLUSION: Perioperative fluid overload is associated with higher risks of early surgical revision and flap-related complications. In contrast, the administration of vasopressors seemed to have no effect on either surgical revision rate or flap-related complications. CLINICAL RELEVANCE: In patients receiving microvascular reconstructions, a balanced fluid administration perioperatively and a targeted use of vasopressors should be the necessary strategy to reduce the complication rates in head and neck surgery.

Robustness to Axon Initial Segment Variation Is Explained by Somatodendritic Excitability in Rat Substantia Nigra Dopaminergic Neurons.

In many neuronal types, axon initial segment (AIS) geometry critically influences neuronal excitability. Interestingly, the axon of rat SNc dopaminergic (DA) neurons displays a highly variable location and most often arises from an axon-bearing dendrite (ABD). We combined current-clamp somatic and dendritic recordings, outside-out recordings of dendritic sodium and potassium currents, morphological reconstructions and multicompartment modeling on male and female rat SNc DA neurons to determine cell-to-cell variations in AIS and ABD geometry, and their influence on neuronal output (spontaneous pacemaking frequency, action potential [AP] shape). Both AIS and ABD geometries were found to be highly variable from neuron to neuron. Surprisingly, we found that AP shape and pacemaking frequency were independent of AIS geometry. Modeling realistic morphological and biophysical variations helped us clarify this result: in SNc DA neurons, the complexity of the ABD combined with its excitability predominantly define pacemaking frequency and AP shape, such that large variations in AIS geometry negligibly affect neuronal output and are tolerated.SIGNIFICANCE STATEMENT In many neuronal types, axon initial segment (AIS) geometry critically influences neuronal excitability. In the current study, we describe large cell-to-cell variations in AIS length or distance from the soma in rat substantia nigra pars compacta dopaminergic neurons. Using neuronal reconstruction and electrophysiological recordings, we show that this morphological variability does not seem to affect their electrophysiological output, as neither action potential properties nor pacemaking frequency is correlated with AIS morphology. Realistic multicompartment modeling suggests that this robustness to AIS variation is mainly explained by the complexity and excitability of the somatodendritic compartment.

Surgical safety in radical cystectomy: the anesthetist's point of view-how to make a safe procedure safer.

PURPOSE: The aim of this review is to present an anesthesiological overview on surgical safety for radical cystectomy implementing the cornerstones of today's rapidly evolving field of perioperative medicine. METHODS: This is a narrative review of current perioperative medicine and surgical safety concepts for major surgery in general with special focus on radical cystectomy. RESULTS: The tendency for perioperative care and surgical safety is to consider it a continuous proactive pathway rather than a single surgical intervention. It starts at indication for surgery and lasts until full functional recovery. Preoperative optimization leads to superior outcome by mobilizing and/or increasing physiological reserve. Multidisciplinary teamwork involving all the relevant parties from the beginning of the pathway is crucial for outcome rather than an isolated specialist approach. This fact has gained importance in times of an ageing frail population and rising health care cost. We also present our 2019 Cystectomy Enhanced Recovery Approach for optimization of perioperative care for open radical cystectomy in a high caseload center. CONCLUSIONS: With the implementation of in itself simple but crucial steps in perioperative medicine such as multimodal prehabilitation, safety checks, better perioperative monitoring and enhanced recovery concepts, even complex surgical procedures such as radical cystectomy can be performed safer. Emphasis has to be laid on a more global view of the patients' path through the perioperative process than on the surgical procedure alone.

Intra-operative norepinephrine administration and cancer-related outcomes following radical cystectomy for bladder cancer: A cohort study.

BACKGROUND: The impact of anaesthetic techniques on recurrence of cancers is controversial. Elevated plasma catecholamine levels have been implicated in angiogenesis and metastasis in various cancers. OBJECTIVES: To assess the potential association between continuous intra-operative norepinephrine administration and tumour-related outcome in muscle-invasive bladder cancer patients undergoing radical cystectomy with urinary diversion. DESIGN: Retrospective observational cohort study. SETTING: Single tertiary centre, from 2000 to 2017. PATIENTS: We included a consecutive series of 1120 urothelial carcinoma patients undergoing radical cystectomy and urinary diversion, including 411/1120 patients (37%) who received a continuous intra-operative administration of more than 2 µg kg BW h norepinephrine. MAIN OUTCOME MEASURES: The primary outcome was time to tumour recurrence within 5 years after surgery, with death as competing outcome. We used inverse probability of treatment weighting to adjust for imbalances between treatment groups, one having received more than 2 µg kg BW h norepinephrine and the other having received less. We furthermore adjusted for intra-operative variables or years of surgery as sensitivity analyses. RESULTS: The continuous administration of more than 2 µg kg BW h norepinephrine slightly increased tumour recurrence (hazard ratio: 1.47, 95% CI 0.98 to 2.21; P = 0.061). After adjustment for intra-operative variables, and year of surgery hazard ratios were 1.82 (95% CI 1.13 to 2.91, P = 0.013) and 1.85 (95% CI 1.12 to 3.07, P = 0.017), respectively. Overall mortality (with or without tumour recurrence) was not affected by norepinephrine (hazard ratio: 0.84, 95% CI 0.65 to 1.08, P = 0.170). CONCLUSION: Continuous administration of more than 2 µg kg BW h norepinephrine was associated with a slightly increased hazard ratio for tumour recurrence if adjusted for intra-operative variables and year of surgery. This observation could reflect a low potential pro-oncogenic effect of norepinephrine during the intra-operative period. TRIAL REGISTRATION: Not applicable.

Subsaturation of the N-methyl-D-aspartate receptor glycine site allows the regulation of bursting activity in juvenile rat nigral dopamine neurons.

The activation of N-methyl-D-aspartate receptors (NMDARs) in substantia nigra pars compacta (SNc) dopamine (DA) cells is central to generate the bursting activity, a phasic signal linked to DA-related behaviours via the change in postsynaptic DA release. NMDARs are recruited during excitatory synaptic transmission by glutamate release, but the glycine site level of occupancy of these receptors during basal action potential-dependent activity is not known for SNc DA neurons. We explored NMDAR-dependent signals during exogenous applications of co-agonists in midbrain slices from juvenile rats. We found that both glycine and D-serine strengthened the NMDAR-dependent component of excitatory postsynaptic currents (EPSCs) in a concentration-dependent manner. EPSCs were also increased by endogenous glycine via the blockade of the glycine transport. The glycine site of NMDARs contributing to synaptic transmission is therefore subsaturated. The behaviourally relevant burst firing was more sensitive to exogenous D-serine and endogenous glycine than to exogenous glycine. The mechanisms regulating the availability of the co-agonists exert consequently a critical influence on the excitability of DA neurons via NMDARs. The modulation of the phasic firing in DA neurons by ambient NMDAR co-agonists may be important for nigral information processing and downstream motor-related behaviour.

Differential Somatic Ca2+ Channel Profile in Midbrain Dopaminergic Neurons.

UNLABELLED: Dopaminergic (DA) neurons located in the ventral midbrain continuously generate a slow endogenous pacemaker activity, the mechanism of which is still debated. It has been suggested that, in the substantia nigra pars compacta (SNc), the pacemaking relies more on Ca(2+) channels and that the density of L-type Ca(2+) channels is higher in these DA neurons than in those located in the ventral tegmental area (VTA). This might lead to a higher Ca(2+) load in SNc DA neurons and explain their higher susceptibility to degeneration. However, direct evidence for this hypothesis is lacking. We found that the L-type current and channel density are indeed higher in the somata of rat SNc DA neurons and that this current undergoes less inactivation in this region. Nonstationary fluctuation analysis measurements showed a much higher number of L-type channels in the soma of SNc DA neurons, as well as a smaller single-channel conductance, pointing to a possible different molecular identity of L-type channels in DA neurons from the two areas. A major consequence of this is that pacemaking and, even more so, bursting are associated with a larger Ca(2+) entry through L-type channels in SNc DA neurons than in their VTA counterparts. Our results establish a molecular and functional difference between two populations of midbrain DA neurons that may contribute to their differential sensitivity to neurodegeneration. SIGNIFICANCE STATEMENT: Dopamine neurons from the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) are involved in various brain functions, such as movement initiation and goal directed behavior, respectively. This work shows that, although both neurons fire in a similar regular and slow pacemaker mode, this firing activity is supported by different calcium channel landscapes. Indeed, the L-type calcium current is larger in the soma of dopamine neurons of the SNc, leading to a higher charge transfer through L-type channels during pacemaking and bursting. Therefore, these neurons may be physiologically exposed to a larger stress than their neighbors from the VTA.

High dendritic expression of Ih in the proximity of the axon origin controls the integrative properties of nigral dopamine neurons.

KEY POINTS: The hyperpolarization-activated cation current Ih is expressed in dopamine neurons of the substantia nigra, but the subcellular distribution of the current and its role in synaptic integration remain unknown. We used cell-attached patch recordings to determine the localization profile of Ih along the somatodendritic axis of nigral dopamine neurons in slices from young rats. Ih density is higher in axon-bearing dendrites, in a membrane area close to the axon origin, than in the soma and axon-lacking dendrites. Dual current-clamp recordings revealed a similar contribution of Ih to the waveform of single excitatory postsynaptic potentials throughout the somatodendritic domain. The Ih blocker ZD 7288 increased the temporal summation in all dendrites with a comparable effect in axon- and non-axon dendrites. The strategic position of Ih in the proximity of the axon may influence importantly transitions between pacemaker and bursting activities and consequently the downstream release of dopamine. ABSTRACT: Dendrites of most neurons express voltage-gated ion channels in their membrane. In combination with passive properties, active currents confer to dendrites a high computational potential. The hyperpolarization-activated cation current Ih present in the dendrites of some pyramidal neurons affects their membrane and integration properties, synaptic plasticity and higher functions such as memory. A gradient of increasing h-channel density towards distal dendrites has been found to be responsible for the location independence of excitatory postsynaptic potential (EPSP) waveform and temporal summation in cortical and hippocampal pyramidal cells. However, reports on other cell types revealed that smoother gradients or even linear distributions of Ih can achieve homogeneous temporal summation. Although the existence of a robust, slowly activating Ih current has been repeatedly demonstrated in nigral dopamine neurons, its subcellular distribution and precise role in synaptic integration are unknown. Using cell-attached patch-clamp recordings, we find a higher Ih current density in the axon-bearing dendrite than in the soma or in dendrites without axon in nigral dopamine neurons. Ih is mainly concentrated in the dendritic membrane area surrounding the axon origin and decreases with increasing distances from this site. Single EPSPs and temporal summation are similarly affected by blockade of Ih in axon- and non-axon-bearing dendrites. The presence of Ih close to the axon is pivotal to control the integrative functions and the output signal of dopamine neurons and may consequently influence the downstream coding of movement.