Introduction

Prone positioning has become an increasingly common approach for thoracoscopic esophageal cancer surgery to facilitate surgical exposure. It has been associated with better surgical outcomes and improved perioperative safety compared to the classical lateral decubitus position [1]; however, it may significantly impact ventilation. Partial lung collapse and intrathoracic insufflation of carbon dioxide (CO₂), commonly used in these procedures, may contribute to significant alterations in respiratory physiology and acid-base balance.

Clinically, elevations in serum potassium levels associated with acute respiratory acidosis are often observed during these surgeries. While acidosis is generally known to affect potassium distribution, respiratory acidosis is typically considered to cause only minimal or no elevation in serum potassium compared to metabolic acidosis [2–3]. However, recent clinical reports challenge this view in the setting of critical illness; for instance, Pathak and Nanda described cases of severe, refractory hyperkalemia in COVID-19 patients where acute respiratory acidosis was identified as a major contributing factor [4]. Nevertheless, the combination of prone positioning, ventilatory compromise, and CO₂ insufflation may alter the expected physiological response.

The primary aim of this study is to quantify the magnitude of serum potassium elevation associated with acute respiratory acidosis during prone-position esophagectomy. Furthermore, we aim to explore the physiological drivers of this phenomenon, including the respective contributions of respiratory and metabolic factors. Ultimately, this research may contribute to enhancing the safety of ventilation strategies and optimizing electrolyte management for these complex procedures.

Methods

Discussion

This study protocol was designed to address a critical clinical observation: a greater-than-expected elevation in serum potassium during prone-position esophagectomy. This finding stands in contrast to the conventional physiological understanding that respiratory acidosis—a common consequence of this procedure—causes minimal or no elevation in serum potassium, particularly when compared to metabolic acidosis [2–3]. Therefore, the primary objective of this study is first to confirm and quantify the mean increase in serum potassium between the supine (baseline) and prone-position phases. Given that acute respiratory acidosis is an almost inevitable event during this surgical phase, demonstrating a statistically significant potassium increase would, in itself, strongly suggest a clinically relevant phenomenon that challenges existing knowledge. However, we recognize that major surgery introduces multiple confounding variables that could influence potassium levels, such as metabolic stress. To address this complexity, our secondary analyses are designed to (1) assess the robustness of our primary finding via sensitivity analysis that controls for the effect of metabolic acidosis, and (2) explore the association between the potassium increase and various physiological drivers, including the severity of respiratory acidosis itself.

In particular, surgical techniques involving partial lung collapse and intrathoracic CO₂ insufflation may lead to rapid external CO₂ loading, resulting in acid-base changes distinct from those seen in endogenous respiratory acidosis. Multiple mechanisms, including H⁺/K⁺ exchange and altered ATPase activity, may contribute to this response. The body’s compensatory systems may not be able to fully respond to the acute rise in PaCO₂, potentially leading to more pronounced potassium fluctuations than typically expected.

The challenge of managing this surgically-induced state of respiratory compromise aligns with the central theme of our previous research: using specific, non-physiological models of difficult ventilation to elucidate fundamental truths about respiratory physiology. For instance, in our previous study, we focused on patients with severe airway stenosis undergoing airway stenting—another scenario involving extreme, surgically-created ventilatory compromise. In that setting, we challenged the conventional wisdom that muscle relaxants are contraindicated. Our previous prospective study demonstrated that controlled positive-pressure ventilation with muscle relaxants significantly reduced hypoxic events compared to maintaining spontaneous respiration [7]. That study highlighted how standard management approaches can fail in such unique circumstances. The current study extends this principle from the primary challenge of ‘ventilation failure’ to its secondary consequence, ‘electrolyte failure’. Both studies, therefore, underscore a common lesson: the body’s response under these non-physiological conditions can be far more significant than conventionally anticipated.

The potential findings of this study are expected to have direct implications for the perioperative management of patients undergoing prone-position esophagectomy. If a significant potassium increase is confirmed, it would strongly suggest that rigorous monitoring is essential. This implies that arterial blood gas analysis should be considered whenever significant hypercapnia is suspected, even in the absence of desaturation (low SpO₂). This is particularly crucial given the potential for a large arterial to end-tidal CO₂ gradient (PaCO₂-ETCO₂) in this setting, which can mask the true severity of respiratory acidosis [8]. Early detection of hyperkalemia would enable timely therapeutic interventions to mitigate the risk of adverse events. Furthermore, as this surgery involves direct manipulation in close proximity to the heart, it inherently carries a high risk of cardiac arrhythmias. The addition of acute hyperkalemia—a known pro-arrhythmic factor—could substantially amplify this risk, making its detection and management a critical safety priority.

Beyond this specific surgical procedure, our findings hold potential implications for the management of critically ill patients in the ICU, particularly those with respiratory failure. Patients with conditions such as Acute Respiratory Distress Syndrome (ARDS) often present with comorbid cardiac or renal dysfunction, making them exceptionally vulnerable to the life-threatening consequences of hyperkalemia. Our findings may suggest that hyperacute respiratory acidosis, in particular, warrants closer monitoring of electrolyte balance than previously appreciated. This perspective may also prompt a re-evaluation of permissive hypercapnia strategies. While permissive hypercapnia is employed to protect the lungs, its potential impact on electrolyte homeostasis is not fully understood.

Our exploratory multivariable analysis, by seeking to identify predictors for the magnitude of potassium increase, may help in identifying surrogate markers to define the safe limits of hypercapnia in critically ill patients.

This study has several methodological strengths. First and foremost, the use of a paired-design, where each patient serves as their own control, is a powerful approach to minimize the influence of inter-patient variability. Second, its two-center nature increases the generalizability of our findings. Furthermore, the collection of detailed, serial arterial blood gas data allows for a granular analysis of the acute physiological changes. Finally, our pre-specified plan to conduct a sensitivity analysis demonstrates a rigorous effort to isolate the effects attributable to respiratory changes, thereby strengthening the specificity of our conclusions.

Several limitations of this study should be acknowledged. First, its retrospective design leads to inherent variability in the timing of blood gas sampling and a lack of standardized protocols. Second, our study includes only patients in whom blood gas analysis was performed, potentially introducing selection bias. However, we believe this may have selectively enriched our sample with patients exhibiting more severe respiratory compromise, which aligns with our primary research question. Finally, distinguishing the precise contributions of respiratory and metabolic components to a mixed acid-base disorder is inherently challenging.

In conclusion, this study protocol describes a robust investigation into the clinically significant hyperkalemia associated with hyperacute respiratory acidosis, a phenomenon particularly relevant in modern thoracic surgery. While a randomized controlled trial comparing prone and lateral surgical approaches might have once been considered the ideal design, such a trial is likely no longer ethically or practically feasible given the established clinical benefits of the prone-position approach.

Therefore, a well-designed, multicenter observational study such as the present one represents the best available methodology to elucidate this important physiological question. The insights gained from this research have the potential to refine electrolyte management, prompt a re-evaluation of concepts like permissive hypercapnia, and ultimately improve the safety of patients both in the operating room and the intensive care unit.