Introduction

Systemic capillary leak syndrome (SCLS), also known as Clarkson’s disease, is a rare life-threatening disorder of uncertain etiology characterized by increased capillary permeability.1 The etiology of SCLS remains unidentified; however, several days prior to the acute or leak phase, various triggers may manifest, including influenza or common colds, hematologic disorders, medication use, or significant physical exercise in combination with fluid intake deficits.1,2

The natural course of this condition comprises several phases. The first phase consists of a 1–2-day prodrome characterized by the presence of general malaise, myalgias, asthenia, fever, and abdominal pain.1 The second and third phases are known as hemoconcentration phase, with the former being characterized by a rapid and progressive (minutes/hours) deterioration of consciousness, oliguria, hypotension and hypoperfusion, and the latter by the leak phase (hours), with hypoalbuminemia and generalized edema.1 Since these two phases occur within minutes and hours, they are also known as the acute phase. During the acute phase, due to increased vascular permeability, fluids and high molecular weight proteins leak into the interstitial space, causing complications such as ascites, pleural effusions, rhabdomyolysis, shock and multiple organ dysfunction, and even compartment syndrome due to increased edema size.1-3 Moreover, in this phase, given the large loss of intravascular fluid, patients may present distributive shock, which can be life-threatening.3 If the individual survives the acute phase, 24 to 72 hours later, during the post-leak phase, the functionality of the capillary barrier is restored, which allows pulling back fluids into the intravascular space, resulting in osmotic equilibrium.1-3

Although it is a rare condition, SCLS has been reported to have a high mortality rate (14%).2,4,5 It should be noted that it is not possible to accurately estimate its prevalence and incidence due to, among other reasons, the lack of large-scale studies, the fact that many patients are not diagnosed as they do not survive the first episode, and the unavailability of specific diagnostic criteria, which may lead to a misdiagnosis of this syndrome in patients with other disorders such as Gleich’s syndrome.3,4

SCLS usually affects middle-aged adults regardless of sex and race.1,4 The diagnosis is made by exclusion, being sepsis of unknown origin the main differential diagnosis.1,3 While there are still no well-defined diagnostic criteria, the diagnosis is usually based on the presence of the following clinical signs in the absence of any other known cause: recurrent episodes of edema, hypotension, hemoconcentration, and hypoalbuminemia.1 Likewise, the presence of a peak in monoclonal Igγ has been described in several cases, which could indicate its possible etiology, although there is no consensus on this matter.1-3,5

The treatment of SCLS in the acute phase aims at achieving an adequate fluid balance by replacing intravascular volume with colloids and albumin, as well as reducing interstitial volume with diuretics.1,2,4 Once proper vascular patency has been achieved, several treatments have been proposed to prevent new episodes, including the combined use of terbutaline + theophylline or immunosuppressants. Nevertheless, evidence on the efficacy of these treatments is limited due to the small sample size of these studies.1,4

Due to fluid leakage into the intravascular space and fluid accumulation in the interstitial space, patients with this condition may present several complications, with limb compartment syndrome being a rare one.1-4,6-8 Compartment syndrome is characterized by volume overload during the leak phase, producing an increase in tissue pressure that results in muscle ischemia and cell death. It also occurs most frequently in multiple compartments and fasciotomy is the treatment of choice.2,6-8

Since the literature on SCLS is sparse, and even sparser regarding compartment syndrome as a complication,1,3-5 we present below the case of a 34-year-old man who suffered compartment syndrome in different extremities as a complication of SCLS. This has been done in order to increase the body of evidence on this condition, given that, due to its high mortality rate, early detection and timely treatment are paramount.

Case presentation

A 34-year-old man with a history of dextrocardia and exophthalmos presented to the emergency room of a tertiary care center in Segovia, Spain, due to myalgia and paresthesia in the left lower limb during the last 24 hours. Based on the anamnesis, the patient had not overexerted himself or suffered any trauma or experienced any symptoms of a cold in the last few days. In view of the above, analgesic (fentanyl 1.5mg intravenous [ V] [bolus], dexketoprofen 50mg IV, and paracetamol orally [VO] 1g) and pharmacological (methylprednisolone 60mg IV and fluid replacement with 500mL of saline) therapy was started.

Once the administration of these drugs was completed, a new physical examination was performed, showing increased volume in the anterior and lateral compartment of the left leg and reduced hallux extension (Daniels scale score: 2/5). The patient also reported an increase in pain intensity and paresthesia despite analgesic therapy, as well as the onset of the same symptoms in the contralateral lower limb. Laboratory tests performed three hours after admission to the emergency room indicated a high hematocrit count (54.1%) and elevated creatine phosphokinase (CPK, 700 U/L) for no obvious reason.

Considering that the clinical manifestations of the patient suggested compartment syndrome, a fasciotomy of the anterior and lateral compartments of both lower limbs was performed. A decrease in color intensity in the anterior compartment muscles of the left leg and the extensor hallucis longus muscle that did not react to electrical stimuli were observed.

Although pain intensity and paresthesia in both lower limbs gradually decreased over the first hours after the procedure, the patient began to show similar symptomatology in the right upper limb, thus requiring the initiation of fluid resuscitation with physiological saline solution (1000 mL in 24h). Likewise, since the physical examination revealed a slight increase in muscle tone in the hand and forearm without clinical evidence of neurological or distal vascular alteration, watchful waiting was recommended.

Six hours after fasciotomy, the patient presented generalized edema that progressively increased, as well as dizziness, difficulty in communication, general deterioration of health status, oliguria, pallor, and hypotension despite fluid resuscitation. He was then admitted to the intensive care unit (ICU) due to suspicion of distributive shock, requiring invasive mechanical ventilation with orotracheal tube 9 hours after surgery.

During his stay in the ICU, 24 hours after fasciotomy, follow-up laboratory tests showed increased hematocrit count (66.3%), low albumin levels (2.5 g/L), monoclonal peak (23% of gamma globulins in proteinogram), and elevated CPK level (5000 U/L), but normal renal function (glomerular filtration rate >90 mL/min/1.73m²). Consequently, intensive fluid resuscitation was started with up to 4000mL of crystalloids and colloids, continuous infusion of noradrenaline at 0.7 µg/kg/min, and furosemide at 0.5/µg/kg/min. On the same day, blood culture samples were taken and broad-spectrum antibiotic therapy was started with vancomycin (1g/12h) and meropenem (1g/8h) to rule out possible sepsis of unknown origin.

On the second day after fasciotomy, given the clinical manifestations observed in the right upper limb during the first hours after surgery and due to the difficulty in performing a physical examination as a result of intubation, the intracompartmental pressure of that limb was measured, obtaining the following findings: interosseous muscle pressure of the hand: 40 mmHg; posterior forearm compartment pressure: 30 mmHg; anterior forearm compartment pressure: 20 mmHg. Intracompartmental pressure measurements were also taken in the other compartments of the lower limbs and the left upper limb, all of which showed normal values. In view of the suspicion of compartment syndrome in the right upper limb as a new complication of SCLS, fasciotomy of the tenar, hypothenar and interosseous muscles of the hand and the extensor and flexor muscles of the forearm in that limb was performed. All compartments were found to be under tension, but the muscles were reactive to electrical stimuli and had adequate coloration during the intervention (Figure 1).

Figure 1. Right upper limb fasciotomy performed 2 days after the first fasciotomy. A. Anterior aspect. B. Posterior aspect.

Source: Image obtained while treating the patient.

After the second fasciotomy, the patient’s clinical condition began to improve, with reduction of generalized edema and gradual decrease in the dose of noradrenaline until its administration was suspended on the sixth day of hospital stay (i.e., 4 days after the second surgical intervention). Moreover, follow-up laboratory tests performed on the same day showed an improvement in hematocrit (48%) and CPK (1000 U/L) levels.

Considering the improvement of his clinical condition, on day 7 of hospitalization the patient was extubated and the administration of furosemide was suspended. Then, after 11 days, the patient was discharged from the ICU and transferred to the general hospital ward without fluid therapy. There, specialists from the internal medicine service performed a new anamnesis in search of the possible causes of the hypovolemic shock he had experienced. On this matter, the patient reported that in recent years he had suffered episodes of fatigue and low-intensity pain in the lower limbs that had resolved spontaneously after experiencing symptoms of common cold, which had prompted him to go to the emergency room on several occasions, where he was diagnosed with anxiety attacks.

Follow-up laboratory tests were performed daily, showing normalization of CPK (40U/L), hematocrit (45.5%) and albumin (3.5 g/L) levels, as well as the disappearance of the monoclonal peak in the proteinogram after fifteen days of hospitalization. On the other hand, since the blood cultures taken during his stay in the ICU were negative, on the 14th day of hospitalization tests for autoimmune diseases were performed, with negative results for rheumatoid factor, anti-DNA antibodies, antinuclear antibodies (ANA), anti-neutrophil cytoplasmic antibodies (ANCA), and beta-2 glycoprotein 1 antibodies, as well as absence of C1 esterase inhibitor alterations. Similarly, antibody tests for cytomegalovirus and varicella Zoster virus were negative, but positivity against influenza A virus was noted, thus leading to a diagnosis of SCLS following influenza A, once other etiologies were ruled out.

On day 20 of hospitalization, the lower limb fasciotomies were completely closed. With regard to the upper limb fasciotomy, since there was a 5x1cm coverage defect with granulation tissue at the base of the defect, it was decided to close the surgical wound by secondary intention (Figure 2).

Figure 2. Surgical wounds from fasciotomies after 20 days of hospitalization. A. Anterior aspect of the right upper limb. B. Dorsal aspect of the right upper limb. C. External lateral aspect of left lower limb. D. External lateral aspect of right lower limb.

Source: Image obtained while treating the patient.

The patient was finally discharged 22 days after the first fasciotomy with indication for analgesic therapy (paracetamol 1g/8h and dexketoprofen 25mg/8h), follow-up in the wound unit for the care of the wounds closed by secondary intention, and follow-up with the orthopedic and trauma surgery service. At discharge, the patient reported no pain or other symptoms in the lower limbs or right arm, and the only sequelae observed was reduced hallux extension strength in the left lower limb (muscle strength of 2/5 on the Daniels scale).

In a follow-up appointment with the orthopedic and trauma surgery service 6 weeks after the first procedure, an improvement was observed in the extension strength of the left hallux (Daniels scale score: 3/5) and adequate healing and closure of the surgical wounds. After 6 months of follow-up, the extension strength deficit in the left hallux persisted (4/5), but full recovery of muscle strength was observed in the remaining muscle groups of that limb and the other limbs (5/5). At 8 months follow-up, the patient did not present prodromes or symptomatology associated with a new episode of SCLS.

Discussion

Even though compartment syndrome is diagnosed based on clinical manifestations, it is advisable to confirm the diagnosis by measuring intracompartmental pressure (pressure difference greater than >30mmHg compared with diastolic pressure or an isolated intracompartmental pressure >40mm Hg),7-9 especially in cases of decreased level of consciousness (hemoconcentration phase), as occurred in our patient. The standard treatment is fasciotomy, a procedure that improves muscle irrigation, preventing the development of complications such as Volkmann’s ischemic contracture,6-8 hence the importance of performing this procedure urgently.

In our patient’s case, compartment syndrome symptoms were mild during the initial assessment and affected only the left lower limb, but became progressively worse, also affecting the right lower limb. Therefore, a selective fasciotomy was performed, and loss of contractility was observed in the left tibialis anterior. Notwithstanding the above and although the intensity of the symptoms decreased in the lower limbs, the patient began to experience pain and paresthesia in the right upper limb during the first hours after surgery, with subsequent worsening of his clinical condition and the need for admission to the ICU and invasive mechanical ventilation. As a result, intracompartmental measurements were taken, identifying increased compartment pressures in the right forearm and hand that required a right upper limb fasciotomy and constant monitoring of the compartments of the other limbs through periodic compartment pressure measurements to rule out new episodes of this complication of SCLS.

The literature has described only 15 cases of patients who, like our patient, presented concomitant compartment syndromes in various limbs, with greater involvement of the lower limbs (Table 1). Since 2000, the number of cases has increased, probably due to a growing awareness of SCLS.

Table 1. Cases reported in the literature of patients with concomitant compartment syndromes in various limbs.

Author and year	Compartment syndrome localization	Place and time of diagnosis	Treatment	Sequelae	Associated complications
Balcarek et al., 20052	1st case: both legs (first procedure): left forearm (second procedure)	Inpatient ward - after fluid therapy	Fasciotomy	Partial loss of function of the extensor muscles of both legs.	Multiple surgical debridements
	2nd case: both forearms and thighs	ICU - after fluid therapy		Bilateral median and ulnar nerve neuropathy
Milner et al., 20067	Both legs and forearms	ICU - after fluid therapy	Fasciotomy	Skin defect and partial loss of extensor muscle function in the left forearm and muscle function in all compartments of the left leg, except for the anterolateral compartment	Kidney failure Multiple surgical debridements
Sanghavi et al., 200610	Both legs	ICU - after fluid therapy	Fasciotomy	No	Kidney failure requiring dialysis Multiple surgical debridements
Matusumura et al., 200711	Pretibial compartment on both legs	ICU - after fluid therapy	Fasciotomy	Bilateral dorsiflexion limitation	No
Perry et al., 20099	Both legs and right thigh	ICU - after fluid therapy	Fasciotomy	N/A	Death
Simon et al., 20108	Both legs, thighs, forearms, and arms	ICU - after fluid therapy	Fasciotomy	Skin defect and residual deficits of the median and ulnar nerves of the left forearm	Kidney failure requiring dialysis
Saugel et al., 201012	Both legs and thighs	Emergency room	Fasciotomy	No	Pleural effusion
Brown et al., 201113	Both legs, thighs, and forearms	ICU - after fluid therapy	Fasciotomy	No	No
Miyata et al., 201314	Both legs	ICU - after fluid therapy	Fasciotomy	No	Stroke with right hemiparesis
Lamou et al., 201415	Both legs, thighs, forearms, and arms	ICU - after fluid therapy	Fasciotomy	Weakness in dorsal flexion in both feet	Compartment syndrome in abdominal compartment Acute renal failure requiring dialysis
Iwasa et al., 201416	Both legs	ICU - after fluid therapy	Fasciotomy	Mild motor and sensory disturbance in both lower limbs	Acute renal failure requiring dialysis Ascites
Case et al., 202017	Both legs and arms	ICU - after fluid therapy	Fasciotomy	No	Anasarca
Kasugai et al., 20206	1st stage: Pretibial compartment in both legs 2nd stage: both forearms	ICU - after fluid therapy	Fasciotomy	Bilateral common peroneal nerve palsy and Volkmann’s contracture.	Disseminated intravascular coagulation Acute kidney failure requiring dialysis
Davies et al., 202118	Both legs and right forearm	After surgery	Fasciotomy	No	Cardiogenic shock
García et al., 2024 (this report )	1st stage: both legs 2nd stage: right hand and forearm	1st stage: Emergency room 2nd stage: ICU - after fluid therapy	Fasciotomy	Decreased left hallux extensus strength Skin defect on right forearm	No

Source: Own elaboration.

In all cases (Table 2), patients required fasciotomies and most were diagnosed with SCLS in the ICU after intensive intravascular fluid resuscitation,2,6-11,13-17 meaning that the presence of compartment syndrome was confirmed by measuring intracompartmental pressures, similar to what occurred in our patient in the right upper limb. For this reason, it is important to suspect this complication in patients with SCLS and decreased level of consciousness and to take intracompartmental pressure measurements to confirm the diagnosis and perform fasciotomy in a timely manner.

As for the sequelae, in six of the cases found in the literature, weakness in the lower limbs was observed,2,6,7,8,12,18 probably due to prolonged bed rest and subsequent muscle loss. Sequelae such as reduced hallux extension strength or dorsal flexion have also been described in lower limbs.2,6,7,8,12,18 In this regard, our patient presented decreased strength in left hallux extensus. Other complications include the need for debridement after fasciotomies or the development of skin defects after surgical wound closure.7,8

It is worth mentioning that in all the patients described in the literature, including ours, a partial improvement of the sequelae was achieved with rehabilitation treatment. Another notable point is that our patient, unlike the other cases published in the literature, did not present any medical complications such as anasarca or kidney failure, despite the fact that there were no epidemiological differences with these patients.2,6-11,13-17 Finally, although it has been described that SCLS has a high mortality rate,2,4,5 only 1 of these 16 patients died (multiple organ dysfunction syndrome),9 so it could be assumed that mortality is low in this subgroup.

Conclusion

SCLS is a rare disease that requires a high diagnostic suspicion and a joint and comprehensive assessment by intensivists and traumatologists to prevent complications such as compartment syndrome, which, although rare, implies a high comorbidity.

Since most of these patients have a decreased level of consciousness and intensive fluid therapy is a predisposing factor for compartment syndrome, we recommend constantly monitoring the intracompartmental pressure of the compartments most frequently affected by this syndrome (e.g., thighs, forearms, and pretibial compartment) to achieve a rapid diagnosis and initiate treatment in a timely manner, thus reducing the risk of possible sequelae. However, further studies are needed to evaluate the effectiveness of monitoring in larger samples, as the scarce evidence in this regard comes only from case reports.

Informed consent

The patient’s informed consent was obtained for the preparation of this case report, authorizing the use of his clinical data for academic purposes.

Conflicts of interest

None stated by the authors.

Funding

None stated by the authors.

Acknowledgments

None stated by the authors.

References

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