Introduction
In the field of cardiac surgery, few intraoperative challenges are as formidable as pulmonary hypertension (PH). Patients undergoing valvular heart surgery frequently present with elevated pulmonary arterial pressures, often secondary to long-standing left-sided heart disease. In such cases, the operating room becomes a delicate theater where anesthesiologists and surgeons must manage not only diseased valves but also the tenuous balance between the pulmonary vasculature and the right ventricle. A sudden rise in pulmonary vascular resistance (PVR) can precipitate acute right ventricular (RV) failure, catastrophic hemodynamic collapse, and even perioperative mortality.
Traditional management strategies for PH during cardiac surgery include inhaled nitric oxide, prostacyclin infusions, and phosphodiesterase inhibitors. Each has its merits and drawbacks. Nitric oxide, for instance, provides potent and selective pulmonary vasodilation but requires specialized delivery systems, is costly, and carries the risk of rebound PH upon discontinuation. Intravenous prostacyclin is powerful but lacks pulmonary selectivity and frequently causes systemic hypotension. Thus, the quest for an agent that can lower pulmonary pressures without destabilizing systemic hemodynamics remains ongoing.
Enter sildenafil citrate, a phosphodiesterase type 5 (PDE5) inhibitor widely recognized for its role in treating erectile dysfunction and chronic pulmonary arterial hypertension. By preventing the degradation of cyclic guanosine monophosphate (cGMP), sildenafil amplifies nitric oxide signaling, resulting in relaxation of pulmonary vascular smooth muscle. Importantly, PDE5 expression is disproportionately high in the pulmonary vasculature compared to systemic arteries, granting sildenafil a degree of pulmonary selectivity. The study by Shim and colleagues in 2006 evaluated the perioperative role of oral sildenafil in patients with PH undergoing valvular surgery—a clinical setting fraught with risk and in dire need of better pharmacologic tools.
Pulmonary Hypertension in Cardiac Surgery: A Dangerous Companion
Pulmonary hypertension complicates a significant proportion of patients undergoing valve surgery, especially those with mitral stenosis, mitral regurgitation, or advanced left ventricular dysfunction. Chronic elevation of left atrial pressure translates upstream to pulmonary venous hypertension, pulmonary arterial remodeling, and eventual right ventricular strain. When such patients arrive in the operating room, their pulmonary circulation is not only stiff but also exquisitely reactive to stressors such as hypoxia, hypercarbia, and surgical manipulation.
Intraoperatively, PH increases the risk of:
- Right ventricular failure due to increased afterload.
- Hypotension secondary to impaired cardiac output.
- Difficult weaning from cardiopulmonary bypass.
- Higher rates of morbidity and mortality post-surgery.
Managing PH requires precision. Lower PVR too aggressively and systemic hypotension follows; neglect it, and right ventricular collapse looms. The ideal agent must be pulmonary-selective, fast-acting, safe, and practical. This is where sildenafil demonstrates potential superiority.
The Biological Rationale for Sildenafil
The pathophysiology of PH is deeply intertwined with endothelial dysfunction and impaired nitric oxide–cGMP signaling. In health, nitric oxide produced by endothelial cells diffuses into adjacent smooth muscle, activating guanylyl cyclase and increasing cGMP. This cascade results in smooth muscle relaxation, vasodilation, and reduced pulmonary pressures.
In PH, endothelial nitric oxide production is reduced, while PDE5 activity is upregulated, leading to excessive cGMP degradation. The result is sustained vasoconstriction and vascular remodeling. Sildenafil interrupts this vicious cycle by blocking PDE5, thereby preserving cGMP and restoring vasodilation. The pulmonary circulation’s high PDE5 expression makes it particularly responsive to sildenafil, whereas systemic arteries, with lower PDE5 activity, are relatively spared. This selectivity theoretically allows sildenafil to lower pulmonary pressures without precipitating systemic hypotension—a key requirement in fragile surgical patients.
Preclinical studies and trials in chronic pulmonary arterial hypertension had already demonstrated sildenafil’s capacity to reduce pulmonary arterial pressures and improve functional status. However, its intraoperative use in valvular heart surgery remained unexplored until Shim et al. brought it to the operating theater.
Study Design: Sildenafil Meets the Operating Room
The study was a prospective, randomized, double-blind, placebo-controlled trial—a gold standard in clinical research. A total of 53 patients scheduled for valvular heart surgery with confirmed pulmonary hypertension (mean pulmonary arterial pressure >30 mmHg) were recruited. Patients were randomized into two groups:
- Sildenafil group: received 50 mg oral sildenafil approximately 10 minutes before induction of anesthesia.
- Placebo group: received a matched placebo under identical conditions.
Hemodynamic parameters were meticulously monitored at baseline, 30 minutes, and 60 minutes after administration. Measurements included systolic and mean pulmonary arterial pressure (SPAP, MPAP), pulmonary vascular resistance index (PVRI), systemic arterial pressures, systemic vascular resistance index (SVRI), and right ventricular function.
This design addressed the core clinical question: can sildenafil lower pulmonary pressures intraoperatively without destabilizing systemic circulation?
Key Findings: Selective Pulmonary Vasodilation Without Systemic Collapse
The results were both clear and clinically relevant.
At 30 minutes post-administration, the sildenafil group demonstrated:
- Significant reductions in systolic pulmonary arterial pressure (SPAP), mean pulmonary arterial pressure (MPAP), and pulmonary vascular resistance index (PVRI) compared to placebo.
- No significant change in systemic arterial pressure or systemic vascular resistance, highlighting the drug’s pulmonary selectivity.
At 60 minutes, the sildenafil group maintained more stable pulmonary hemodynamics, suggesting not only rapid onset but also sustained action during the early intraoperative period. Importantly, systemic hypotension—a feared complication of vasodilators—was not observed.
In addition, there were indications of improved right ventricular performance, though this was not the primary endpoint. Together, these results established sildenafil as a safe, selective pulmonary vasodilator in the high-stakes setting of cardiac surgery.
Mechanistic Interpretation: Why Does Sildenafil Spare the Systemic Circulation?
The pulmonary selectivity of sildenafil lies in its pharmacology. PDE5 is highly expressed in pulmonary arteries and hypertrophied right ventricles but less so in systemic vascular beds. Thus, inhibiting PDE5 disproportionately enhances pulmonary vasodilation while sparing systemic circulation.
Moreover, the perioperative state favors pulmonary selectivity further. During cardiac surgery, systemic vascular tone is maintained by sympathetic activation and anesthetic agents, which limit excessive systemic vasodilation. Meanwhile, pulmonary arteries—exposed to chronic pressure overload and endothelial dysfunction—remain exquisitely sensitive to PDE5 inhibition.
This selective targeting explains why sildenafil, unlike intravenous prostacyclin or systemic vasodilators, lowers pulmonary pressures without destabilizing the patient. In the controlled environment of anesthesia, this property becomes especially valuable.
Clinical Implications
The implications of these findings are substantial. For anesthesiologists managing patients with PH during cardiac surgery, sildenafil offers:
- A practical oral agent that can be administered preoperatively without specialized equipment.
- Selective pulmonary vasodilation that lowers pulmonary pressures while preserving systemic hemodynamics.
- Potential myocardial protection by reducing RV afterload, thereby safeguarding cardiac output during and after surgery.
Sildenafil thus emerges as an attractive alternative or adjunct to inhaled nitric oxide, particularly in centers where the latter is unavailable or prohibitively expensive. It may also reduce the need for high-dose intravenous vasodilators, minimizing systemic side effects.
Limitations and Caveats
While promising, the study is not without limitations. The sample size was modest, and the follow-up limited to the intraoperative period. Long-term outcomes such as postoperative RV function, incidence of right heart failure, and mortality were not assessed. Additionally, the study focused exclusively on valvular heart surgery, leaving its applicability to coronary bypass or other procedures less certain.
Another limitation lies in the timing and dosing. A single 50 mg oral dose may not reflect optimal pharmacokinetics for all patients. The onset of action, influenced by absorption and metabolism, may vary. Intravenous formulations of sildenafil—available in some regions—might provide more predictable effects but were not evaluated here.
Finally, while no systemic hypotension was observed, the potential for interaction with anesthetics, vasopressors, or cardiopulmonary bypass conditions requires ongoing vigilance.
The Broader Context: Expanding Sildenafil’s Portfolio
Sildenafil’s story illustrates the broader theme of drug repurposing. Initially developed for angina, it found fame in erectile dysfunction and later secured a niche in chronic pulmonary arterial hypertension. Now, with evidence from Shim et al. and others, it may add another chapter: an intraoperative tool for pulmonary hypertension in cardiac surgery.
This evolution reflects both the adaptability of PDE5 inhibition and the creativity of clinicians willing to look beyond labels. In many ways, sildenafil embodies modern pharmacology’s pragmatism—recycling well-characterized molecules to meet new challenges rather than endlessly inventing from scratch.
The broader lesson is that innovation in medicine often comes not from entirely new discoveries but from applying known tools in unfamiliar contexts. Sildenafil’s migration from the bedroom to the operating room is a case in point.
Conclusion
The management of pulmonary hypertension during cardiac surgery is one of the most delicate balancing acts in perioperative medicine. The study by Shim and colleagues demonstrated that a single oral dose of sildenafil citrate can significantly reduce pulmonary arterial pressures and vascular resistance without compromising systemic hemodynamics. This selective pulmonary vasodilation offers a safe, practical, and potentially protective strategy for patients with PH undergoing valvular surgery.
While larger trials are needed to confirm long-term outcomes, the findings mark sildenafil as more than a drug for erectile dysfunction or chronic PH. In the right patient, at the right time, it becomes an intraoperative ally, helping surgeons and anesthesiologists navigate the treacherous waters of pulmonary hypertension during open-heart procedures.
For clinicians, the message is pragmatic: sildenafil is not a magic bullet, but it is a useful addition to the armamentarium. In an era where surgical patients are older, sicker, and more complex, such tools are invaluable.
FAQ
1. Can sildenafil replace inhaled nitric oxide in managing pulmonary hypertension during surgery?
Not entirely. Sildenafil provides selective pulmonary vasodilation but lacks the immediate titratability of inhaled nitric oxide. However, it may serve as an adjunct or alternative in settings where nitric oxide is unavailable or unsuitable.
2. Is there a risk of systemic hypotension when giving sildenafil during surgery?
In this study, systemic pressures remained stable, reflecting sildenafil’s pulmonary selectivity. Nevertheless, anesthesiologists must monitor closely, especially when combining sildenafil with other vasodilators or under cardiopulmonary bypass conditions.
3. Should sildenafil be used routinely in all cardiac surgery patients with pulmonary hypertension?
Not yet. While evidence supports its safety and efficacy intraoperatively, larger trials and longer-term outcomes are needed. For now, it is best reserved for high-risk patients with significant PH undergoing valvular surgery, under expert supervision.
